Pre-ovulatory hormone surge and ovulation may be controlled by novel circadian hiearchy.

Studies in rodents have revealed a novel circadian hierarchy critical for the coordination of pre-ovulatory luteinizing hormone (LH) surge and ovulation.

The research in hamsters and mice suggests that the suprachiasmatic nucleus (SCN) has dual roles in the regulation of ovulation, reported Lance Kriegsfeld, PhD, of the University of California Berkeley, and colleagues, published online April 14.

“Based on our findings, we propose that the SCN signals the kisspeptin and systems via direct neuronal projections to positively drive the LH surge,” the researchers wrote. “Concurrently, the SCN directly and perhaps more likely, indirectly, signals the RFamide-related peptide 3 (RFRP-3) system to coordinate the suppression of estradiol negative feedback with this positive drive.”

Circadian clock timing has been shown to be critical in mammalian reproduction, and evidence suggests that this timing is regulated by gonadotropins.

Research has shown that women with irregular work or sleep cycles can have reduced fertility and an increased chance for spontaneous abortions, Kriegsfeld’s group explained.

“The circadian system coordinates the timing of ovulation and sexual behavior to coincide with an individual’s species-specific temporal niche, with the pre-ovulatory LH surge occurring in the early morning in women and diurnal rodents and late afternoon in nocturnal rodents,” the researchers wrote. They added that in species with spontaneous ovulation, the timing of the LH surge is controlled by the master circadian pacemaker in the SCN of the anterior hypothalamus.

Estrogen negative feedback is responsible for restraining the GnRH neuronal system for most of the ovulatory cycle, but immediately before ovulation this feedback is removed to allow stimulation of the pre-ovulatory GnRH/LH surge by the circadian clock in SCN.

Kriegsfeld and colleagues examined the neurochemical pathway by which SCN controls RFRP-3 activity. They also attempted to determine if the RFRP-3 system exhibits time-dependent responsiveness to SCN signaling to time LH surge.

“We found that RFRP-3 cells in female Syrian hamsters (Mesocricetus auratus) receive close appositions from vasopressin (AVP)-ergic and SCN-derived vasoactive intestinal polypeptide (VIP)-ergic terminal fibers,” they wrote. “Central VIP administration markedly suppressed RFRP-3 cellular activity in the evening, but not the morning, relative to saline controls, whereas AVP was without effect at either time point. Double-label in situ hybridization (ISH) for Rfrp-3 and the VIP receptors VPAC₁ and VPAC₂, revealed that the majority of RFRP-3 cells do not co-express either receptor in Syrian hamsters or mice, suggesting that SCN VIP-ergic signaling inhibits RFRP-3 cells indirectly.”

The research showed that both the GnRH and RFRP-3 systems maintain their own circadian time to ensure the precise coordination of the “stimulation and disinhibition of the reproductive axis,” they noted.

“Given that epidemiological and experimental findings indicate a pronounced negative impact of circadian disruption on female reproductive health, systematically uncovering the mechanisms underlying the circadian control of the female reproductive axis has potential clinical implications,” they wrote.