The ovarian cycle emerges from the interaction between biological oscillators operating on distinct timescales. A slow, infradian timer within the hypothalamic-pituitary-gonadal (HPG) axis integrates hormonal signals, notably estrogen (E2), and maintains a cycle of 28–29 days in humans and 4 days in rodents, while a system of circadian clocks in the hypothalamus and ovaries regulates the pulsatile release of gonadotropins on a much shorter timescale [4]. Both systems rely on feedback mechanisms, and despite cycle-to-cycle variability, the ovarian cycle functions as a long-term, highly precise clock [5]. These clocks of differing timescales interact in as-yet incompletely understood ways to maintain robust but adaptable physiological regulation over environmental and hormonal fluctuations.

The circadian circuit that mediates adaptation to jet lag also encodes seasonal photoperiod information [6]. Both menstrual and estrous cycles tend to lengthen under short photoperiods and shorten under long photoperiods. This implies that the hypothalamic circuitry regulating the ovarian cycle is intricately linked to the circadian clock. The suprachiasmatic nucleus (SCN), the central circadian pacemaker, contains arginine vasopressin (AVP)- and vasoactive intestinal polypeptide (VIP)-expressing neurons that serve distinct but complementary roles [7]. AVP neurons project to the anteroventral periventricular nucleus (AVPV), a key regulator of reproductive function and a site of kisspeptin-1 expression [8]. VIP neurons, by contrast, project to gonadotropin-releasing hormone (GnRH) neurons and upstream interneurons, and modulate circadian gating of reproductive output. Yet, despite extensive experimental data from anatomical and functional studies, the full logic of how these circadian signals are integrated into coherent reproductive rhythms remains unresolved.

This timing circuit is especially relevant in understanding how mood stabilizers adversely impact reproductive cycles in women. Lithium, widely used to treat mood disorders such as bipolar disorder, illustrates this circadian connection. It robustly lengthens circadian period and modulates molecular rhythms across species [9,10]. The dynamic interplay between circadian oscillators and the hormonal accumulator clock in the HPG axis may underlie the disruptive effects of lithium and other mood stabilizers that also affect circadian rhythms. An integrative understanding of rhythmic interactions within this circuit could lead to individualized treatments that balance mood stabilization with reproductive health.

The ovarian cycle serves as a tractable model to investigate how circadian clocks govern the rhythmic regulation of physiological and affective states. Addressing this intersection will likely require computational and theoretical frameworks that account for multitimescale circuit dynamics. Nevertheless, this integration can offer a promising path toward improving women’s mental and physical well-being through rhythm-informed diagnostics and therapies.