Sage Journals: Discover world-class research

Abstract

Whereas long-period temporal structures in endocrine dynamics have been well studied, endocrine rhythms on the scale of hours are relatively unexplored. The study of these ultradian rhythms (URs) has remained nascent, in part, because a theoretical framework unifying ultradian patterns across systems has not been established. The present overview proposes a conceptual coupled oscillator network model of URs in which oscillating hormonal outputs, or nodes, are connected by edges representing the strength of node-node coupling. We propose that variable-strength coupling exists both within and across classic hormonal axes. Because coupled oscillators synchronize, such a model implies that changes across hormonal systems could be inferred by surveying accessible nodes in the network. This implication would at once simplify the study of URs and open new avenues of exploration into conditions affecting coupling. In support of this proposed framework, we review mammalian evidence for (1) URs of the gut-brain axis and the hypothalamo-pituitary-thyroid, -adrenal, and -gonadal axes, (2) UR coupling within and across these axes; and (3) the relation of these URs to body temperature. URs across these systems exhibit behavior broadly consistent with a coupled oscillator network, maintaining both consistent URs and coupling within and across axes. This model may aid the exploration of mammalian physiology at high temporal resolution and improve the understanding of endocrine system dynamics within individuals.

Keywords

biological rhythms personalized medicine HPA HPG HPT GBA

The “what” of endocrinology, or the study of central and peripheral endocrine factors and their genesis, has a long history of systematic investigation from the organismal to the molecular scales. In contrast, the temporal dynamics of hormonal secretions, or the “when” of endocrinology, is not defined with comparable precision. Endocrine activity varies across infradian (>1 day), circadian (~1 day), and ultradian (<1 day) timescales, with the majority of scientific investigation focused on understanding the longer 2 periodicities. Examination of infradian and circadian endocrine rhythms has advanced our understanding of basic physiology by providing temporal structures that explain substantial variance of measured outputs within and among individuals. This knowledge has facilitated translational breakthroughs, exemplified by personalized chronotherapy, for example, in which the timing of pharmaceutical administration is aligned to the patient’s circadian peak of receptivity to treatment (Giacchetti et al., 2006; Lévi et al., 2010). Whereas ultradian variation also provides clinically relevant information (Hompes et al., 1992; Sturis et al., 1992) and has long been suggested to be central to mammalian physiology (Brandenberger et al., 1987; Lloyd, 1992; Miyata et al., 2016; Veldhuis et al., 2008), there is no single accepted systems-level framework to unify the study of ultradian rhythms (URs) at the organismal level (Bashan et al., 2012; Bourguignon and Storch, 2017; Prendergast and Zucker, 2016). Because of the absence of a unifying framework, as well as the technical challenges of measuring endocrine systems at ultradian timescales, circadian studies outnumber ultradian studies nearly 32:1 (Landgraf et al., 2014; Prendergast and Zucker, 2016). In the present overview, we propose a framework to aid future investigation of URs within individuals based on the notion that crosstalk among hormonal systems is predictably organized. Through researchers working across disciplines to further understand this level of organization, such knowledge of URs can help guide research, predictive medicine, and clinical interventions in much the same way as has knowledge of circadian rhythms.

Overview and Implications of a Coupled Oscillator Network Model of URs

Circadian rhythms exhibit coupled oscillator behavior (Feillet et al., 2014; Hannay et al., 2015; Stoleru et al., 2004), driving independent oscillators to a stable phase relationship (Komarov and Pikovsky, 2015). We propose that this principle likely applies to URs across endocrine axes. Two criteria must be met for a coupled oscillator, ultradian, endocrine network to exist: 1) in unmanipulated organisms, URs appear across endocrine systems, and 2) URs exhibit the physiological substrate for, or direct evidence of, coupling. The present overview outlines evidence for both of these requirements with examples from canonical endocrine axes: the gut-brain axis (GBA) and the hypothalamic-pituitary-thyroid (HPT), -adrenal (HPA), and -gonadal (HPG) axes (Fig. 1). These systems regulate a range of core processes, including energy acquisition (GBA), allocation (HPT), production and maintenance of gametes (HPG), and arousal (HPA), providing important functional significance for networked URs. We first provide evidence that nodes within these axes exhibit ultradian oscillations by reviewing findings that illustrate the presence of the most common periodicities of UR (i.e., 1-4 h). We then review evidence for coupling across endocrine axes through neural and hormonal signaling (Laferrère et al., 2006). A comprehensive summary of ultradian oscillations in these axes is available in Table 1. Furthermore, we present evidence that body temperature shapes, and is shaped by, URs across endocrine axes, providing a highly tractable measure of inter-UR coupling (i.e., a tightly coupled network manifests as high-amplitude body temperature URs). Finally, we conclude with a consideration of translational implications for personalized, predictive medicine.

Figure 1.

Canonical axes in mammalian physiology exhibit 1- to 4-h ultradian rhythms. The hypothalamus and pituitary (HP) coordinate feedback loops across physiological systems. The gut-brain axis influences feeding and digestion, the HP-thyroid axis influences metabolism, the HP-adrenal axis regulates the arousal and stress responses, and the HP-gonadal axis regulates reproductive function. The 1- to 4-h ultradian rhythms occur in outputs of each of these axes, are coupled within and among axes, and modulate body temperature output.

Table 1.

Characteristics of endocrine ultradian rhythms.

Axis	Output(s)	UR Period (h)	Temporal Relationship	Species	Sample Frequency (min)	Sample Duration (h)	Sex	Age (years)	Ovulatory Cycle Phase	Source(s)
GBA	Feeding	2-4.1	NA	Human, nonhuman primates, mouse	Continuous	24-168	F, M	Juvenile or adult	NA	Matsuda et al., 2014; Miyata et al., 2016; Reid et al., 2014; Tolle et al., 2002
GBA	GHRH, SS, GH	1, 5	GHRH and SS (1 h), GH (1 h and 5 h) is in antiphase with SS	Goat	15	8	M	2-3	NA	Mogi et al., 2004
GBA	GHRH, SS, GH	3	GHRH and SS (1 h) simulated antiphase, GH is in phase with GHRH	Rat	15	6	M	Adult	NA	Tannenbaum and Ling, 1984; Wagner et al., 1998, 2009
GBA	GH	2-3.5, 5	Within-individual harmonics	Human, rabbit, rat, goat	5-20	6-24	M	7-14, Adult or NA	NA	Goji, 1993; Kimura and Tsai, 1984; Minamitani et al., 1989; Mitsugi and Kimura, 1986; Tannenbaum and Ling, 1984; Tannenbaum and Martin, 1976; Yonezawa et al., 2010
GBA	Glucose, insulin	1.5-3	Synchronous, decouple with age	Human, dairy cow	2-20	8-53	F, M	NA or 21-70	NA	Brandenberger et al., 1987; Lefcourt et al., 1999; Polonsky et al., 1988; Schaefer et al., 2003; Scheen et al., 1996; Shapiro et al., 1988; Simon and Brandenberger, 2002; Simon et al., 1987; Sturis et al., 1992
GBA	Ghrelin	2-4.8	NA	Human, rat	10-20	8-24	F, M	NA or 28-36	NA	Bagnasco et al., 2002a; Mingrone et al., 2006; Tolle et al., 2002
GBA	Leptin	1, 3-6, 12	Harmonic	Human, rat	7-15	12-24	F, M	Adult or 18-55	Diestrus, luteal	Bagnasco et al., 2002a; Licinio et al., 1997, 1998a, 1998b; Saad et al., 1998; Simon et al., 1998; Sinha et al., 1996
GBA	Ghrelin, leptin	4	65% synchronous	Rat	5	3	F	Adult	Diestrus	Bagnasco et al., 2002a
GBA	Gut activity	1.5-2	NA	Human, mouse, dog	NA or 10	6-12	F, M	Adult	NA	Code and Marlett, 1975; Deloose et al., 2015; Hoogerwerf et al., 2010; Husebye et al., 1990
GBA, HPA	Leptin, ACTH, CORT	0.75	Leptin is antiphase to ACTH and CORT	Human	NA	NA	NA	NA	NA	Licinio et al., 1997
GBA, HPA	Glucose, insulin, CORT	3, 1.5	Many glucose/insulin peaks (1.5 h) are synchronous with CORT (3 h)	Human	15	24	F, M	21-33	NA	Shapiro et al., 1988
HPA	CRH	1.5	NA	Macaque hypothalamus	10	20	M	15	NA	Mershon et al., 1992
HPA	ACTH, CORT	1.4	Synchronous	Human	NA	NA	NA	21-26	NA	Brandenberger et al., 1987
HPA	CORT	1, 5-8	Harmonics are occasionally reported	Human, rat	10-30	8-24	F, M	Adult	NA	Jasper and Engeland, 1991; Smarr et al., 2016a; Waite et al., 2012
HPG	GnRH	4	NA	Human, nonhuman primate, rat, ewe	10	13-48	F	Adult	Luteal	Clarke et al., 1987; Moenter et al., 1991
HPG	GnRH	1	NA	Human, mare, rat	5-10	4-48	F, M	Adult	Follicular, periovulatory, NA	Alexander and Irvine, 1987; Clarke et al., 1987; Moenter et al., 1991; Phelps et al., 1992
HPG	GnRH, LH, FSH	2-4	90% synchronous	Ram, mare	10	8	F, M	NA	Periovulatory	Alexander and Irvine, 1987; Caraty and Locatelli, 1988
HPG	LH	4.0 STD 2.0	Large intraindividual variation	Human, rhesus monkey	10-20	12-24	F	Adult or 22-42	Mid-luteal	Backstrom et al., 1982; Filicori et al., 1984; Genazzani et al., 1991; Jain et al., 2001; Nakajima et al., 1990; Nóbrega et al., 2009; Soules et al., 1988; Veldhuis et al., 1988; Vugt et al., 1984
HPG	LH	1-1.5	NA	Human, heifer, rat, mouse, ewe	10-20	8-24	F, M	Adult or 18-42	Follicular, periovulatory, or NA	Backstrom et al., 1982; Bray et al., 1991; Ginther et al., 1998; van Leckwyck et al., 2016; Matsumoto and Bremner, 1984; Pincus et al., 1998; Rossmanith and Yen, 1987; Soules et al., 1988; Steiner et al., 1982; Vugt et al., 1984; Wu et al., 1996; Yen et al., 1972
HPG	FSH	1.5-3	Low/undetectable amplitude, shorter period in follicular phase	Human	10-17	7-24	F	18-38	All	Backstrom et al., 1982; Filicori et al., 1984; Venturoli et al., 1988
HPG	PRL	1-2.5, 4	4 h during luteal phase	Human, cow	10-20	12-24	F, M	NA or 21-40	All	Backstrom et al., 1982; Lefcourt et al., 1994; Veldhuis and Johnson, 1988
HPG	Inhibin	1.5	NA	Human	20	24	F	23-33	Mid-luteal	Nakajima et al., 1990
HPG	Estradiol	2, 3	Longer period during luteal phase	Human	10-15	6-24	F	18-38 or NA	All	Backstrom et al., 1982; Rossmanith et al., 1990b; Venturoli et al., 1988
HPG	Progesterone	1-4	High interindividual variability, synchronous with LH in Soules et al., 1989	Human	10-20	6-24	F	NA	Mid-luteal	Backstrom et al., 1982; Genazzani et al., 1991; Rossmanith et al., 1990a; Soules et al., 1989; Veldhuis and Johnson, 1988
HPG	Testosterone	1	Often synchronous with estrogen pulses	Human	10-15	4-8	M	20-40	NA	Beaven et al., 2010; Nóbrega et al., 2009; Sisk and Desjardins, 1986; Winters and Troen, 1986
HPG	LH, FSH, testosterone	1-2.5	Synchronous LH and FSH, testosterone lags 10-40 min	Human, ferret	5-20	4-24	F, M	Adult	All or menopausal	Genazzani et al., 1993; Pincus et al., 1998; Sisk and Desjardins, 1986; Veldhuis et al., 1991
HPG	LH, FSH, PRL, estradiol, estrone	1 (LH), 1.3-2 (other)	Nearly synchronous	Human	10	8-24	F	18-30	Luteal	Alexander and Irvine, 1987; Venturoli et al., 1988
HPT	TRH	4	NA	Rat	NA	24	NA	NA	NA	Okauchi et al., 1996
HPT	TSH	1-2.5	Amplitude but not period is associated with aging, feeding state, disease state	Human	10-15	24	F, M	20-83	Follicular or NA	Adriaanse et al., 1993; Greenspan et al., 1991; Roelfsema et al., 2014; Romijn et al., 1990; Samuels et al., 1993
HPT	T3, T4, CBT	1.5	T4 precedes CBT by 2-3 h	Dairy cow	15	48	F	Adult	NA	Bitman et al., 1994
CBT	CBT	1-4	NA	Human, rat, mouse	1	24->336	F, M	Adult	NA	Ruis et al., 1987; Smarr et al., 2016a, 2016b, 2017
CBT, GBA	CBT, leptin, glucose, insulin	1, 5	Half of leptin pulses are preceded by insulin by ~30 min; CBT is in phase with leptin	Human	10	24	M	21-25	NA	Simon et al., 1998

GBA = gut-brain axis; NA = not applicable; F = female; M = male; GHRH = growth hormone–releasing hormone; SS = somatostatin; GH = growth hormone; ACTH = adrenocorticotropic hormone; CORT = glucocorticoid; HPA = hypothalamic-adrenal axis; GnRH = gonadotropin-releasing hormone; HPG = hypothalamic-gonadal axis; LH = luteinizing hormone; FSH = follicle-stimulating hormone; STD = standard deviation; PRL = prolactin; HPT = hypothalamic-pituitary-thyroid axis; TRH = thyrotropin-releasing hormone; CBT = core body temperature.

URs and Coupling Within Endocrine Axes

URs and Coupling within the GBA

In the present overview, the GBA is defined as neural and hormonal signaling among the brain, gastrointestinal tract, and supporting organs that mediate functions from food-seeking behavior to digestion and elimination (Collins and Bercik, 2009; Pigrau et al., 2016). Hunger, food consumption, satiety, and digestion display URs in mammals (Matsuda et al., 2014; Miyata et al., 2016; Reid et al., 2014), with most hormones involved exhibiting coupled URs with periods (τ) ranging from 1 to 4 h. Two hormones, the orexigenic and anorexigenic peptides ghrelin and leptin (Avau et al., 2013; García-García et al., 2014; Miyata et al., 2016), respectively, provide a temporal link among hormonal and organ URs in the GBA. Ghrelin (García-García et al., 2014; Mingrone et al., 2006) and leptin (Licinio et al., 1998b, 1998a; Saad et al., 1998; Simon et al., 1998; Sinha et al., 1996) exhibit URs, most often with τ = 1 to 5 h in humans and rodents; in rodents, pulses of these hormones often occur within minutes of one another (Bagnasco et al., 2002a; Kalra et al., 2003; Otukonyong et al., 2005). In addition, ghrelin URs couple to 1- to 5-h URs in the growth hormone axis (Goji, 1993; Minamitani et al., 1989; Mitsugi and Kimura, 1986; Mogi et al., 2004; Tannenbaum et al., 2003; Tannenbaum and Ling, 1984; Tolle et al., 2002; Wagner et al., 2009, 1998; Yonezawa et al., 2010), ghrelin and leptin to ~3-h URs in glucose and insulin in the fed state (Brandenberger et al., 1987; Lefcourt et al., 1999; Otukonyong et al., 2005; Poher et al., 2018; Polonsky et al., 1988; Sinha et al., 1996; Thaela et al., 1998; Tolle et al., 2002). In addition, 2- to 8-h URs in intestinal activity (Ariga et al., 2007; Code and Marlett, 1975; Deloose et al., 2012, 2015; Fujino et al., 2003; Hoogerwerf, 2010; Husebye et al., 1990; Masuda et al., 2000; Zheng et al., 2009) can be initiated by administration of ghrelin or the related peptide motilin. In rats, plasma ghrelin and leptin and, in humans, glucose and insulin URs occur both in fed and fasted conditions (Bagnasco et al., 2002b; Schaefer et al., 2003; Scheen et al., 1996; Shapiro et al., 1988; Simon et al., 1987; Simon et al., 1998; Simon and Brandenberger, 2002; Sturis et al., 1992), suggesting that these rhythms are not only food entrained but also endogenously maintained.

Although interindividual variability makes clear that multiple stable states of varying periodicity exist, the periodicities and phase alignments of GBA components provide compelling evidence for a temporally organized GBA network structure on an ultradian timescale. Considering results across studies in humans and rats, ghrelin, leptin, and growth hormone oscillate approximately in phase with the most common τ = ~1 and 3 h (Bagnasco et al., 2002b; Goji, 1993; Kimura and Tsai, 1984; Licinio et al., 1998a, 1998b; Mingrone et al., 2006; Sinha et al., 1996; Tannenbaum and Martin, 1976; Tolle et al., 2002). Approximately antiphase to these 3 hormones (Licinio et al., 1997; Shapiro et al., 1988), glucose and insulin oscillate in near synchrony with τ = 1.5 to 3 h (Polonsky et al., 1988a; Scheen et al., 1996; Simon et al., 1987). At the harmonic circhoral (rhythms of ~1 h), hypothalamic growth hormone–releasing hormone (GHRH) oscillates in phase with ghrelin/leptin and growth hormone (Mogi et al., 2004; Tannenbaum and Ling, 1984).

URs and Coupling within the HPT Axis

The HPT axis is responsible for regulating metabolism. Hypothalamic release of thyrotropin-releasing hormone (TRH) into the hypophyseal portal system stimulates production and release of thyroid-stimulating hormone (TSH) from the pituitary. TSH stimulates production of thyroid hormones from the thyroid gland. Thyroid hormones are initially produced as thyroglobulin, which is converted primarily to thyroxine (T₄). T₄ is considered inactive and is the most abundant thyroid hormone in circulation. T₄ can be converted into the active thyroid hormone, triiodothyronine (T₃). T₃ is present in relatively low quantities in circulation.

Although data about HPT axis function at high temporal resolution in unmanipulated animals are limited, elements of the HPT axis show URs with τ = 1 to 5 h (Buff et al., 2007; Roelfsema et al., 2014; Romijn et al., 1990). To our knowledge, the only high temporal resolution TRH study reports ultradian release with τ = 3 to 5 h in male rats (Okauchi et al., 1996). TSH, however, consistently oscillates in circulation with τ = 1 to 4 h in mammals (Adriaanse et al., 1993; Buff et al., 2007; Cauter, 2004; Greenspan et al., 1986, 1991; Guyot et al., 2007; Jansen et al., 2015; Joustra et al., 2016; Keenan et al., 2003; MacCagnan et al., 1999; Roelfsema et al., 2014; Romijn et al., 1990; Rookh et al., 1979; Samuels et al., 1993; Stewart et al., 1994; Veldhuis et al., 1990). Some studies in dairy cows and humans also show ultradian T₃/T₄ release with ~1.5-h URs (Bitman et al., 1994; Russell et al., 2008). Given strong associations between plasma concentrations of TSH and T₃ in humans (Jansen et al., 2015; Russell et al., 2008), it is possible that TSH oscillates with double the period of T₃/T₄, therefore using a harmonic to retain a stable phase relationship over many cycles.

URs and Coupling within the HPA Axis

The HPA axis regulates arousal under normal conditions and promotes rapid availability of stored energy in response to acute challenges (e.g., predation or fasting). Hypothalamic release of corticotropin-releasing hormone (CRH) stimulates release of adrenocorticotropic hormone (ACTH). In systemic circulation, ACTH acts on the adrenal cortex to stimulate glucocorticoid (CORT) release. CORT acts broadly within the body and generates negative feedback at both the hypothalamus and the pituitary to inhibit its own production. The 1.5- to 3-h URs in CRH neuron excitation and CRH release have been observed in rodents, rams, and macaque hypothalamus but not extensively characterized (Caraty et al., 1988; Ixart et al., 1991; Mershon et al., 1992; Ono et al., 2015; Vrang et al., 1995). As one would expect, ACTH and CORT release show URs and are highly synchronized (τ = ~2-3 h; Brandenberger et al., 1987; Dallman et al., 1987; Henley et al., 2009; Jasper and Engeland, 1991; Lightman and Conway-Campbell, 2010; Smarr et al., 2016a; Spencer and Deak, 2017; Spiga et al., 2011, 2014; Waite et al., 2012). Stable CORT URs likely impose periodic inhibition on CRH neurons through negative feedback regulation, perpetuating ultradian output within the axis (Watts, 2005).

URs and Coupling within the HPG Axis

The HPG axis controls reproduction, including the generation and maintenance of gametes and the appropriate expression of sexual behavior. Release of hypothalamic gonadotropin-releasing hormone (GnRH) triggers the release of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH then stimulate sex steroid (i.e., estradiol, progesterone, and testosterone) synthesis in the gonads. These sex steroids feed back onto the HPG axis to regulate GnRH and the gonadotropins. As with other axes described, HPG axis URs appear to be coordinated with predictable changes in UR features across the axis based on the time of the ovulatory cycle in females.

GnRH release (Caraty and Locatelli, 1988; Clarke et al., 1987; Gore et al., 2004; Grattan et al., 1995; Levine and Ramirez, 1982; Meredith and Levine, 1992; Moenter et al., 1991; Phelps et al., 1992; Ramirez et al., 1991) and LH (Alexander and Irvine, 1987; Ar, 1985; Backstrom et al., 1982; Ben Jebara et al., 1994; Caraty and Locatelli, 1988; Czieselsky et al., 2016; Ellis and Desjardins, 1984; Evans et al., 1979; Ginther et al., 1998; Hodges, 1978; Irvine and Alexander, 1994; Jain et al., 2007; Joustra et al., 2016; Levine and Ramirez, 1982; Luboshitzky et al., 1996; Matsumoto and Bremner, 1984; Mulligan et al., 1995; Nordéus et al., 2012; Rossmanith et al., 1990b; Sisk and Desjardins, 1986; Soules et al., 1988, 1989; Steiner et al., 1982; Urban et al., 1988; van Leckwyck et al., 2016; Veldhuis et al., 1988; Vugt et al., 1984; Wu et al., 1996) oscillates with τ = ~ 1 to 4 h in both sexes, and these pulses are consistently coupled, within minutes within individuals (Alexander and Irvine, 1987; Bergendahl et al., 1996; Caraty et al., 1992; Caraty and Locatelli, 1988; Chandolia et al., 1997; Gazal et al., 1998; Irvine and Alexander, 1994; Levine and Ramirez, 1982). FSH exhibits low-amplitude URs that are often concomitant with LH (Booth et al., 1996; Genazzani et al., 1993; Joustra et al., 2016; Lockwood et al., 1998; Matsumoto and Bremner, 1984; Pincus et al., 1998; Stewart et al., 1994; Urban et al., 1988; Veldhuis et al., 1991; Yen et al., 1972), although pulsatile FSH is not always detectable in general circulation (Filicori et al., 1984; Ginther et al., 1998; McNeilly et al., 2003; Spratt et al., 1988; Yen et al., 1972). Gonadotropins are also coupled to gonadal hormone production on ultradian frequencies; LH peaks usually precede peaks in testosterone and progesterone by 10 to 40 min (Backstrom et al., 1982; Beaven et al., 2010; Bray et al., 1991; Filicori et al., 1984; Genazzani et al., 1991; Ginther et al., 1998; Lewis et al., 1995; Nakajima et al., 1990; Nóbrega et al., 2009; Rossmanith et al., 1990a; Sisk and Desjardins, 1986; Soules et al., 1989; Spratt et al., 1988; Urban et al., 1988; Veldhuis et al., 1988; Winters and Troen, 1986), and estrogen pulses occur either concomitant with or just after testosterone or progesterone in men (Winters and Troen, 1986) and women (Backstrom et al., 1982; Licinio et al., 1998a; Venturoli et al., 1988), respectively. Finally, inhibin (a hormone produced by the gonads that inhibits FSH) also shows weak URs at approximately circhoral frequencies (τ = 1-1.7 h) in antiphase with the gonadotropins (Lockwood et al., 1998; Nakajima et al., 1990).

The ovulatory cycle has well-documented effects on the period and coupling strength of HPG axis URs. Coupling among the release of reproductive hormones (e.g., GnRH, LH/FSH, and progesterone) is more consistent during the follicular phase than the luteal phase (Booth et al., 1996; Clarke et al., 1987; Genazzani et al., 1991, 1993). The period of GnRH and LH pulses decreases across the follicular phase, reaching a minimum before ovulation (Ginther et al., 1998; Moenter et al., 1991; Rossmanith et al., 1990a; Stewart et al., 1994), and most mammals exhibit the longest GnRH, LH, progesterone, and estradiol UR periods during the luteal phase (Ar, 1985; Backstrom et al., 1982; Czieselsky et al., 2016; Filicori et al., 1984; Genazzani et al., 1991; Ginther et al., 1998; Gore et al., 2004; Healy et al., 1984; Licinio et al., 1998a; Moenter et al., 1991; Nakajima et al., 1990; Prendiville et al., 1996; Rossmanith et al., 1990b, 1990a; Soules et al., 1989; Tani et al., 1999; Venturoli et al., 1988; Vugt et al., 1984). The reason for these changes in UR periodicity and coupling across the ovulatory cycle are not well understood. However, the presence of these patterns across ovulatory cycles of different species, which differ in duration, argue for a shared role for URs in ovulatory cycle regulation.

URs and Coupling Across Endocrine Axes

The presence of URs coupled within single axes is not sufficient evidence for a body-wide UR network. Coupling must also occur across axes such that all URs in the hypothetical network are directly or indirectly linked. Such an arrangement would allow for sampling from one node to inform rhythmic patterns at other nodes. We propose that the GBA and HPT axes, in their regulation of energy acquisition and allocation, are functionally and dynamically tied to the HPA and HPG axes to appropriately allocate the use of available energy (Tena-Sempere, 2013). This proposition is based on findings pointing to cross-axis ultradian coupling for well-studied systems, as well as hormonal and neural substrates for coupling among all four axes. For example, GBA-HPA axis crosstalk coordinates extraction of energy following food intake, as CORT inhibits insulin secretion (Lambillotte et al., 1997; Plat et al., 1996), increases leptin levels (Laferrère et al., 2006), and stimulates protein breakdown (Spiga et al., 2014). Leptin URs show an inverse phase relationship to insulin and glucose (Simon et al., 1998), and to ACTH and CORT (Licinio et al., 1997). This might imply that glucose and insulin oscillate in phase with ACTH and CORT. Although acute glucose ingestion amplifies pulsatile ACTH and CORT secretion (Iranmanesh et al., 2011), other investigations have not identified a stable phase relationship among these outputs (Brandenberger et al., 1987; Shapiro et al., 1988).

GBA URs also couple to HPG axis URs, as leptin, LH, and estrogen peaks often oscillate in synchrony in women (Licinio et al., 1998a). Although not studied at an ultradian timescale, the HPG axis likely couples to the HPT axis, as TSH and thyroid volume change with ovulatory cycle phase (Doufas and Mastorakos, 2000). CORT and sex steroids influence patterns of GBA and HPT axis activity via actions on numerous neural substrates. Briefly, hunger-regulating circuits in the arcuate and paraventricular nuclei are sensitive to CORT feedback (Leon-Mercado et al., 2017; Ramos et al., 2005). Likewise, feeding and drinking behavior are modulated by testosterone and intracerebroventricular-administered estradiol (Clegg et al., 2006; Mauvais-Jarvis, 2011). Furthermore, one potential driver of URs in locomotor activity and appetitive behavior (including feeding) was recently located in CORT-tunable neurons in central dopaminergic circuitry (Berry et al., 2016; Blum et al., 2014). Finally, the HPT expresses receptors for numerous products released by the GBA and vice versa (Kluge et al., 2010; Sirakov and Plateroti, 2011; van den Beukel and Grefhorst, 2014), providing support for reciprocal interactions between these axes (Miller et al., 1978; Mullur et al., 2014). Taken together, there is substantial evidence that all four axes described exhibit 1) ultradian oscillations and 2) coupling at multiple levels within and across axes. As a result, these axes should behave as a coupled oscillator network in unperturbed individuals.

Implications of Ultradian Coupled Oscillator Network Properties for Research and Clinical Applications: A Case for Body Temperature

If the endocrine system operates as a coupled UR network, this system has the potential to provide continuous and noninvasive access to information about individual nodes of the network to researchers and clinicians without the need for high-frequency sampling of biological material (e.g., blood). Electrical outputs such as heart rate, heart rate variability, gastric contractions, and cortical power provide physiological information, but none of these measures exhibit clear relationships to all of the axes discussed above. In contrast, all four axes have well-documented influences on body temperature, a measure that exhibits URs of a similar periodicity in rodents and humans (Huang et al., 2014; Lindsley et al., 1999; Prendergast and Zucker, 2016; Ruis et al., 1987; Smarr et al., 2016a, 2016b; Smarr et al., 2017). Body temperature may therefore provide continuous information about the UR network. Evidence below provides support for the notion that body temperature is shaped by, and in turn shapes, each axis on an ultradian timescale.

HPT Axis and GBA Influence Core Body Temperature

It has been accepted since the 1800s that energy regulation influences the rate of heat production through the HPT axis and the GBA (Magnus-Levy, 1895). In fact, it has been argued that endothermy evolved from the cold response of the HPT axis in ectotherms (Little and Seebacher, 2014), suggesting a long evolutionary history of HPT responsiveness to temperature. Temperature change can influence HPT axis activity, as low temperatures stimulate HPT activity in humans (Smolander et al., 2009) and rodents (Ikegami et al., 2015); conversely, HPT axis dysfunction impairs core body temperature (CBT) rhythms (Mazzoccoli et al., 2004; Mullur et al., 2014). Thyroid-stimulated metabolic activity can be used directly for thermogenesis, as in brown fat thermogenesis, but many digestive and metabolic activities intrinsically generate heat (Clapham, 2012).

Body temperature profiles are dependent on GBA activity, including feeding schedules (Yoon et al., 2012); feeding-related changes to body temperature manifest in 2 forms: facultative and obligatory (Brundin et al., 1997). Facultative changes occur as the body anticipates incoming energy by increasing metabolism. For example, ghrelin stimulates both appetite and brown fat thermogenesis (Lin and Sun, 2012). Obligatory increases in temperature arise from the metabolic activity of breaking down food (e.g., protein, sugar, and fat content of a meal) and shape subsequent thermogenesis (Kus et al., 2008; Landsberg and Young, 1978; Quatela et al., 2016). Protein intake, for example, causes an increase in human CBT within 1 h (Brundin and Wahren, 1994), whereas fat intake causes a temperature decrease (Maffeis et al., 2001). Antagonizing the metabolism of glucose in the brain via intracerebroventricular injection of 2-deoxyglucose causes a dose-dependent hypothermic response that lasts 2 to 3 h in rats (Fiorentini and Müller, 1975). Similarly, insulin secretion decreases CBT (Sanchez-Alavez et al., 2010). Temperature may also feed back on this axis, exerting a synchronizing effect (Buhr et al., 2010). For instance, some insulin receptors expressed in the pancreas are sensitive to temperature changes within the physiological range (Uchida and Tominaga, 2011; e.g., TRPV4 [27-41°C], TRPM2 [>36°C]). This finding suggests a role for CBT URs in insulin regulation and provides a mechanism to close the feedback loop of food intake and metabolism affecting CBT.

Beyond the immediate impact on metabolic activity, food intake can shape neural control of homeostatic thermogenesis. For example, leptin is involved in increasing thermogenesis in response to cold stress in mice (Rozhavskaya-Arena et al., 2000; a response that takes 3-4 h), and glucose intake affects this thermoregulation by enhancing the leptin sensitivity of neurons in the feeding circuit (Mounien et al., 2010). Finally, extensive literature attests to the immediate and long-timescale effects of GBA and HPT activity on body temperature, strongly supporting its potential use in monitoring changes occurring on an ultradian timescale in these systems.

HPA Axis Influences CBT

There is some evidence that human cortisol URs have a stable phase relationship to URs of core and distal body temperature both in isolation and under natural conditions (Smarr et al., 2016a). Similarly, an injection of CORT or adrenaline at doses mimicking acute stress results in an acute decrease in CBT over the subsequent hour (Kainuma et al., 2009; Watanabe et al., 2008). ACTH and CORT also have opposing effects on brown fat activation in rodents (Soumano et al., 2000; Strack et al., 1995; van den Beukel et al., 2014; Viengchareun et al., 2001), with ACTH increasing thermogenesis and CORT in turn muting this activation. Reciprocally, corticosteroid-binding globulin is temperature sensitive, enabling changes in HPA signaling in response to thermoregulatory challenges (Lightman and Conway-Campbell, 2010).

HPG Axis Influences CBT

The gross effects of estradiol and testosterone on the temporal pattern of CBT have been documented for decades, giving rise to the term in heat for an ovulating, sexually receptive female mammal (Marrone et al., 1976). The preovulatory spike in estradiol on days of ovulation in mice and rats is associated with a plateau of high CBT (Sanchez-Alavez et al., 2010; Smarr et al., 2017). Acutely, estradiol raises CBT and lowers skin temperature in females (Mittelman-Smith et al., 2012; Rance et al., 2013; Williams et al., 2010), and OVX mice show a sustained increase in tail temp that is reversed with treatment by estradiol (Ding et al., 2013). In males, testosterone acutely raises muscle temperature while lowering adipose temperature but can also be aromatized to estradiol, thereby affecting CBT through similar mechanisms as estradiol in females (Clarke et al., 2012; Mauvais-Jarvis, 2011). Changes in thermogenesis associated with sex steroids likely occur through influence on hypothalamic neurons that regulate pulsatile release of LH as well as body temperature (Mittelman-Smith et al., 2012; Rance et al., 2013).

In summary, there is ample evidence that temperature is modulated on an ultradian timescale by output of the GBA, HPT, HPA, and HPG axes. Thus, if these axes operate as coupled oscillators, then body temperature should oscillate with a stable phase relationship to the oscillations within these axes. In turn, resulting temperature URs may reinforce coordination among these axes.

Discussion

The existence of 1- to 4-h URs and coupling in the GBA, HPT, HPA, and HPG axes support a coupled oscillator network model of URs. This network provides a testable framework that makes several predictions relevant to academic and clinical endocrinology. First, information from one endocrine axis carries information about other axes. Second, there may be shared outputs, including body temperature, that provide high temporal resolution information about the entire endocrine network through noninvasive means. While lacking the precision of direct chemical assays, such shared outputs enable a range of endocrine studies not currently possible. For example, such an arrangement would permit combined longitudinal and high temporal resolution assessment of physiological dynamics within individuals (Bashan et al., 2012). Such an assessment may uncover changes to endocrine dynamics particular to specific states (e.g., obesity, diabetes, fertility). For example, continuous, high temporal resolution data have already been shown to enable predictions of future physiological changes, including pregnancy outcomes in mice and sepsis onset in hospital patients (Drewry et al., 2013; Smarr et al., 2016b). Alongside the rapid evolution of wearable technology, conceptualizing endocrine dynamics as a coupled oscillator UR network may assist in the development of predictive medical analytics by pairing traditional endocrine studies with hypotheses generated from noninvasive, biologically relevant data gathered continuously within individuals from broad populations. Although a great deal of additional knowledge is needed to inform the type of and extent to which a coupled oscillator network model correctly describes endocrine interactions and dynamics, such information will likely be invaluable as a clinical diagnostic or for noninvasive data collection across systems.

Considerations and Caveats

Networks are composed of nodes and edges. Here, nodes represent oscillating, measurable outputs (e.g., CORT, LH, ghrelin) with edges representing coupling between nodes (see Fig. 2). Edges contain 2 dimensions, with weight representing coupling strength (degree to which a change in one node will affect change in an adjacent node) and length representing phase delay (the time delay of propagation from change in one node to change in the connected node). In this arrangement, all nodes and edges of the proposed network could be experimentally mapped. The properties of edges likely change over time and condition. For example, the length of an edge might change as a function of sleep and wakefulness, hunger, sex, ovulatory phase or age. Nodes themselves are likely to change across development, as in the rise in prominence of the estradiol node at puberty. A useful model will therefore require complexity and flexibility. Our simplistic model gives at least 3 testable predictions, which may inform network-mapping efforts.

Figure 2.

Hypothetical Coupled Oscillator Network and Properties. Schematic of the hypothetical ultradian rhythm network with URs represented as sines (A) exemplifying node and edge properties. Oscillating outputs are represented by nodes. The presence of coupling is represented by edges, with edge thickness proportional to the consistency with which a modulation of one node is associated with response in its neighbors (i.e., coupling strength), and edge length indicating the time delay between modulation of one node and response of another. Arrowheads indicate that coupling is directed. The white arrow indicates a perturbation that spreads from the stomach contraction node to neighboring nodes and indicates that perturbation may propagate through multiple nodes and influence subsequent feedback to the originally perturbed node. (B) Hypothetical ACTH ultradian rhythm approximated as a sine wave, with ΤauACTH indicating period. (C) ACTH ultradian rhythm from (B) with overlaid hypothetical CORT ultradian rhythm, illustrating the concept of coupled oscillations with a stable phase difference. (D) Hypothetical Core Body Temperature (CBT) ultradian rhythm resulting from combined influence of ACTH, CORT, and stomach contractions, highlighting potential for detecting network disruptions as rhythm perturbations. (E) Hypothetical ultradian rhythms in stomach contractions, illustrating a phase advance from a mistimed early meal. This perturbation is visible in the rapid dampening of the composite CBT signal, and in the depressed amplitude as the systems recover and realign (black and white arrows).

UR Parameters: Maintenance of Fundamental Frequency and Harmonics

In an unperturbed individual, coupled nodes may share a fundamental frequency at the ultradian timescale. That is, they may have a single lowest common frequency, as in circhoral pulses superimposed on 3-h oscillations. Thus, individual rhythms need not share the same frequency to maintain a stable phase relationship, and it would be expected that abolishing or perturbing signaling at one timescale would predictably perturb oscillations at others (Baker and Driver, 2007; Smarr et al., 2012). Body temperature provides an example of a node that is strongly modulated by other hormonal outputs and exhibits a single dominant frequency in the 1- to 4-h range in individuals (Fig. 2). URs may also have stable frequencies at harmonics (i.e., whole-number multiples of the fundamental frequency). For example, an individual might have LH peaks every hour, CORT peaks every 2 h, and feed every 4 h without violating this expectation. As many URs appear to be primarily circhoral, this is an important component of ultradian network stability. If constituent nodes influencing body temperature were not coupled, each node would contribute an independent frequency and phase of UR. When these unrelated frequencies overlap to modulate the body temperature UR, the composite frequency space would lack the structure of superimposed harmonics, obscuring URs in body temperature (Fig. 3A). The fact that a dominant 1- to 4-h rhythm is observed in temperature supports the coupling hypothesis (Fig. 3B, C). Experimental mapping of the ultradian frequencies of hormonal outputs within an individual, along with widely coupled outputs such as temperature, could be used to test this prediction.

Figure 3.

Real data can be compared to simple models to explore harmonics. Simulated body temperature data (A, C) was generated by superimposing sinewaves of circadian and ultradian frequencies and compared to 4 days of real mouse core body temperature data (B). (A) Two ultradian frequencies overlap with an average periodicity of 2 h but with each component sine wave set to a noninteger, non–whole-number-multiple (i.e., nonharmonic) of the other. Linear depiction of the simulated waveform (above) across 4 simulated days; the same data plotted as a raster plot of temperature (color, D), per minute (x-axis) per day (y-axis) allows comparison of peak-timing across days. (B) Real mouse body temperature data (based on data published in Smarr et al., 2017) show circadian and ultradian rhythms overlapping, as well as reactions to sudden changes in the light:dark cycle (yellow and black bars) not included in our data for the sake of simplicity. (C) Simulated data with only 1 dominant frequency (τ = 2 h) results in perfect ultradian alignment across days. Comparisons across animals and conditions would allow quantitative testing of conditions under which harmonics emerge, as appears to be the case in the real data (B) during the late inactive phase (preceding ZT 0). Notably, UR frequency appears to be modulated at the circadian timescale. (D) Color scale bar.

Active Decoupling and Recovery

If endocrine nodes are usually coupled, then lack of coordinated activity in adjacent nodes would imply the presence of a decoupling force. Thus, if an endogenous rhythmic pattern is known, then predictable perturbations should be detectable following a disruptive event. In addition, stable phase relationships should reemerge following recovery from disruption (Fig. 2B, C). Sufficiently strong disruptions might shift the entire network to a new stable state, whereas smaller disruptions would be expected to result in transient perturbation. For example, decoupling could arise from a phase-shift of gastric output due to an ill-timed meal, with the meal’s influence on gastric activity acting to temporarily decouple gastric activity from the surrounding network (see Fig. 2E). Decoupling could also manifest along an edge. For example, if the edge between the nodal outputs ACTH and CORT were pharmacologically suppressed by an ACTH receptor antagonist, then a lack of coordinated pulsatility would be expected between these 2 hormones because of the decoupling action of the antagonist. One implication is that disruptions to network synchrony might be detectable through the appearance of destructive interference in a shared output such as body temperature (Fig. 2D). As each day in an individual’s life does not share identical timing (e.g., sleep, meals, etc.), another implication is that a degree of system-wide perturbation is expected to arise from environmental factors, and perfect regularity of URs is not expected from real-world data (Fig. 3B). At present, sparse literature has investigated active decoupling and recovery at the timescale of hours. Modeling of these relationships has begun in isolated axes but, to our knowledge, has yet to be investigated using a holistic framework to incorporate across-axes interactions (Caplan et al., 2010; Lightman and Terry, 2014).

Network-wide Predictions

With sufficient knowledge of a network’s nodes and edges, measurement of the UR phase of one node should allow reasonable predictions about the UR phase of any other node in the network. Measured deviation from these predictions would imply either imperfect mapping of the network or the presence of disruptions. This property speaks to the potential utility of easily acquired outputs, like body temperature, for estimating the state of more difficult-to-measure hormonal dynamics. For example, research into coupling among blood glucose, blood insulin, and body temperature under various conditions might allow diabetes management by continuous temperature measurement without the need for frequent blood samples.

Past and Present Challenges to Collecting and Analyzing UR Data

There are many reasons why it is not yet clear if endocrine systems comprise a coupled oscillator network, despite an abundance of evidence that individual axes both have URs and couple. In part, our lack of understanding reflects the complexity of the system being mapped. However, methodological barriers including limitations in sampling frequency from tissues, interindividual variability of period and network state, and intra-individual variability across days due to modern environmental disruptions have made those mapping efforts more difficult.

Adequate sampling frequency and duration across multiple hormones is difficult in small mammals and can be cost prohibitive in humans. Detection of URs requires high-frequency sampling: for a 4-h rhythm, a sample every 2 h is the mathematical minimum sampling frequency required to avoid aliasing (i.e., the Nyquist critical frequency) (Durkin and Callaghan, 2005). Even if sampling is adequately frequent, a short duration of data collection (i.e., a small number of cycles) also decreases the likelihood of accurately detecting the oscillation. Sampling periods of only a few hours, even at high sampling frequencies, are biased toward the detection of ultrashort URs (Bagnasco et al., 2002b; Otukonyong et al., 2005). Some studies have attempted to bypass these challenges by measuring ultradian outputs in tissue explants (Chou and Johnson, 1987; Lewy et al., 1996); however, if URs rely extensively on network feedback, a node isolated from network feedback may not exhibit the same periodic behavior as it would in vivo. An ideal tool would be able to measure a node continuously over many days at high temporal resolution. Hormone-proxy measures from easy-to-measure variables such as body temperature are therefore of great potential value. Likewise, newer devices that allow continuous monitoring (e.g., glucose or lactate monitors) will aid researchers and practitioners interested in studying URs.

Once data have been collected, choice of analytical method can influence the detection of periodicities in measured outputs. Widely used pulse-detection algorithms (e.g., PREDETEK, Genazzani et al., 1991; ULTRA, Polonsky et al., 1988; Saad et al., 1998; Simon et al., 1998) have user-specified detection thresholds. In these analyses, a lower threshold for pulse detection results in a larger number of detected peaks. As the peak number is often divided by the duration of measurement, detection threshold can directly affect the determination of periodicity, with a lower threshold leading to a shorter estimated period, and a bias toward missing large, but slow, peaks. As alluded to earlier, these analyses may bias results of studies conducted over a short interval toward detection of high-frequency rhythms that may or may not be the dominant frequency observed over a longer interval (Otukonyong et al., 2005). Signal-processing techniques such as wavelet transformations (Leise et al., 2013), dynamic time warping (Tan et al., 2015), or delay differential analysis (Lainscsek and Sejnowski, 2015) provide a more unbiased picture of the frequency compositions of, and relationships between, hormonal signals over many cycles.

After accounting for variability arising from sampling and analytical methods, within-individual variability may still account for a substantial amount of total variability. For example, intraindividual variability in periodicity of intestinal contractions accounts for about 50% of population variability (Husebye et al., 1990), more than the contributions of expected sources of variability, such as sex or age. If individuals comprise unique UR networks, then averaging across individuals or even by time of day within individuals will “wash out” higher frequencies. Nonetheless, because of the infeasibility and expense of high temporal resolution sample collection, URs in the literature are almost exclusively a reflection of averages across individuals. In some cases, modern computational techniques allow researchers to revisit existing raw data with an eye to understanding individual-specific features (e.g., periodicity, period variability, rhythmic strength), rather than average values at a given time of day.

Despite these sources of variance, remarkable UR consolidation exists in one model organism, laboratory rats. Examined separately, rats have consistent 3- to 4-h rhythms in serum GH (Tannenbaum and Martin, 1976), CORT (Mitsugi and Kimura, 1986), body temperature (Harper et al., 1996; Ruis et al., 1989), ghrelin (Bagnasco et al., 2002b; Kalra et al., 2003) and leptin (Bagnasco et al., 2002b; Kalra et al., 2003). Although we should expect greater variability in humans who have more environmental and genetic variability than model animals raised in laboratory conditions, the potential consolidation of within-individual URs across outputs is an avenue worthy of further investigation. Simultaneous monitoring of multiple URs in a single individual will be important for expanding understanding of UR dynamics.

Conclusion and Implications: Building Personalized Medicine Through Modeling and Wearable Devices

The present overview suggests that neuroendocrine physiology operates as a network of coupled ultradian oscillators. More research is needed to fully characterize and verify the proposed model by acquiring new data and reanalyzing existing data using signal-processing techniques. Focusing on intraindividual comparisons sidesteps challenges associated with interindividual variability and allows identification of information-rich nodes that can be noninvasively assayed (Skarke et al., 2017). Such metrics have the potential to replace costly and disruptive measures such as blood draws and enable personalized medicine through comparison of individuals to themselves over time, rather than by comparison of a single measure to the population mean. For example, if temperature dynamics accurately reflect reproductive or digestive state, individual monitoring of fertility or individually tailored times to eat or exercise might be garnered noninvasively. Although the present overview focuses on body temperature as a proxy for hormonal dynamics, other noninvasive metrics like heart rate and heart rate variability, EEG components, skin conductivity, and so forth may also provide information on hormonal and nonhormonal physiological nodes.

In research, reliable proxy measures would allow more detailed descriptions of endocrine dynamics and identification of conditions that perturb those dynamics. Future work designed within this framework could aid in the development of network models of disease that could help explain increasingly common, cross-axes comorbidities such as polycystic ovary syndrome and obesity (Naderpoor et al., 2015), gastrointestinal imbalance and depression (Dash et al., 2015), and adrenal fatigue and infertility (Hompes et al., 1992). With the aid of new technologies and analyses, it is feasible to collect data longitudinally at high temporal resolution and across multiple nodes. Such advances may enable rapid progress in understanding endocrine URs and the potential translational applications they carry.

Footnotes

Acknowledgements

We thank Dr. Irv Zucker for his helpful comments on an earlier version of this manuscript. The preparation of this manuscript is supported by National Institutes of Health grants HD-050470 (L.J.K.), ES-027509 (B.L.S), and HD-081957 (B.L.S).

Conflict of Interest Statement

The authors have no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

Adriaanse

Romijn

Brabant

Endert

Wiersinga

(1993) Pulsatile thyrotropin secretion in nonthyroidal illness. J Clin Endocrinol Metab 77:1313-1317.

Alexander

Irvine

CHG

(1987) Secretion rates and short-term patterns of gonadotrophin-releasing hormone, FSH and LH throughout the periovulatory period in the mare. J Endocrinol 114:351-362.

(1985) Studies of hormone patterns during the oestrous cycle of beef cows. Reprod Nutr Dev 25:919-927.

Ariga

Tsukamoto

Chen

Mantyh

Pappas

Takahashi

(2007) Endogenous acyl ghrelin is involved in mediating spontaneous phase III-like contractions of the rat stomach. Neurogastroenterol Motil Off J Eur GastrointestMotil Soc 19:675-680.

Avau

Carbone

Tack

Depoortere

(2013) Ghrelin signaling in the gut, its physiological properties, and therapeutic potential. Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc 25:720-732.

Backstrom

McNeilly

Leask

Baird

(1982) Pulsatile secretion of LH, FSH, prolactin, oestradiol, and progesterone during the human menstrual cycle. Clin Endocrinol (Oxf) 17:29-42.

Bagnasco

Kalra

(2002a) Ghrelin and leptin pulse discharge in fed and fasted rats. Endocrinology 143:726–729.

Bagnasco

Kalra

(2002b) Plasma leptin levels are pulsatile in adult rats: effects of gonadectomy. Neuroendocrinology 75:257-263.

Baker

Driver

(2007) Circadian rhythms, sleep and the menstrual cycle. Sleep Med 8:613-622.

10.

Bashan

Bartsch

Kantelhardt

Havlin

Ivanov

(2012) Network physiology reveals relations between network topology and physiological function. Nat Commun 3:702.

11.

Beaven

Ingram

Gill

Hopkins

(2010) Ultradian rhythmicity and induced changes in salivary testosterone. Eur J Appl Physiol 110:405-413.

12.

Ben Jebara

Carrière

Priceand

(1994) Decreased pulsatile LH secretion in heifers superovulated with eCG or FSH. Theriogenology 42:685-694.

13.

Bergendahl

Evans

Veldhuis

(1996) Current concepts on ultradian rhythms of luteinizing hormone secretion in the human. Hum Reprod Update 2:507-518.

14.

Berry

Saunders

Sharrett-Field

Reynolds

Bardo

Pauly

Prendergast

(2016) Corticosterone enhances N-methyl-D-aspartate receptor signaling to promote isolated ventral tegmental area activity in a reconstituted mesolimbic dopamine pathway. Brain Res Bull 120:159-165.

15.

Bitman

Kahl

Wood

Lefcourt

(1994) Circadian and ultradian rhythms of plasma thyroid hormone concentrations in lactating dairy cows. Am J Physiol 266:R1797-1803.

16.

Blum

Zhu

Moquin

Kokoeva

Gratton

Giros

Storch

K-F

(2014) A highly tunable dopaminergic oscillator generates ultradian rhythms of behavioral arousal. eLife 3:e05105.

17.

Booth

Jr Weltman

Yankov

Murray

Davison

Rogol

Asplin

Johnson

Veldhuis

Evans

(1996) Mode of pulsatile follicle-stimulating hormone secretion in gonadal hormone-sufficient and-deficient women–a clinical research center study. J Clin Endocrinol Metab 81:3208-3214.

18.

Bourguignon

Storch

K-F

(2017) Control of rest: activity by a dopaminergic ultradian oscillator and the circadian clock. Front Neurol 8:614.

19.

Brandenberger

Simon

Follenius

(1987) Ultradian endocrine rhythms: a multioscillatory system. J Interdiscip Cycle Res 18:307-315.

20.

Bray

Muneyyirci-Delale

Kofinas

Reyes

(1991) Circadian, ultradian, and episodic gonadotropin and prolactin secretion in human pseudocyesis. Acta Endocrinol (Copenh) 124:501-509.

21.

Brundin

Aksnes

Wahren

(1997) Whole body and splanchnic metabolic and circulatory effects of glucose during beta-adrenergic receptor inhibition. Am J Physiol 272:E678-E687.

22.

Brundin

Wahren

(1994) Influence of protein ingestion on human splanchnic and whole-body oxygen consumption, blood flow, and blood temperature. Metabolism 43:626-632.

23.

Buff

Messer

Cogswell

Johnson

Keisler

Ganjam

(2007) Seasonal and pulsatile dynamics of thyrotropin and leptin in mares maintained under a constant energy balance. Domest Anim Endocrinol 33:430-436.

24.

Buhr

Yoo

S-H

Takahashi

(2010) Temperature as a universal resetting cue for mammalian circadian oscillators. Science 330:379-385.

25.

Caplan

Tannenbaum

Johnstone

(2010) An enzymatic model of the growth hormone-releasing hormone oscillator incorporating neuronal synchronization. J Theor Biol 264:984-989.

26.

Caraty

Bouchard

Blanc

(1992) Studies of LHRH secretion into the hypophyseal portal blood of the ram: gonadal regulation of LH secretion is exerted mainly at the hypothalamic level In: Crowley

Jr Conn

, editors. Modes of action of GnRH and GnRH analogs. New York (NY): Springer. p 193-210.

27.

Caraty

Grino

Locatelli

Oliver

(1988) Secretion of corticotropin releasing factor (CRF) and vasopressin (AVP) into the hypophysial portal blood of conscious, unrestrained rams. Biochem Biophys Res Commun 155:841-849.

28.

Caraty

Locatelli

(1988) Effect of time after castration on secretion of LHRH and LH in the ram. J Reprod Fertil 82:263-269.

29.

Cauter

(2004) Diurnal and ultradian rhythms in human endocrine function: a minireview. Horm Res Paediatr 34:45-53.

30.

Chandolia

Honaramooz

Bartlewski

Beard

Rawlings

(1997) Effects of treatment with LH releasing hormone before the early increase in LH secretion on endocrine and reproductive development in bull calves. J Reprod Fertil 111:41-50.

31.

Chou

Johnson

(1987) Luteinizing hormone secretion from anterior pituitary cells of the cockerel: evidence for an ultradian rhythm. Poult Sci 66:732-740.

32.

Clapham

(2012) Central control of thermogenesis. Neuropharmacology 63:111-123.

33.

Clarke

Thomas

Yao

Cummins

(1987) GnRH secretion throughout the ovine estrous cycle. Neuroendocrinology 46:82-88.

34.

Clarke

Rao

Cowley

Henry

(2012) Sex differences in the metabolic effects of testosterone in sheep. Endocrinology 153:123-131.

35.

Clegg

Brown

Woods

Benoit

(2006) Gonadal hormones determine sensitivity to central leptin and insulin. Diabetes 55:978-987.

36.

Code

Marlett

(1975) The interdigestive myo-electric complex of the stomach and small bowel of dogs. J Physiol 246:289-309.

37.

Collins

Bercik

(2009) The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology 136:2003-2014.

38.

Czieselsky

Prescott

Porteous

Campos

Clarkson

Steyn

Campbell

Herbison

(2016) Pulse and surge profiles of luteinizing hormone secretion in the mouse. Endocrinology 157:4794-4802.

39.

Dallman

Akana

Cascio

Darlington

Jacobson

Levin

(1987) Regulation of ACTH secretion: variations on a theme of B. Recent Prog Horm Res 43:113-173.

40.

Dash

Clarke

Berk

Jacka

(2015) The gut microbiome and diet in psychiatry: focus on depression. Curr Opin Psychiatry 28:1-6.

41.

Deloose

Janssen

Depoortere

Tack

(2012) The migrating motor complex: control mechanisms and its role in health and disease. Nat Rev Gastroenterol Hepatol 9:271-285.

42.

Deloose

Vos

Corsetti

Depoortere

Tack

(2015) Endogenous motilin, but not ghrelin plasma levels fluctuate in accordance with gastric phase III activity of the migrating motor complex in man. Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc 27:63-71.

43.

Ding

Yao

Zhao

Mao

Chen

Brinton

(2013) Ovariectomy induces a shift in fuel availability and metabolism in the hippocampus of the female transgenic model of familial Alzheimer’s. PloS One 8:e59825.

44.

Doufas

Mastorakos

(2000) The hypothalamic-pituitary-thyroid axis and the female reproductive system. Ann N Y Acad Sci 900:65-76.

45.

Drewry

Fuller

Bailey

Hotchkiss

(2013) Body temperature patterns as a predictor of hospital-acquired sepsis in afebrile adult intensive care unit patients: a case-control study. Crit Care Lond Engl 17:R200.

46.

Durkin

Callaghan

(2005) Effects of minimum sampling rate and signal reconstruction on surface electromyographic signals. J Electromyogr Kinesiol 15:474-481.

47.

Ellis

Desjardins

(1984) Orchidectomy unleashes pulsatile luteinizing hormone secretion in the rat. Biol Reprod 30:619-627.

48.

Evans

Hughes

Neely

Stabenfeldt

Winger

(1979) Episodic LH secretion patterns in the mare during the oestrous cycle. J Reprod Fertil Suppl 27:143-150.

49.

Feillet

Krusche

Tamanini

Janssens

Downey

Martin

Teboul

Saito

Lévi

Bretschneider

et al . (2014) Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle. Proc Natl Acad Sci U S A 111:9828-9833.

50.

Filicori

Butler

Crowley

(1984) Neuroendocrine regulation of the corpus luteum in the human. Evidence for pulsatile progesterone secretion. J Clin Invest 73:1638-1647.

51.

Fiorentini

Müller

(1975) Sensitivity of central chemoreceptors controlling blood glucose and body temperature during glucose deprivation. J Physiol 248:247-271.

52.

Fujino

Inui

Asakawa

Kihara

Fujimura

Fujimiya

(2003) Ghrelin induces fasted motor activity of the gastrointestinal tract in conscious fed rats. J Physiol 550:227-240.

53.

García-García

Juárez-Aguilar

Santiago-García

Cardinali

(2014) Ghrelin and its interactions with growth hormone, leptin and orexins: implications for the sleep-wake cycle and metabolism. Sleep Med Rev 18:89-97.

54.

Gazal

Leshin

Stanko

Thomas

Keisler

Anderson

Williams

(1998) Gonadotropin-releasing hormone secretion into third-ventricle cerebrospinal fluid of cattle: correspondence with the tonic and surge release of luteinizing hormone and its tonic inhibition by suckling and neuropeptide Y. Biol Reprod 59:676-683.

55.

Genazzani

Guardabasso

Petraglia

Genazzani

(1991) Specific concordance index defines the physiological lag between LH and progesterone in women during the midluteal phase of the menstrual cycle. Gynecol Endocrinol 5:175-184.

56.

Genazzani

Petraglia

Volpogni

D’Ambrogio

Facchinetti

Genazzani

(1993) FSH secretory pattern and degree of concordance with LH in amenorrheic, fertile, and postmenopausal women. Am J Physiol Endocrinol Metab 264:E776-E781.

57.

Giacchetti

Bjarnason

Garufi

Genet

Iacobelli

Tampellini

Smaaland

Focan

Coudert

Hublet

et al . (2006) Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group. J Clin Oncol Off J Am Soc Clin Oncol 24:3562-3569.

58.

Ginther

Bergfelt

Kulick

Kot

(1998) Pulsatility of systemic FSH and LH concentrations during follicular-wave development in cattle. Theriogenology 50:507-519.

59.

Goji

(1993) Pulsatile characteristics of spontaneous growth hormone (GH) concentration profiles in boys evaluated by an ultrasensitive immunoradiometric assay: evidence for ultradian periodicity of GH secretion. J Clin Endocrinol Metab 76:667-670.

60.

Gore

Windsor-Engnell

Terasawa

(2004) Menopausal increases in pulsatile gonadotropin-releasing hormone release in a nonhuman primate (Macaca mulatta). Endocrinology 145:4653-4659.

61.

Grattan

Park

Selmanoff

(1995) Orchidectomy and NMDA increase GnRH secretion as measured by push-pull perfusion of rat anterior pituitary. Am J Physiol Endocrinol Metab 268:E685-E692.

62.

Greenspan

Klibansk

Schqenfeld

Ridgway

(1986) Pulsatile secretion of thyrotropin in man. J Clin Endocrinol Metab 63:661-668.

63.

Greenspan

Klibanski

Rowe

Elahi

(1991) Age-related alterations in pulsatile secretion of TSH: role of dopaminergic regulation. Am J Physiol 260:E486-E491.

64.

Guyot

Sulon

Beckers

J-F

Closset

Lebreton

de Oliveira

Rollin

(2007) Development and validation of a radioimmunoassay for thyrotropin in cattle. J Vet Diagn Invest 19:643-651.

65.

Hannay

Booth

Forger

(2015) Collective phase response curves for heterogeneous coupled oscillators. Phys Rev E Stat Nonlin Soft Matter Phys 92:022923.

66.

Harper

Tornatzky

Miczek

(1996) Stress induced disorganization of circadian and ultradian rhythms: comparisons of effects of surgery and social stress. Physiol Behav 59:409-420.

67.

Healy

Schenken

Lynch

Williams

Hodgen

(1984) Pulsatile progesterone secretion: its relevance to clinical evaluation of corpus luteum function. Fertil Steril 41:114-121.

68.

Henley

Leendertz

Russell

Wood

Taheri

Woltersdorf

Lightman

(2009) Development of an automated blood sampling system for use in humans. J Med Eng Technol 33:199-208.

69.

Hodges

(1978) Effects of gonadectomy and oestradiol treatment on plasma luteinizing hormone concentrations in the marmoset monkey, Callithrix jacchus. J Endo 76(2):271-281.

70.

Hompes

Scheele

Gooren

Schoemaker

(1992) Pulsatile secretory patterns of luteinizing hormone in two patients with secondary amenorrhea suffering from Cushing’s disease, before and after transsphenoidal adenectomy. Fertil Steril 57:924-926.

71.

Hoogerwerf

Shahinian

Cornélissen

Halberg

Bostwick

Timm

Bartell

Cassone

(2010) Rhythmic changes in colonic motility are regulated by period genes. Am J Physiol Gastrointest Liver Physiol 298:G143-G150.

72.

Huang

Tamura

Chen

Kitamura

Nemoto

Kanaya

(2014) Characterization of ultradian and circadian rhythms of core body temperature based on wavelet analysis. Conf Proc IEEE Eng Med Biol Soc 2014:4220-4223.

73.

Husebye

Skar

Aalen

Osnes

(1990) Digital ambulatory manometry of the small intestine in healthy adults: estimates of variation within and between individuals and statistical management of incomplete MMC periods. Dig Dis Sci 35:1057-1065.

74.

Ikegami

Atsumi

Yorinaga

Ono

Murayama

Nakane

Ota

Arai

Tega

Iigo

et al . (2015) Low temperature-induced circulating triiodothyronine accelerates seasonal testicular regression. Endocrinology 156:647-659.

75.

Iranmanesh

Lawson

Dunn

Veldhuis

(2011) Glucose ingestion selectively amplifies ACTH and cortisol secretory-burst mass and enhances their joint synchrony in healthy men. J Clin Endocrinol Metab 96(9):2882-2888.

76.

Irvine

Alexander

(1994) The dynamics of gonadotrophin-releasing hormone, LH and FSH secretion during the spontaneous ovulatory surge of the mare as revealed by intensive sampling of pituitary venous blood. J Endocrinol 140:283-295.

77.

Ixart

Barbanel

Nouguier-Soulé

Assenmacher

(1991) A quantitative study of the pulsatile parameters of CRH-41 secretion in unanesthetized free-moving rats. Exp Brain Res 87:153-158.

78.

Jain

Polotsky

Rochester

Berga

Loucks

Zeitlian

Gibbs

Polotsky

Feng

Isaac

et al . (2007) Pulsatile luteinizing hormone amplitude and progesterone metabolite excretion are reduced in obese women. J Clin Endocrinol Metab 92:2468-2473.

79.

Jansen

Roelfsema

van der Spoel

Akintola

Postmus

Ballieux

Slagboom

Cobbaert

van der Grond

Westendorp

et al . (2015) Familial longevity is associated with higher TSH secretion and strong TSH-fT3 relationship. J Clin Endocrinol Metab 100:3806-3813.

80.

Jasper

Engeland

(1991) Synchronous ultradian rhythms in adrenocortical secretion detected by microdialysis in awake rats. Am J Physiol 261:R1257-R1268.

81.

Joustra

Roelfsema

Endert

Ballieux

BEPB

van Trotsenburg

ASP

Fliers

Corssmit

EPM

Bernard

Oostdijk

Wit

et al . (2016) Pituitary hormone secretion profiles in IGSF1 deficiency syndrome. Neuroendocrinology 103:408-416.

82.

Kainuma

Watanabe

Tomiyama-Miyaji

Inoue

Kuwano

Ren

Abo

(2009) Association of glucocorticoid with stress-induced modulation of body temperature, blood glucose and innate immunity. Psychoneuroendocrinology 34:1459-1468.

83.

Kalra

Bagnasco

Otukonyong

Dube

Kalra

(2003) Rhythmic, reciprocal ghrelin and leptin signaling: new insight in the development of obesity. Regul Pept 111:1-11.

84.

Keenan

Roelfsema

Biermasz

Veldhuis

(2003) Physiological control of pituitary hormone secretory-burst mass, frequency, and waveform: a statistical formulation and analysis. Am J Physiol Regul Integr Comp Physiol 285:R664-R673.

85.

Kimura

Tsai

(1984) Ultradian rhythm of growth hormone secretion and sleep in the adult male rat. J Physiol 353:305-315.

86.

Kluge

Riedl

Uhr

Schmidt

Zhang

Yassouridis

Steiger

(2010) Ghrelin affects the hypothalamus–pituitary–thyroid axis in humans by increasing free thyroxine and decreasing TSH in plasma. Eur J Endocrinol 162:1059-1065.

87.

Komarov

Pikovsky

(2015) Intercommunity resonances in multifrequency ensembles of coupled oscillators. Phys Rev E Stat Nonlin Soft Matter Phys 92:012906.

88.

Kus

Prazak

Brauner

Hensler

Kuda

Flachs

Janovska

Medrikova

Rossmeisl

Jilkova

et al . (2008) Induction of muscle thermogenesis by high-fat diet in mice: association with obesity-resistance. Am J Physiol Endocrinol Metab 295:E356-E367.

89.

Laferrère

Abraham

Awad

Jean-Baptiste

Hart

Garcia-Lorda

Kokkoris

Russell

(2006) Inhibiting endogenous cortisol blunts the meal-entrained rise in serum leptin. J Clin Endocrinol Metab 91:2232-2238.

90.

Lainscsek

Sejnowski

(2015) Delay differential analysis of time series. Neural Comput 27:594-614.

91.

Lambillotte

Gilon

Henquin

(1997) Direct glucocorticoid inhibition of insulin secretion: an in vitro study of dexamethasone effects in mouse islets. J Clin Invest 99:414-423.

92.

Landgraf

McCarthy

Welsh

(2014) Circadian clock and stress interactions in the molecular biology of psychiatric disorders. Curr Psychiatry Rep 16:483.

93.

Landsberg

Young

(1978) Fasting, feeding and regulation of the sympathetic nervous system. N Engl J Med 298:1295-1301.

94.

Lefcourt

Akers

Wood

Bitman

(1994) Circadian and ultradian rhythms of peripheral prolactin concentrations in lactating dairy cows. Am J Phys 267:R1461-R1466.

95.

Lefcourt

Huntington

Akers

Wood

Bitman

(1999) Circadian and ultradian rhythms of body temperature and peripheral concentrations of insulin and nitrogen in lactating dairy cows. Domest Anim Endocrinol 16:41-55.

96.

Leise

Indic

Paul

Schwartz

(2013) Wavelet meets actogram. J Biol Rhythms 28:62-68.

97.

Leon-Mercado

Herrera Moro Chao

Basualdo

MDC

Kawata

Escobar

Buijs

(2017) The arcuate nucleus: a site of fast negative feedback for corticosterone secretion in male rats. eNeuro 4.

98.

Lévi

Okyar

Dulong

Innominato

Clairambault

(2010) Circadian timing in cancer treatments. Annu Rev Pharmacol Toxicol 50:377-421.

99.

Levine

Ramirez

(1982) Luteinizing hormone-releasing hormone release during the rat estrous cycle and after ovariectomy, as estimated with push-pull cannulae. Endocrinology 111:1439-1448.

100.

Lewis

Greenblatt

Amanda Rittenhouse

Veldhuis

Jaffe

(1995) Pulsatile release patterns of luteinizing hormone and progesterone in relation to symptom onset in women with premenstrual syndrome. Fertil Steril 64:288-292.

101.

Lewy

Naor

Ashkenazi

(1996) Rhythmicity of luteinizing hormone secretion expressed in vitro. Eur J Endocrinol 135:455-463.

102.

Licinio

Mantzoros

Negrão

Cizza

Wong

Bongiorno

Chrousos

Karp

Allen

Flier

et al . (1997) Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nat Med 3:575-579.

103.

Licinio

Negrão

Mantzoros

Kaklamani

Wong

Bongiorno

Mulla

Cearnal

Veldhuis

Flier

et al . (1998a) Synchronicity of frequently sampled, 24-h concentrations of circulating leptin, luteinizing hormone, and estradiol in healthy women. Proc Natl Acad Sci U S A 95:2541-2546.

104.

Licinio

Negrão

Mantzoros

Kaklamani

Wong

Bongiorno

Negro

Mulla

Veldhuis

Cearnal

et al . (1998b) Sex differences in circulating human leptin pulse amplitude: clinical implications. J Clin Endocrinol Metab 83:4140-4147.

105.

Lightman

Terry

(2014) The importance of dynamic signalling for endocrine regulation and drug development: relevance for glucocorticoid hormones. Lancet Diabetes Endocrinol 2:593-599.

106.

Lightman

Conway-Campbell

(2010) The crucial role of pulsatile activity of the HPA axis for continuous dynamic equilibration. Nat Rev Neurosci 11:710-718.

107.

Lin

Sun

(2012) Thermogenic characterization of ghrelin receptor null mice. Methods Enzymol 514:355-370.

108.

Lindsley

Dowse

Burgoon

Kolka

Stephenson

(1999) A persistent circhoral ultradian rhythm is identified in human core temperature. Chronobiol Int 16:69-78.

109.

Little

Seebacher

(2014) The evolution of endothermy is explained by thyroid hormone-mediated responses to cold in early vertebrates. J Exp Biol 217:1642-1648.

110.

Lloyd

(1992) Ultradian rhythms in life processes: an inquiry into fundamental principles of chronobiology and psychobiology. London (UK): Springer-Verlag.

111.

Lockwood

Muttukrishna

Groome

Matthews

Ledger

(1998) Mid-follicular phase pulses of inhibin B are absent in polycystic ovarian syndrome and are initiated by successful laparoscopic ovarian diathermy: a possible mechanism regulating emergence of the dominant follicle. J Clin Endocrinol Metab 83:1730-1735.

112.

Luboshitzky

Lavi

Thuma

Lavie

(1996) Nocturnal melatonin and luteinizing hormone rhythms in women with hyperprolactinemic amenorrhea. J Pineal Res 20:72-78.

113.

MacCagnan

Oliveira

Castro

Abucham

(1999) Abnormal circadian rhythm and increased non-pulsatile secretion of thyrotrophin in Sheehan’s syndrome. Clin Endocrinol (Oxf) 51:439-447.

114.

Maffeis

Schutz

Grezzani

Provera

Piacentini

Tatò

(2001) Meal-Induced thermogenesis and obesity: is a fat meal a risk factor for fat gain in children? J Clin Endocrinol Metab 86:214-219.

115.

Magnus-Levy (1895) Uber den respiratorischen Gaswechsel unter dem Ein fluss der Thyroidea sowie unter verschiedenen pathologischen Zustanden. Berl Klin 650-652.

116.

Marrone

Gentry

Wade

(1976) Gonadal hormones and body temperature in rats: effects of estrous cycles, castration and steroid replacement. Physiol Behav 17:419-425.

117.

Masuda

Tanaka

Inomata

Ohnuma

Tanaka

Itoh

Hosoda

Kojima

Kangawa

(2000) Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun 276:905-908.

118.

Matsuda

Akiyama

Tuuga

Bernard

Clauss

(2014) Daily feeding rhythm in proboscis monkeys: a preliminary comparison with other non-human primates. Primates 55:313-326.

119.

Matsumoto

Bremner

(1984) Modulation of pulsatile gonadotropin secretion by testosterone in man. J Clin Endocrinol Metab 58:609-614.

120.

Mauvais-Jarvis

(2011) Estrogen and androgen receptors: regulators of fuel homeostasis and emerging targets for diabetes and obesity. Trends Endocrinol Metab 22:24-33.

121.

Mazzoccoli

Giuliani

Carughi

De Cata

Puzzolante

La Viola

Urbano

Perfetto

Tarquini

(2004) The hypothalamic-pituitary-thyroid axis and melatonin in humans: possible interactions in the control of body temperature. Neuro Endocrinol Lett 25:368-372.

122.

McNeilly

Crawford

Taragnat

Nicol

McNeilly

(2003) The differential secretion of FSH and LH: regulation through genes, feedback and packaging. Reprod Camb Engl Suppl 61:463-476.

123.

Meredith

Levine

(1992) Effects of castration on LH-RH patterns in intrahypophysial microdialysates. Brain Res 571:181-188.

124.

Mershon

Sehlhorst

Rebar

Liu

(1992) Evidence of a corticotropin-releasing hormone pulse generator in the macaque hypothalamus. Endocrinology 130:2991-2996.

125.

Miller

Gorman

(1978) Gut-thyroid interrelationships. Gastroenterology 75:901-911.

126.

Minamitani

Chihara

Kaji

Kodama

Kita

Fujita

(1989) Ultradian rhythm of growth hormone secretion in unrestrained, conscious male rabbits: role of endogenous somatostatintdagger. J Neuroendocrinol 1:147-151.

127.

Mingrone

Granato

Valera-Mora

Iaconelli

Calvani

Bracaglia

Manco

Nanni

Castagneto

(2006) Ultradian ghrelin pulsatility is disrupted in morbidly obese subjects after weight loss induced by malabsorptive bariatric surgery. Am J Clin Nutr 83:1017-1024.

128.

Mitsugi

Kimura

(1986) Corticosterone and growth hormone secretions during long-term thiopental anesthesia in the male rat. Neuroendocrinology 44:457-461.

129.

Mittelman-Smith

Williams

Krajewski-Hall

McMullen

Rance

(2012) Role for kisspeptin/neurokinin B/dynorphin (KNDy) neurons in cutaneous vasodilatation and the estrogen modulation of body temperature. Proc Natl Acad Sci U S A 109:19846-19851.

130.

Miyata

Kuwaki

Ootsuka

(2016) The integrated ultradian organization of behavior and physiology in mice and the contribution of orexin to the ultradian patterning. Neuroscience 334:119-133.

131.

Moenter

Caraty

Locatelli

Karsch

(1991) Pattern of gonadotropin-releasing hormone (GnRH) secretion leading up to ovulation in the ewe: existence of a preovulatory GnRH surge. Endocrinology 129:1175-1182.

132.

Mogi

Yonezawa

Chen

D-S

J-Y

Suzuki

Yamanouchi

Sawasaki

Nishihara

(2004) Relationship between growth hormone (GH) pulses in the peripheral circulation and GH-releasing hormone and somatostatin profiles in the cerebrospinal fluid of goats. J Vet Med Sci 66:1071-1078.

133.

Mounien

Marty

Tarussio

Metref

Genoux

Preitner

Foretz

Thorens

(2010) Glut2-dependent glucose-sensing controls thermoregulation by enhancing the leptin sensitivity of NPY and POMC neurons. FASEB J Off Publ Fed Am Soc Exp Biol 24:1747-1758.

134.

Mulligan

Iranmanesh

Gheorghiu

Godschalk

Veldhuis

(1995) Amplified nocturnal luteinizing hormone (LH) secretory burst frequency with selective attenuation of pulsatile (but not basal) testosterone secretion in healthy aged men: possible Leydig cell desensitization to endogenous LH signaling—a clinical research center study. J Clin Endocrinol Metab 80:3025-3031.

135.

Mullur

Liu

Y-Y

Brent

(2014) Thyroid hormone regulation of metabolism. Physiol Rev 94:355-382.

136.

Naderpoor

Shorakae

Joham

Boyle

De Courten

Teede

(2015) Obesity and polycystic ovary syndrome. Minerva Endocrinol 40:37-51.

137.

Nakajima

McLachlan

Cohen

Clifton

Bremner

Soules

(1990) The immunoreactive inhibin secretion pattern in the midluteal phase: relationships with luteinizing hormone And progesterone. Clin Endocrinol (Oxf) 33:709-717.

138.

Nóbrega

LHC

Azevedo

Lima

Ferriani

Spritzer

Sá

MFS

Maranhão

TMO

(2009) Analysis of testosterone pulsatility in women with ovulatory menstrual cycles. Arq Bras Endocrinol Metabol 53:1040-1046.

139.

Nordéus

Båge

Gustafsson

Söderquist

(2012) Changes in LH pulsatility profiles in dairy heifers during exposure to oestrous urine and vaginal mucus. Reprod Domest Anim Zuchthyg 47:952-958.

140.

Okauchi

Takahashi

Mizobuchi

Bando

Saito

(1996) Thyrotropin-releasing hormone release in normal and hyperthyroid rats as measured by microdialysis. Tokushima J Exp Med 43:93-100.

141.

Ono

Honma

(2015) Circadian and ultradian rhythms of clock gene expression in the suprachiasmatic nucleus of freely moving mice. Sci Rep 5:12310.

142.

Otukonyong

Dube

Torto

Kalra

(2005) Central leptin differentially modulates ultradian secretory patterns of insulin, leptin and ghrelin independent of effects on food intake and body weight. Peptides 26:2559-2566.

143.

Phelps

Kalra

(1992) In vivo pulsatile LHRH release into the anterior pituitary of the male rat: effects of castration. Brain Res 569:159-163.

144.

Pigrau

Rodiño-Janeiro

Casado-Bedmar

Lobo

Vicario

Santos

Alonso-Cotoner

(2016) The joint power of sex and stress to modulate brain-gut-microbiota axis and intestinal barrier homeostasis: implications for irritable bowel syndrome. Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc 28:463-486.

145.

Pincus

Padmanabhan

Lemon

Randolph

Rees Midgley

(1998) Follicle-stimulating hormone is secreted more irregularly than luteinizing hormone in both humans and sheep. J Clin Invest 101:1318-1324.

146.

Plat

Byrne

Sturis

Polonsky

Mockel

Féry

Van Cauter

(1996) Effects of morning cortisol elevation on insulin secretion and glucose regulation in humans. Am J Physiol 270:E36-E42.

147.

Poher

A-L

Tschöp

Müller

(2018) Ghrelin regulation of glucose metabolism. Peptides 100:236–242.

148.

Polonsky

Given

Van Cauter

(1988) Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest 81:442-448.

149.

Prendergast

Zucker

(2016) Ultradian rhythms in mammalian physiology and behavior. Curr Opin Neurobiol Syst Neurosci 40:150-154.

150.

Prendiville

Enright

Crowe

Finnerty

Roche

(1996) Normal or induced secretory patterns of luteinising hormone and follicle-stimulating hormone in anoestrous gonadotrophin-releasing hormone-immunized and cyclic control heifers. Anim Reprod Sci 45:177-190.

151.

Quatela

Callister

Patterson

MacDonald-Wicks

(2016) The energy content and composition of meals consumed after an overnight fast and their effects on diet induced thermogenesis: a systematic review, meta-analyses and meta-regressions. Nutrients 8.

152.

Ramirez

Pickle

Lin

(1991) In vivo models for the study of gonadotropin and LHRH secretion. J Steroid Biochem Mol Biol 40:143-154.

153.

Ramos

EJB

Meguid

Campos

ACL

Coelho

JCU

(2005) Neuropeptide Y, alpha-melanocyte-stimulating hormone, and monoamines in food intake regulation. Nutr 21:269-279.

154.

Rance

Dacks

Mittelman-Smith

Romanovsky

Krajewski-Hall

(2013) Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes. Front Neuroendocrinol 34:211-227.

155.

Reid

Baron

Zee

(2014) Meal timing influences daily caloric intake in healthy adults. Nutr Res N Y N 34:930-935.

156.

Roelfsema

Pijl

Kok

Endert

Fliers

Biermasz

Pereira

Veldhuis

(2014) Thyrotropin secretion in healthy subjects is robust and independent of age and gender, and only weakly dependent on body mass index. J Clin Endocrinol Metab 99:570-578.

157.

Romijn

Adriaanse

Brabant

Prank

Endert

Wiersinga

(1990) Pulsatile secretion of thyrotropin during fasting: a decrease of thyrotropin pulse amplitude. J Clin Endocrinol Metab 70:1631-1636.

158.

Rookh

Azukizawa

Distefano

Ogihara

Hershman

(1979) Pituitary-thyroid hormone periodicities in serially sampled plasma of unanesthetized rats. Endocrinology 104:851-856.

159.

Rossmanith

Laughlin

Mortola

Johnson

Veldhuis

Yen

SSC

(1990a) Pulsatile cosecretion of estradiol and progesterone by the midluteal phase corpus luteum: temporal link to luteinizing hormone pulses. J Clin Endocrinol Metab 70:990-995.

160.

Rossmanith

Liu

Laughlin

Mortola

Suh

Yen

(1990b) Relative changes in LH pulsatility during the menstrual cycle: using data from hypogonadal women as a reference point. Clin Endocrinol (Oxf) 32:647-660.

161.

Rossmanith

Yen

(1987) Sleep-associated decrease in luteinizing hormone pulse frequency during the early follicular phase of the menstrual cycle: evidence for an opiodergic mechanism. J Clin Endocrinol Metab 65:715-718.

162.

Rozhavskaya-Arena

Lee

Leinung

Grasso

(2000) Design of a synthetic leptin agonist: effects on energy balance, glucose homeostasis, and thermoregulation. Endocrinology 141:2501-2507.

163.

Ruis

Rietveld

Buys

(1987) Effects of suprachiasmatic nuclei lesions on circadian and ultradian rhythms in body temperature in ocular enucleated rats. J Interdiscip Cycle Res 18:259-273.

164.

Ruis

Talamini

Buys

Rietveld

(1989) Effects of time of feeding on recovery of food-entrained rhythms during subsequent fasting in SCN-lesioned rats. Physiol Behav 46:857-866.

165.

Russell

Harrison

Smith

Darzy

Shalet

Weetman

Ross

(2008) Free triiodothyronine has a distinct circadian rhythm that is delayed but parallels thyrotropin levels. J Clin Endocrinol Metab 93:2300-2306.

166.

Saad

Riad-Gabriel

Khan

Sharma

Michael

Jinagouda

Boyadjian

Steil

(1998) Diurnal and ultradian rhythmicity of plasma leptin: effects of gender and adiposity. J Clin Endocrinol Metab 83:453-459.

167.

Samuels

Henry

Luther

Ridgway

(1993) Pulsatile TSH secretion during 48-hour continuous TRH infusions. Thyroid 3:201-206.

168.

Sanchez-Alavez

Tabarean

Osborn

Mitsukawa

Schaefer

Dubins

Holmberg

Klein

Klaus

Gomez

et al . (2010) Insulin causes hyperthermia by direct inhibition of warm-sensitive neurons. Diabetes 59:43-50.

169.

Schaefer

Simon

Viola

Piquard

Geny

Brandenberger

(2003) l-Arginine: an ultradian-regulated substrate coupled with insulin oscillations in healthy volunteers. Diabetes Care 26:168-171.

170.

Scheen

Sturis

Polonsky

Van Cauter

(1996) Alterations in the ultradian oscillations of insulin secretion and plasma glucose in aging. Diabetologia 39:564-572.

171.

Shapiro

Tillil

Polonsky

Fang

Rubenstein

Van Cauter

(1988) Oscillations in insulin secretion during constant glucose infusion in normal man: relationship to changes in plasma glucose. J Clin Endocrinol Metab 67:307-314.

172.

Simon

Brandenberger

(2002) Ultradian oscillations of insulin secretion in humans. Diabetes 51:S258-S261.

173.

Simon

Brandenberger

Follenius

(1987) Ultradian oscillations of plasma glucose, insulin, and C-peptide in man during continuous enteral nutrition. J Clin Endocrinol Metab 64:669-674.

174.

Simon

Gronfier

Schlienger

Brandenberger

(1998) Circadian and ultradian variations of leptin in normal man under continuous enteral nutrition: relationship to sleep and body temperature. J Clin Endocrinol Metab 83:1893-1899.

175.

Sinha

Sturis

Ohannesian

Magosin

Stephens

Heiman

Polonsky

Caro

(1996) Ultradian oscillations of leptin secretion in humans. Biochem Biophys Res Commun 228:733-738.

176.

Sirakov

Plateroti

(2011) The thyroid hormones and their nuclear receptors in the gut: from developmental biology to cancer. Biochim Biophys Acta 1812:938-946.

177.

Sisk

Desjardins

(1986) Pulsatile release of luteinizing hormone and testosterone in male ferrets. Endocrinology 119:1195-1203.

178.

Skarke

Lahens

Rhoades

Campbell

Bittinger

Bailey

Hoffmann

Olson

Chen

Yang

et al . (2017) A pilot characterization of the human chronobiome. Sci Rep 7:17141.

179.

Smarr

Burnett

Mesri

Pister

KSJ

Kriegsfeld

(2016a) A wearable sensor system with circadian rhythm stability estimation for prototyping biomedical studies. IEEE Trans Affect Comput 7:220-230.

180.

Smarr

Grant

Zucker

Prendergast

Kriegsfeld

(2017) Sex differences in variability across timescales in BALB/c mice. Biol Sex Differ 8:7.

181.

Smarr

Morris

de la Iglesia

(2012) The dorsomedial suprachiasmatic nucleus times circadian expression of Kiss1 and the luteinizing hormone surge. Endocrinology 153:2839-2850.

182.

Smarr

Zucker

Kriegsfeld

(2016b) Detection of successful and unsuccessful pregnancies in mice within hours of pairing through frequency analysis of high temporal resolution core body temperature data. PloS One 11:e0160127.

183.

Smolander

Leppäluoto

Westerlund

Oksa

Dugue

Mikkelsson

Ruokonen

(2009) Effects of repeated whole-body cold exposures on serum concentrations of growth hormone, thyrotropin, prolactin and thyroid hormones in healthy women. Cryobiology 58:275-278.

184.

Soules

Clifton

Cohen

Bremner

Steiner

(1989) Luteal phase deficiency: abnormal gonadotropin and progesterone secretion patterns. J Clin Endocrinol Metab 69:813-820.

185.

Soules

Clifton

Steiner

Cohen

Bremner

(1988) The corpus luteum: determinants of progesterone secretion in the normal menstrual cycle. Obstet Gynecol 71:659-666.

186.

Soumano

Desbiens

Rabelo

Bakopanos

Camirand

Silva

(2000) Glucocorticoids inhibit the transcriptional response of the uncoupling protein-1 gene to adrenergic stimulation in a brown adipose cell line. Mol Cell Endocrinol 165:7-15.

187.

Spencer

Deak

(2017) A users guide to HPA axis research. Physiol Behav 178:43-65.

188.

Spiga

Waite

Liu

Kershaw

Aguilera

Lightman

(2011) ACTH-dependent rhythm of coricosterone secretion. Endocrinology 152(4):1448-1457.

189.

Spiga

Walker

Terry

Lightman

(2014) HPA axis-rhythms. Compr Physiol 4:1273-1298.

190.

Spratt

O’Dea

Schoenfeld

Butler

Rao

Crowley

(1988) Neuroendocrine-gonadal axis in men: frequent sampling of LH, FSH, and testosterone. Am J Physiol Endocrinol Metab 254:E658-E666.

191.

Steiner

Bremner

Clifton

(1982) Regulation of luteinizing hormone pulse frequency and amplitude by testosterone in the adult male rat. Endocrinology 111:2055-2061.

192.

Stewart

Stevenson

Minton

(1994) Serum hormones during the estrous cycle and estrous behavior in heifers after administration of propylthiouracil and thyroxine. Domest Anim Endocrinol 11:1-12.

193.

Stoleru

Peng

Agosto

Rosbash

(2004) Coupled oscillators control morning and evening locomotor behaviour of Drosophila. Nature 431:862-868.

194.

Strack

Bradbury

Dallman

(1995) Corticosterone decreases nonshivering thermogenesis and increases lipid storage in brown adipose tissue. Am J Physiol 268:R183-R191.

195.

Sturis

Polonsky

Shapiro

Blackman

O’Meara

van Cauter

(1992) Abnormalities in the ultradian oscillations of insulin secretion and glucose levels in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 35:681-689.

196.

Tan

Alwan

Kossan

Cody

Taylor

(2015) Dynamic time warping and sparse representation classification for birdsong phrase classification using limited training data. J Acoust Soc Am 137:1069-1080.

197.

Tani

Inaba

Nonami

Matsuyama

Takamori

Torii

Tamada

Kawate

Sawada

(1999) Increased lh pulse frequency and estrogen secretion associated with termination of anestrus followed by enhancement of uterine estrogen receptor gene expression in the beagle bitch. Theriogenology 52:593-607.

198.

Tannenbaum

Epelbaum

Bowers

(2003) Interrelationship between the novel peptide ghrelin and somatostatin/growth hormone-releasing hormone in regulation of pulsatile growth hormone secretion. Endocrinology 144:967-974.

199.

Tannenbaum

Ling

(1984) The interrelationship of growth hormone (GH)-releasing factor and somatostatin in generation of the ultradian rhythm of GH secretion. Endocrinology 115:1952-1957.

200.

Tannenbaum

Martin

(1976) Evidence for an endogenous ultradian rhythm governing growth hormone secretion in the rat. Endocrinology 98:562-570.

201.

Tena-Sempere

(2013) Interaction between energy homeostasis and reproduction: central effects of leptin and ghrelin on the reproductive axis. Horm Metab Res Horm Stoffwechselforschung Horm Metab 45:919-927.

202.

Thaela

Jensen

Cornélissen

Halberg

Nöddegaard

Jakobsen

Pierzynowski

(1998) Circadian and ultradian variation in pancreatic secretion of meal-fed pigs after weaning. J Anim Sci 76:1131-1139.

203.

Tolle

Bassant

M-H

Zizzari

Poindessous-Jazat

Tomasetto

Epelbaum

Bluet-Pajot

M-T

(2002) Ultradian rhythmicity of ghrelin secretion in relation with GH, feeding behavior, and sleep-wake patterns in rats. Endocrinology 143:1353-1361.

204.

Uchida

Tominaga

(2011) The role of thermosensitive TRP (transient receptor potential) channels in insulin secretion. Endocr J 58:1021-1028.

205.

Urban

Evans

Rogol

Kaiser

Johnson

Veldhuis

(1988) Contemporary aspects of discrete peak-detection algorithms. I. The paradigm of the luteinizing hormone pulse signal in men. Endocr Rev 9:3-37.

206.

van den Beukel

Grefhorst

(2014) Interactions between the gut, the brain and brown adipose tissue function. Front Horm Res 42:107-122.

207.

van den Beukel

Grefhorst

Quarta

Steenbergen

Mastroberardino

Lombès

Delhanty

Mazza

Pagotto

van der Lely

et al . (2014) Direct activating effects of adrenocorticotropic hormone (ACTH) on brown adipose tissue are attenuated by corticosterone. FASEB J 28:4857-4867.

208.

van Leckwyck

Kong

Burton

Amati

Vionnet

Pralong

(2016) Decreasing insulin sensitivity in women induces alterations in LH pulsatility. J Clin Endocrinol Metab 101:3240-3249.

209.

Veldhuis

Christiansen

Evans

Kolp

Rogol

Johnson

(1988) Physiological profiles of episodic progesterone release during the midluteal phase of the human menstrual cycle: analysis of circadian and ultradian rhythms, discrete pulse properties, and correlations with simultaneous luteinizing hormone release. J Clin Endocrinol Metab 66:414-421.

210.

Veldhuis

Johnson

(1988) Operating characteristics of the hypothalamo-pituitary-gonadal axis in men: circadian, ultradian and pulsatile release of prolactin and temporal coupling with luteinizing hormone. J Clin Endocrinol Metab 67:116-123.

211.

Veldhuis

Iranmanesh

Johnson

Lizarralde

(1990) Twenty-four-hour rhythms in plasma concentrations of adenohypophyseal hormones are generated by distinct amplitude and/or frequency modulation of underlying pituitary secretory bursts. J Clin Endocrinol Metab 71:1616-1623.

212.

Veldhuis

Johnson

Seneta

(1991) Analysis of the copulsatility of anterior pituitary hormones. J Clin Endocrinol Metab 73:569-576.

213.

Veldhuis

Keenen

Pincus

(2008) Motivations and methods for analyzing pulsatile hormone secretion. Endocr Rev 7:8230864.

214.

Venturoli

Porcu

Fabbri

Magrini

Gammi

Paradisi

Forcacci

Bolzani

Flamigni

(1988) Episodic pulsatile secretion of FSH, LH, prolactin, oestradiol, oestrone, and LH circadian variations in polycystic ovary syndrome. Clin Endocrinol (Oxf) 28:93-107.

215.

Viengchareun

Penfornis

Zennaro

Lombès

(2001) Mineralocorticoid and glucocorticoid receptors inhibit UCP expression and function in brown adipocytes. Am J Physiol Endocrinol Metab 280:E640-E649.

216.

Vrang

Larsen

Mikkelsen

(1995) Direct projection from the suprachiasmatic nucleus to hypophysiotrophic corticotropin-releasing factor immunoreactive cells in the paraventricular nucleus of the hypothalamus demonstrated by means of Phaseolus vulgaris-leucoagglutinin tract tracing. Brain Res 684:61-69.

217.

Vugt

Lam

Ferin

(1984) Reduced frequency of pulsatile luteinizing hormone secretion in the luteal phase of the rhesus monkey: involvement of endogenous opiates. Endocrinology 115:1095-1101.

218.

Wagner

Caplan

Tannenbaum

(2009) Interactions of ghrelin signaling pathways with the GH neuroendocrine axis: a new and experimentally tested model. J Mol Endocrinol 43:105-119.

219.

Wagner

Caplan

Tannenbaum

(1998) Genesis of the ultradian rhythm of GH secretion: a new model unifying experimental observations in rats. Am J Physiol 275:E1046-E1054.

220.

Waite

McKenna

Kershaw

Walker

Cho

Piggins

Lightman

(2012) Ultradian corticosterone secretion is maintained in the absence of circadian cues. Eur J Neurosci 36:3142-3150.

221.

Watanabe

Tomiyama-Miyaji

Kainuma

Inoue

Kuwano

Ren

Shen

Abo

(2008) Role of alpha-adrenergic stimulus in stress-induced modulation of body temperature, blood glucose and innate immunity. Immunol Lett 115:43-49.

222.

Watts

(2005) Glucocorticoid regulation of peptide genes in neuroendocrine CRH neurons: a complexity beyond negative feedback. Front Neuroendocrinol 26:109-130.

223.

Williams

Dacks

Rance

(2010) An improved method for recording tail skin temperature in the rat reveals changes during the estrous cycle and effects of ovarian steroids. Endocrinology 151:5389-5394.

224.

Winters

Troen

(1986) Testosterone and estradiol are co-secreted episodically by the human testis. J Clin Invest 78:870-873.

225.

Butler

Kelnar

Huhtaniemi

Veldhuis

(1996) Ontogeny of pulsatile gonadotropin releasing hormone secretion from midchildhood, through puberty, to adulthood in the human male: a study using deconvolution analysis and an ultrasensitive immunofluorometric assay. J Clin Endocrinol Metab 81:1798-1805.

226.

Yen

SSC

Tsai

Naftolin

Vandenberg

Ajabor

(1972) Pulsatile patterns of gonadotropin release in subjects with and without ovarian function. J Clin Endocrinol Metab 34:671-675.

227.

Yonezawa

Mogi

Sako

Manabe

Yamanouchi

Nishihara

(2010) Negative correlation between neuropeptide Y profile in the cerebrospinal fluid and growth hormone pulses in the peripheral circulation in goats. Neuroendocrinology 91:308-317.

228.

Yoon

J-A

Han

D-H

Noh

J-Y

Kim

M-H

Son

Kim

C-J

Pak

Cho

(2012) Meal time shift disturbs circadian rhythmicity along with metabolic and behavioral alterations in mice. PloS One 7:e44053.

229.

Zheng

Ariga

Taniguchi

Ludwig

Takahashi

(2009) Ghrelin regulates gastric phase III-like contractions in freely moving conscious mice. Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc 21:78-84.

Evidence for a Coupled Oscillator Model of Endocrine Ultradian Rhythms

Abstract

Keywords

Overview and Implications of a Coupled Oscillator Network Model of URs

URs and Coupling Within Endocrine Axes

URs and Coupling within the GBA

URs and Coupling within the HPT Axis

URs and Coupling within the HPA Axis

URs and Coupling within the HPG Axis

URs and Coupling Across Endocrine Axes

Implications of Ultradian Coupled Oscillator Network Properties for Research and Clinical Applications: A Case for Body Temperature

HPT Axis and GBA Influence Core Body Temperature

HPA Axis Influences CBT

HPG Axis Influences CBT

Discussion

Considerations and Caveats

UR Parameters: Maintenance of Fundamental Frequency and Harmonics

Active Decoupling and Recovery

Network-wide Predictions

Past and Present Challenges to Collecting and Analyzing UR Data

Conclusion and Implications: Building Personalized Medicine Through Modeling and Wearable Devices

Footnotes

Acknowledgements

Conflict of Interest Statement

References