Circadian Control of the Female Reproductive Axis Through Gated Responsiveness of the RFRP-3 System to VIP Signaling
Open accessAbstract
Throughout most of the ovulatory cycle, estrogen negative feedback restrains the GnRH neuronal system. Just before ovulation, however, estrogen negative feedback is removed to permit stimulation of the preovulatory GnRH/LH surge (positive feedback) by the circadian clock in the suprachiasmatic nucleus (SCN). The mammalian ortholog of avian gonadotropin-inhibitory hormone, RFamide-related peptide 3 (RFRP-3), participates in the circadian-timed removal of estrogen negative feedback to permit the LH surge. The present study examined the specific neurochemical means by which the SCN controls RFRP-3 activity and explored whether the RFRP-3 system exhibits time-dependent responsiveness to SCN signaling to precisely time the LH surge. We found that RFRP-3 cells in female Syrian hamsters (Mesocricetus auratus) receive close appositions from SCN-derived vasopressin-ergic and vasoactive intestinal peptide (VIP)-ergic terminal fibers. Central VIP administration markedly suppressed RFRP-3 cellular activity in the evening, but not the morning, relative to saline controls, whereas vasopressin was without effect at either time point. Double-label in situ hybridization for Rfrp-3 and the VIP receptors VPAC1 and VPAC2 revealed that the majority of RFRP-3 cells do not coexpress either receptor in Syrian hamsters or mice, suggesting that SCN VIP-ergic signaling inhibits RFRP-3 cells indirectly. The timing of this VIP-mediated disinhibition is further coordinated via temporally gated responsiveness of RFRP-3 cells to circadian signaling. Together, these findings reveal a novel circadian hierarchy of control coordinating the preovulatory LH surge and ovulation.
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E2, the main estrogen, feeds back to the brain to control pulsatile GnRH release via bimodal actions on hypothalamic circuits.
“Estrogens, primarily E2, feedback to the brain to control the pulsatile release of GnRH into the primary portal plexus through bimodal interactions with the hypothalamic neurocircuitry that modulate GnRH neurons.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [32]
The Abstract (page unavailable) describes estradiol-mediated negative feedback through RFRP-3 neurons and estrogen-responsive kisspeptin circuitry involved in positive feedback and the GnRH/LH surge. The Discussion (page unavailable) likewise describes these circuits in the context of the preovulatory surge. Our copy does not establish that they control pulsatile GnRH release into the primary portal plexus, the specific process claimed. (LLM, conf=0.84)
Experimental — accuracy not yet measuredRising E2 before the GnRH/LH surge activates SCN neurons to speed downstream kisspeptin release and reduce RFRP-3 inhibition of GnRH.
“Elevated E2 levels preceding the surge of GnRH and LH activate SCN neurons to accelerate the downstream release of kisspeptin and simultaneously decrease the inhibition of GnRH secretion provided by RFRP-332,52.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [32]
The Discussion (page not supplied) proposes that the SCN stimulates the kisspeptin system while suppressing RFRP-3-mediated negative feedback at the LH surge. It does not say that rising estradiol activates SCN neurons or that kisspeptin release accelerates; it describes estrogen-responsive cells as integrating estrogenic and SCN-derived cues. (LLM, conf=0.87)
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References 66 · Cited by 70
Research works printed but not linked: 3
- Karsch FJ, Bowen JM, Caraty A, Evans NP, Moenter SM. Gonad- otropin-releasing hormone requirements for ovulation. Biol Re- prod. 1997;56(2):303-309.
- Norman RL, Blake CA, Sawyer CH. Estrogen-dependent 24-hour periodicity in pituitary LH release in the female hamster. Endocri- nology. 1973;93(4):965-970.
- Van der Beek EM, Horvath TL, Wiegant VM, Van den Hurk R, Buijs RM. Evidence for a direct neuronal pathway from the supra- chiasmatic nucleus to the gonadotropin-releasing hormone system: combined tracing and light and electron microscopic immunocyto- chemical studies. J Comp Neurol. 1997;384(4):569 -579.
- Authors
- Russo, K. A., La, J. L., Stephens, S. B. Z., Poling, M. C., Padgaonkar, N. A., Jennings, K. J., Piekarski, D. J., Kauffman, A. S., & Kriegsfeld, L. J.
- Affiliations
- University of California, Berkeley (US)
- University of California San Diego (US)
- Department of Psychology (K.A.R., J.L.L., N.A.P., K.J.J., D.J.P., L.J.K.), University of California, Berkeley, Berkeley, California 94720
- Corresponding author
- Kriegsfeld, Lance J.
- ORCID
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2015-04-14
- Volume
- 156
- Issue
- 7
- Pages
- 2608-2618
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC4475714
- OpenAlex
- W2105250661
- Cited by
- 70
- References
- 66
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 8 · 2021: 13 · 2020: 3 · 2019: 9 · 2018: 10 · 2017: 4 · 2016: 9 · 2015: 3
- FWCI
- 9.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (1257638, 1025893)
- National Institutes of Health
- UC Berkeley College of Chemistry
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD012303, R01HD050470, T32HD007203)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- RFRP-3, vasopressin, vasoactive intestinal peptide, suprachiasmatic nucleus, circadian clock, luteinizing hormone surge, ovulation, estrogen negative feedback, gonadotropin-releasing hormone, gonadotropin-inhibitory hormone, VIP receptors, golden hamster
- MeSH terms
- Animals, Circadian Rhythm, Female, Cricetinae, Luteinizing Hormone, Gonadotropin-Releasing Hormone, Mesocricetus, Neurons, Neuropeptides, Ovulation, Suprachiasmatic Nucleus, Vasoactive Intestinal Peptide, Vasopressins, Signal Transduction, Estrous Cycle, Receptors, Vasoactive Intestinal Polypeptide, Type I, Receptors, Vasoactive Intestinal Peptide, Type II, Circadian Clocks
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