GnRH pulse generator activity in mouse models of polycystic ovary syndrome
One in ten women in their reproductive age suffer from polycystic ovary syndrome (PCOS) that, alongside subfertility and hyperandrogenism, typically presents with increased luteinizing hormone (LH) pulsatility. As such, it is suspected that the arcuate kisspeptin (ARNKISS) neurons that represent the...
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eLife Sciences Publications Ltd
2025-01-01
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| Online Access: | https://elifesciences.org/articles/97179 |
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| author | Ziyue Zhou Su Young Han Maria Pardo-Navarro Ellen G Wall Reena Desai Szilvia Vas David J Handelsman Allan E Herbison |
| author_facet | Ziyue Zhou Su Young Han Maria Pardo-Navarro Ellen G Wall Reena Desai Szilvia Vas David J Handelsman Allan E Herbison |
| author_sort | Ziyue Zhou |
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| description | One in ten women in their reproductive age suffer from polycystic ovary syndrome (PCOS) that, alongside subfertility and hyperandrogenism, typically presents with increased luteinizing hormone (LH) pulsatility. As such, it is suspected that the arcuate kisspeptin (ARNKISS) neurons that represent the GnRH pulse generator are dysfunctional in PCOS. We used here in vivo GCaMP fiber photometry and other approaches to examine the behavior of the GnRH pulse generator in two mouse models of PCOS. We began with the peripubertal androgen (PPA) mouse model of PCOS but found that it had a reduction in the frequency of ARNKISS neuron synchronization events (SEs) that drive LH pulses. Examining the prenatal androgen (PNA) model of PCOS, we observed highly variable patterns of pulse generator activity with no significant differences detected in ARNKISS neuron SEs, pulsatile LH secretion, or serum testosterone, estradiol, and progesterone concentrations. However, a machine learning approach identified that the ARNKISS neurons of acyclic PNA mice continued to exhibit cyclical patterns of activity similar to that of normal mice. The frequency of ARNKISS neuron SEs was significantly increased in algorithm-identified ‘diestrous stage’ PNA mice compared to controls. In addition, ARNKISS neurons exhibited reduced feedback suppression to progesterone in PNA mice and their gonadotrophs were also less sensitive to GnRH. These observations demonstrate the importance of understanding GnRH pulse generator activity in mouse models of PCOS. The existence of cyclical GnRH pulse generator activity in the acyclic PNA mouse indicates the presence of a complex phenotype with deficits at multiple levels of the hypothalamo-pituitary-gonadal axis. |
| format | Article |
| id | doaj-art-9693746c6a624e2790e6bf1fc3e7780f |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj-art-9693746c6a624e2790e6bf1fc3e7780f2025-01-06T16:20:06ZengeLife Sciences Publications LtdeLife2050-084X2025-01-011310.7554/eLife.97179GnRH pulse generator activity in mouse models of polycystic ovary syndromeZiyue Zhou0https://orcid.org/0000-0003-4725-7543Su Young Han1Maria Pardo-Navarro2Ellen G Wall3Reena Desai4Szilvia Vas5David J Handelsman6Allan E Herbison7https://orcid.org/0000-0002-9615-3022Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United KingdomDepartment of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United KingdomDepartment of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United KingdomDepartment of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United KingdomANZAC Research Institute, University of Sydney, Sydney, AustraliaDepartment of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United KingdomANZAC Research Institute, University of Sydney, Sydney, AustraliaDepartment of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United KingdomOne in ten women in their reproductive age suffer from polycystic ovary syndrome (PCOS) that, alongside subfertility and hyperandrogenism, typically presents with increased luteinizing hormone (LH) pulsatility. As such, it is suspected that the arcuate kisspeptin (ARNKISS) neurons that represent the GnRH pulse generator are dysfunctional in PCOS. We used here in vivo GCaMP fiber photometry and other approaches to examine the behavior of the GnRH pulse generator in two mouse models of PCOS. We began with the peripubertal androgen (PPA) mouse model of PCOS but found that it had a reduction in the frequency of ARNKISS neuron synchronization events (SEs) that drive LH pulses. Examining the prenatal androgen (PNA) model of PCOS, we observed highly variable patterns of pulse generator activity with no significant differences detected in ARNKISS neuron SEs, pulsatile LH secretion, or serum testosterone, estradiol, and progesterone concentrations. However, a machine learning approach identified that the ARNKISS neurons of acyclic PNA mice continued to exhibit cyclical patterns of activity similar to that of normal mice. The frequency of ARNKISS neuron SEs was significantly increased in algorithm-identified ‘diestrous stage’ PNA mice compared to controls. In addition, ARNKISS neurons exhibited reduced feedback suppression to progesterone in PNA mice and their gonadotrophs were also less sensitive to GnRH. These observations demonstrate the importance of understanding GnRH pulse generator activity in mouse models of PCOS. The existence of cyclical GnRH pulse generator activity in the acyclic PNA mouse indicates the presence of a complex phenotype with deficits at multiple levels of the hypothalamo-pituitary-gonadal axis.https://elifesciences.org/articles/97179GnRHkisspeptinPCOS |
| spellingShingle | Ziyue Zhou Su Young Han Maria Pardo-Navarro Ellen G Wall Reena Desai Szilvia Vas David J Handelsman Allan E Herbison GnRH pulse generator activity in mouse models of polycystic ovary syndrome eLife GnRH kisspeptin PCOS |
| title | GnRH pulse generator activity in mouse models of polycystic ovary syndrome |
| title_full | GnRH pulse generator activity in mouse models of polycystic ovary syndrome |
| title_fullStr | GnRH pulse generator activity in mouse models of polycystic ovary syndrome |
| title_full_unstemmed | GnRH pulse generator activity in mouse models of polycystic ovary syndrome |
| title_short | GnRH pulse generator activity in mouse models of polycystic ovary syndrome |
| title_sort | gnrh pulse generator activity in mouse models of polycystic ovary syndrome |
| topic | GnRH kisspeptin PCOS |
| url | https://elifesciences.org/articles/97179 |
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