Estradiol Enables Chronic Corticosterone to Inhibit Pulsatile Luteinizing Hormone Secretion and Suppress Kiss1 Neuronal Activation in Female Mice
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INTRODUCTION: Two common responses to stress include elevated circulating glucocorticoids and impaired luteinizing hormone (LH) secretion. We have previously shown that a chronic stress level of corticosterone can impair ovarian cyclicity in intact mice by preventing follicular-phase endocrine events. OBJECTIVE: This study is aimed at investigating if corticosterone can disrupt LH pulses and whether estradiol is necessary for this inhibition. METHODS: Our approach was to measure LH pulses prior to and following the administration of chronic corticosterone or cholesterol in ovariectomized (OVX) mice treated with or without estradiol, as well as assess changes in arcuate kisspeptin (Kiss1) neuronal activation, as determined by co-expression with c-Fos. RESULTS: In OVX mice, a chronic 48 h elevation in corticosterone did not alter the pulsatile pattern of LH. In contrast, corticosterone induced a robust suppression of pulsatile LH secretion in mice treated with estradiol. This suppression represented a decrease in pulse frequency without a change in amplitude. We show that the majority of arcuate Kiss1 neurons contain glucocorticoid receptor, revealing a potential site of corticosterone action. Although arcuate Kiss1 and Tac2 gene expression did not change in response to corticosterone, arcuate Kiss1 neuronal activation was significantly reduced by chronic corticosterone, but only in mice treated with estradiol. CONCLUSIONS: Collectively, these data demonstrate that chronic corticosterone inhibits LH pulse frequency and reduces Kiss1 neuronal activation in female mice, both in an estradiol-dependent manner. Our findings support the possibility that enhanced sensitivity to glucocorticoids, due to ovarian steroid milieu, may contribute to reproductive impairment associated with stress or pathophysiologic conditions of elevated glucocorticoids.
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The model reproduced the effects of ovarian hormone removal (OVX) and restitution (E2) on HPA and HPG axis dynamics, both under physiological conditions and under exogenous CORT excess.
“The model reproduced the effects of ovarian hormone removal (OVX) and restitution (E2) on the HPA and HPG axes dynamics, both under physiological conditions (Seale et al., 2004b) (Figure 3) and under exogenous CORT excess (Kreisman et al., 2019) (Figure 4).”
From Dynamic Hormone Control of Stress and Fertility (2020) · cites this paper as Kreisman et al., 2019
A pellet delivering a high dose of CORT over 48 h in OVX mice has no effect on LH pulsatility, whereas a significant reduction of LH pulse frequency is observed in OVX animals treated with a 17β-estradiol silastic implant (OVX + E2).
“The study showed that a pellet delivering a high dose of CORT over 48 h in OVX mice has no effect on LH pulsatility, whereas a significant reduction of LH pulse frequency is observed in OVX animals treated with a 17β-estradiol silastic implant (OVX + E2).”
From Dynamic Hormone Control of Stress and Fertility (2020) · cites this paper as Kreisman et al., 2019
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Bo, W., Li, Y., Wang, R., Qiao, X., Zhong, Y., Liu, T., Liang, J., Lai, H., & Huang, W. Z. (2026) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2026.101270 · Cited by 1 · see citing works
de Miera, C. S., Feng, J., Elias, C. F., & Qi, N. (2023) · doi:10.3791/65875-v
Chemogenetic Activation of RFRP Neurons Reduces LH Pulse Frequency in Female but not Male Mice
Sawyer, I. L., Evans, M. C., Mamgain, A., Decourt, C., Iremonger, K. J., & Anderson, G. M. (2024) · Journal of the Endocrine Society · doi:10.1210/jendso/bvae159
Sexually dimorphic distribution of Kiss1 neurons in the bed nucleus of the stria terminalis
Zdon, S. T., Silva, M. S. B., & Navarro, V. M. (2025) · Journal of Neuroendocrinology · doi:10.1111/jne.70049
The Hypothalamus-Pituitary in Males in Health and Disease
Winters, S. J. (2025) · Springer eBooks · doi:10.1007/978-3-031-96376-6_7
Intracerebroventricular injection of neuropeptide Y suppresses luteinizing hormone pulses in mice
Young, L. A., Hurtado, E. R., Jacobs, K. D., Lee, Z. M. M., Nestor, C. C., & McCosh, R. B. (2026) · Journal of Neuroendocrinology · doi:10.1111/jne.70265
Wagenmaker, E. R., Gibson, A. G., Johnson, M. S., Choudhry, A. A., Provenzano, N. M., Dong, B., & Moenter, S. M. (2026) · Endocrinology · doi:10.1210/endocr/bqag070
Bloom, J. C., Torres, E., Pereira, S. A., Arvizu-Sanchez, L., Fontes, A. N., Joffe, H., Page, D. C., & Navarro, V. M. (2026) · JCI Insight · doi:10.1172/jci.insight.207270
Analysis of androgen modulation by natural products
Sharma, K., Yakubu, J., & Pandey, A. V. (2026) · Pharmacological Research · doi:10.1016/j.phrs.2026.108377
Reduced Sperm Counts in Mice with Dmd Exon 51 Frameshift Mutations
Ilchuk, L. A., Filatov, M. A., Dolmatova, D. M., Baikova, I. P., Varlamova, E. A., Tvorogova, A. V., Bruter, A. V., & Silaeva, Y. Y. (2026) · Genes · doi:10.3390/genes17101171
- Authors
- Kreisman, M. J., McCosh, R. B., Tian, K., Song, C. I., & Breen, K. M.
- Affiliations
- University of California System (US)
- Corresponding author
- Breen, Kellie M.
- Venue
- Neuroendocrinology
- Publisher
- S. Karger AG
- Published
- 2019-08-29
- Volume
- 110
- Issue
- 6
- Pages
- 501-516
- ISSN
- 0028-3835 (ISSN-L)
- 1423-0194
- PMC
- PMC7048652
- OpenAlex
- W2975821428
- Cited by
- 42
- References
- 53
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 6 · 2023: 6 · 2022: 6 · 2021: 3 · 2020: 9 · 2019: 2
- FWCI
- 4.78
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Neuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD012303, R01HD086100, P50HD028934, F32HD096811, R24HD102061, T32HD007203)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- estradiol, corticosterone, luteinizing hormone secretion, kisspeptin neurons, glucocorticoid receptor, chronic stress, ovarian cyclicity, ovariectomy, female reproduction, glucocorticoid sensitivity, LH pulse frequency
- MeSH terms
- Animals, Corticosterone, Estradiol, Female, Luteinizing Hormone, Mice, Inbred C57BL, Ovariectomy, Mice, Kisspeptins
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