Adolescent Development of Biological Rhythms in Female Rats: Estradiol Dependence and Effects of Combined Contraceptives

Abstract

Adolescence is a period of continuous development, including the maturation of endogenous rhythms across systems and timescales. Although, these dynamic changes are well-recognized, their continuous structure and hormonal dependence have not been systematically characterized. Given the well-established link between core body temperature (CBT) and reproductive hormones in adults, we hypothesized that high-resolution CBT can be applied to passively monitor pubertal development and disruption with high fidelity. To examine this possibility, we used signal processing to investigate the trajectory of CBT rhythms at the within-day (ultradian), daily (circadian), and ovulatory timescales, their dependence on estradiol (E2), and the effects of hormonal contraceptives. Puberty onset was marked by a rise in fecal estradiol (fE2), followed by an elevation in CBT and circadian power. This time period marked the commencement of 4-day rhythmicity in fE2, CBT, and ultradian power marking the onset of the estrous cycle. The rise in circadian amplitude was accelerated by E2 treatment, indicating a role for this hormone in rhythmic development. Contraceptive administration in later adolescence reduced CBT and circadian power and resulted in disruption to 4-day cycles that persisted after discontinuation. Our data reveal with precise temporal resolution how biological rhythms change across adolescence and demonstrate a role for E2 in the emergence and preservation of multiscale rhythmicity. These findings also demonstrate how hormones delivered exogenously in a non-rhythmic pattern can disrupt rhythmic development. These data lay the groundwork for a future in which temperature metrics provide an inexpensive, convenient method for monitoring pubertal maturation and support the development of hormone therapies that better mimic and support human chronobiology.

Sex Differences in Pubertal Circadian and Ultradian Rhythmic Development Under Semi-naturalistic Conditions

“…The present findings reveal that CBT features measured in a semi-naturalistic environment can be used to monitor adolescent development, with features persisting in the presence of additional variability of sex steroid concentrations and environmental factors. Adolescent trends in CBT and CBT rhythmicity observed in the present study were akin to those of females and males examined in the laboratory (Grant et al, 2021; Kittrell and Satinoff, 1986) with notable sex differences. Males and females exhibited differential trends and amplitude in CR and UR power, with the most prominent being the rapid onset of ovulatory CBT rhythms in females following the early pubertal rise in fE2 and vaginal opening.…”

“…CR power increased from pre- to mid-puberty in both sexes, with females exhibiting higher pubertal CBT and lower CR power than males. Despite the observation of higher and more variable fE2 compared with lab-reported values, females retained a statistically significant correlation between fE2 and CR power after pubertal onset (Grant et al, 2021). In contrast to the coordinated patterns in fE2 and CBT in females, coordinated changes in CBT structure and testosterone were not observed in males.…”

“…This environment provides shelters open to natural changes in light, humidity, and temperature while providing a social partner and standard laboratory housing and food. We hypothesized that the FS environment would result in higher and more variable sex steroid concentrations (Woodruff et al, 2010, 2013) and pubertal timing onset compared with previous reports in the laboratory environment (Grant et al, 2021). We also speculated that these changes would be mirrored in temperature CR and UR patterns, and amplitude.…”

“…Biological rhythms in core body temperature (CBT) change markedly across adolescent development in rodents, enabling unobtrusive monitoring of this trajectory in a laboratory setting (Grant et al, 2021;Hagenauer et al, 2011;Zuloaga et al, 2009). Biological rhythms are coupled across physiological systems (Goh et al, 2019;Grant et al, 2018Grant et al, , 2020Mohawk et al, 2012) at multiple timescales, including within-aday (ultradian rhythms [URs]; Bourguignon, 1988), daily (circadian rhythms [CRs]; Garcia et al, 2001;MacKinnon et al, 1978), and multi-day ovulatory cycles in females (ovulatory rhythms [ORs]; Vidal, 2017).…”

“…Rhythmicity serves numerous functions, including coordination of reproductive development (Albertsson-Wikland et al, 1997; Ankarberg and Norjavaara, 1999; Hagenauer et al, 2011; Norjavaara et al, 1996) and synchronization of internal systems to variation in the environment (Daan and Slopsema, 1978; Hoogenboom et al, 1984; Lewis and Curtis, 2016). We recently applied chronic CBT monitoring to examine rhythmic patterns during female adolescent development in rats under controlled laboratory conditions (Grant et al, 2021). Building on previous analyses of locomotor activity (Hagenauer et al, 2011; Joutsiniemi et al, 1991), this strategy revealed predictable features of CBT across female adolescent development that were coordinated with well-established temperature modulating effects of estrogen (Williams et al, 2010) and progesterone (Buxton and Atkinson, 1948).…”