The Hypothalamic Pituitary Thyroid Axis and Sleep

Abstract

Sleep has a bidirectional relationship with the hypothalamic-pituitary-thyroid (HPT) axis, and both these homeostatic processes are inter-dependent for robust physiological functioning. The quality and quantity of sleep influence the circadian pattern of TSH and thyroid hormone secretion. Short term sleep restriction significantly reduces the amplitude of nocturnal TSH secretion and may modulate active thyroid hormone secretion, likely through an increased sympathetic tone. Conversely, TSH and active thyroid hormone affect the quantity and architecture of sleep. For instance, low TSH values are permissive for slow wave sleep and maintenance of normal sleep architecture, while the hypo- or hyper-secretion of active thyroid hormones adversely affects the quality and quantity of sleep. Structural thyroid disorders may also be associated with an altered circadian clock – a phenomenon warranting further investigation. In this review, we aim to provide readers a comprehensive review on the associations between the HPT axis and sleep patterns.

Introduction

Sleep has a bidirectional relationship with the endocrine system and is a subject of intense interest from both a clinical and a research standpoint.[1] Sleep occurs in at least some form in all animals. While the purpose of sleep remains poorly understood, it is vital for a broad spectrum of critical physiological functions. [2, 3] It is well established that hormones and sleep are highly interdependent in normal physiological functioning. [4] Furthermore, nearly all hormones have a 24-hour rhythm, which is modified by sleep to varying degrees. Thyroid stimulating hormone (TSH) in particular is strongly influenced by sleep and in turn impact the quality and duration of sleep. [5, 6] The interplay between the hypothalamic-pituitary-thyroid (HPT) axis and the sleep cycle regulates energy and metabolic processes, and a disruption in either leads to dysregulation of the other. Hence, there is value in delineating the mechanism and consequences of this interdependence of sleep and the HPT axis. In this review, we discuss the physiology of sleep, the HPT axis and their relationship with each other. We briefly describe the physiology of the HPT axis, summarize sleep physiology and describe their mutual interaction. Subsequently, we discuss the impact of sleep alteration on the HPT axis and that of thyroid disorders on sleep. Finally, we reflect on a possible link between structural thyroid disorders and sleep.

Hypothalamic-Pituitary Thyroid Axis Physiology

The hypothalamic-pituitary-thyroid axis refers to the hormone feedback pathway that begins with the secretion of thyrotropin releasing hormone (TRH) and culminates with the secretion of thyroid hormones. TRH is secreted by the median eminence that receives afferents from multiple neuroendocrine pathways such the suprachiasmatic nucleus (SCN) and pineal body (PB) (described below) and enters the hypothalamic-hypophyseal portal system. [7] (Figure 1) Notably, both SCN and PB are regulated by and influence the circadian clock, based, in part, on photic and sleep related cues. After secretion from the hypothalamus, TRH acts on thyrotropes present in the anterior pituitary gland and stimulates the secretion of TSH. [7] Distally, TSH triggers the synthesis and secretion of the thyroid hormones (TH)— tetraiodothyronine (thyroxine, T4) and triiodothyronine (T3) from the thyroid gland.[8] The downstream secretion of T4 and biologically active T3 regulate the upstream secretion of TRH and TSH through long and short negative feedback loops, respectively, leading to maintenance of euthyroid status in healthy individuals. (Figure 1)

Figure 1:

Control of thyroid hormone secretion. Abbreviations- SCN: Suprachiasmatic Nucleus; PB: Pineal Body; TRH: thyrotropin releasing hormone; TSH: thyroid stimulating hormone.

Sleep Stages and Architecture

Human sleep is both an objective and subjective experiential phenomenon and is divided into different stages [4, 9] consisting of rapid eye movement (REM) and non-rapid eye movement (NREM) periods. [10] NREM stage is further subclassified into N1, N2, N3 based on electroencephalographic (EEG) criteria and depth of sleep. [11] Individuals go through several distinct 90–120 minute sleep cycles (~ 4–5 cycles/night in a young adult) through the course of the night.[9, 12, 13] Every cycle goes in the following order N1, N2, N3 and REM with every successive cycle having a higher percentage of the REM stage.[13]

The Circadian Clock, Sleep and Thyroid Hormone Secretion

Circadian clocks are internal timekeeping mechanisms that regulate many physiological functions in mammals, including humans.[7] These endogenous clocks, integrated at the level of the suprachiasmatic nucleus and the pineal body, create and maintain oscillations over a 24-hour period, generating a ‘circadian rhythm’. This intrinsic circadian rhythm has bidirectional relationships with the sleep-wake cycles and hormone secretion patterns. (Figure 1) The transcriptomics of circadian genes influence the expression of other genes such as those of hormone secretion, in a time-dependent fashion.[14–16] This oscillatory pattern allows for the rapid responses to the environment that are required for maintenance of multiple physiological functions including hormonal axes such as those related to reproduction, stress and metabolism. [17, 18]

Thyroid hormone secretion has a distinct daily rhythm and is controlled, in part, by the circadian clock. [19, 20] TSH levels exhibit a circadian (day/night) pattern in which the lowest levels of TSH are seen between 1500 h and 1900 h, and the highest levels of TSH between 2200 h and 0500 h (~50% rise) as noted in one study. [21] In the same study, free T3 and T4 levels did not demonstrate clear circadian pattern. [21] In contrast, a nocturnal rise in thyroid hormones was reported by Weeke et al in a constant routine study performed under standard photic exposure and revealed free T3 rise by ~15% and free T4 rise by~11%), suggesting a circadian pattern of thyroid hormone secretion. [19] Harrison et al. also reported a distinct circadian rhythm for TSH and free T3, that peaked 90 minutes after TSH, in 86–100% of subjects. [22] A lower proportion of study subjects demonstrated rhythmicity in free T4 levels (76%), and free T4 lacked a clear relationship with TSH levels suggesting that variation in free T4 is not universally present. [22] There is also an evidence that thyroid hormone secretion is influenced by sleep, such that sleep decreases the amplitude of the circadian rhythm of TSH and downstream thyroid hormone levels.[23] It has been suggested that lower TSH (and TH) is permissive for slow wave sleep (SWS) and maintenance of normal sleep architecture. [24, 25] Sleep quality and architecture also influence TSH secretion, with the association of decreased SWS with an increased amplitude of TSH secretion. [26] In the same way, TSH values have been negatively correlated with SWS and slow wave activity. [27] Furthermore, recovery sleep (subsequent to sleep restriction) was shown to suppress TSH to a greater extent than normal sleep, demonstrating the distinct influence of sleep on TSH secretion. [28]

While the influence of TH levels on the sleep-wake cycle is less well defined, there is a clear effect of circulating TH levels on sleep such that high TH levels are associated with shortened sleep. It is proposed that increased T4 as a consequence of sleep deprivation is an adaptive physiological response that helps maintain wakefulness. [29] This hypothesis is further strengthened by the observation from one study that levothyroxine supplementation in euthyroid subjects with idiopathic hypersomnia leads to improved day and nighttime sleep-related symptoms. [29, 30] The authors concluded that patients who responded to levothyroxine (a synthetic oral thyroxine preparation) might have underlying subclinical hypothyroidism. [30]

Mechanistically, TH upregulates mitochondrial number and function, through TH receptors on central and peripheral neuronal mitochondrial membranes. [31, 32] In turn, mitochondria are the sites of adenosine triphosphate (ATP) production via the electron transport chain. Neurons rely on this ATP to fuel neurotransmitter secretion and action and maintain wakefulness. [33] It is believed that in states of non-physiological wakefulness such as sleep deprivation, the heightened demand for neuronal ATP is met by an acute increase in circulating TH. [29] ATP may have an independent role as an excitatory neurotransmitter which may provide a direct pathway for the interplay between TH and sleep. [34, 35] Another mechanism through which TH may influence sleep is by dynamic changes in the balance of TH and dopamine in hypothalamic nuclei. Dopamine (DA), a neurotransmitter-hormone that is secreted by the arcuate nucleus of the hypothalamus, promotes sleep.[36] In contrast, TH promotes wakefulness and is dependent on input from the circadian clock.[37]

It is well known that DA inhibits prolactin, TSH and thyroid hormone secretion, while thyrotropin releasing hormone increases the secretion of these hormones.(Figure 1) [37] A hypothalamic imbalance in favor of neuroexcitatory thyroid hormones over neuroinhibitory DA secretion has been proposed to be causative in the pathophysiology of restless leg syndrome. [37]

Sleep Alteration and its Impact on Thyroid Hormone Secretion

Studies suggest that the effect of alterations in sleep on the HPT axis is dependent on the duration of sleep restriction. Spiegel et al. studied 11 young men after six nights of restricted sleep (4 hours/night) and noted an attenuated nocturnal rise in TSH and lower 24 hour mean TSH secretion that was reversed when the study subjects entered the sleep recovery phase of the study (12 hours/night). [38] Interestingly, restricted sleep led to an exaggerated nocturnal rise in free T4 levels which may be the proximate cause of the decline in TSH associated with restricted sleep. [38, 39] In another seminal study of circadian rhythm and thyroid hormone secretion, Van Cauter et al. studied 17 men and observed a fifty percent decline in the nocturnal TSH rise after less than a day of sleep deprivation. [39] Increased photic stimulation did not produce the same effect on nocturnal TSH in their study, suggesting that sleep deprivation, independent of other circadian cues, influences HPT axis activity. [39] It is proposed that sleep deprivation is a state of acute physiological stress and that the resultant increase in the sympathetic drive directly enhances TH secretion, independent of TSH. [29, 39]

Furthermore, there is an overall decrease in TSH secretion in association with acute sleep deprivation. [26, 38] This decrease in TSH may be mediated by an increase in circulating T4 levels associated with a sleep deficit, triggered by an heightened sympathetic drive, that may acutely suppress TSH secretion. [26](Figure 2)

Figure 2:

The effect of acute sleep restriction on the diurnal variation thyroid stimulating hormone (TSH) and thyroid hormone. Disclaimer: This graph is largely derived from the work of Spiegel et al. and Van Cauter et al. (References 38 and 39) and is merely an abstraction of published reports and is not based on authors’ primary data.

The duration of sleep restriction may determine the pattern of TH secretion as contrary to previous studies, Kessler et al. reported a modest decline in both TSH and free T4 after two weeks of recurrent restricted compared to unrestricted sleep (5.5 vs. 8.5 hours/night).[40] In this study, prolonged sleep restriction resulted in decreased TSH and TH in women but not in men, suggesting sex differences in the influence of sleep on HPT axis activity. Reduced TH in response to long term sleep restriction may reflect a defensive adaptation against a catabolic state to maintain the metabolic demands by the brain. In contrast, shorter terms of sleep deprivation may lead to increased thyroid hormones to maintain wakefulness in states of acute stress. (Figure 2)

The Effects of Thyroid Disorders on Sleep

Hypothyroidism

Hypothyroidism is defined as a state of inadequate circulating thyroid hormone levels and is primarily due to autoimmune destruction or surgical removal of the thyroid gland (primary hypothyroidism) or, rarely, of insufficient production of TSH by the pituitary (central hypothyroidism). [41] In a study of 30 hypothyroid patients there was an increase in sleep stages N1 and N2 and a corresponding decline in N3 and REM compared to controls, without a change in total sleep duration, suggestive of poor sleep quality. [25] An increase in the number of awakenings and reduced SWS have also been reported in hypothyroidism which may be related to the direct actions of TH, TSH and TRH on sleep centers. [42–44] (Table 1) Sleep disturbance due to inadequate TH may be an additional contributor to the fatigue and lethargy frequently seen in hypothyroid patients.

Table 1:

Effects of hypothyroidism and hyperthyroidism on objective measures of sleep

	Hypothyroidism	Hyperthyroidism
NREM 1	↑	↔
NREM 2	↑	↔
NREM 3	↓	↓
REM	↔	↔
Total Sleep Duration	↔	↓
Sleep Efficiency	↔	↓
Sleep latency	↔	↑

NREM: Non-Rapid Eye Movement Sleep; REM: Rapid-Eye Movement Sleep. All comparisons of sleep measures in the table are with respect to a euthyroid state

Hypothyroidism may also affect sleep by triggering or exacerbating pre-existing obstructive sleep apnea (OSA). Patients with hypothyroidism have a higher prevalence of OSA compared to the general population.[45] Furthermore, a meta-analysis of seventeen studies found that adverse markers of OSA such as Apnea–Hypopnea Index, time of sleep with oxygen saturation <90% and Epworth Sleepiness Scale were higher in hypothyroid compared to euthyroid patients with established OSA. [45] Mechanisms linking hypothyroidism to OSA may include blunted responsiveness to hypercapnia and hypoxia, airway resistance due to mucoprotein deposition in the airways, increased BMI and altered respiratory muscle activity. [46]

Hyperthyroidism

Hyperthyroidism is defined as a state of excess circulating thyroid hormone and may be due to immunoglobulin mediated overstimulation or destruction of the thyroid gland, autonomic functional thyroid nodules, excess intake of TH, or rarely, excess TSH secretion by a pituitary tumor. [47, 48] Sleep disruption is a hallmark and a common presenting complaint in patients with hyperthyroidism due to increase TH synthesis or thyrotoxicosis due to release of supraphysiologic amounts of TH in a course of destructive/inflammatory process affecting the thyroid gland. [49, 50] In one of the initial studies, Passouant et al. reported an increase in sleep latency and a reduction in total sleep time and SWS in eight patients with clinical hyperthyroidism. [51]In another clinical case study of a hyperthyroid patient, Kronfol et al. confirmed a decline in sleep efficiency, duration and SWS, [52] although this finding has not been universal. [53] In a recent study of 13 subjects with exogenously induced thyrotoxicosis, Kraemer and colleagues failed to observe a significant effect of exogenous thyrotoxicosis on polysomnographic sleep architecture despite noting an increased density of REM and increased body movements. [49] Similarly in a retrospective observational study subjective measures of sleep were not different in overt hyperthyroidism compared with euthyroid controls.[54] Both these studies had significant methodological limitations. The first study induced thyrotoxicosis with supraphysiologic doses of levothyroxine, thus may not reflect the exact effects of endogenous hyperthyroidism on sleep. Moreover, the number of subjects in the first study were few (n=13) and the duration of iatrogenic thyrotoxicosis was only eight weeks, that maybe lower than the duration of complaints in patients coming to clinical attention for hyperthyroidism. [49] Their results contradicting previous reports were acknowledged by authors of both studies. [49, 54] In another recent report, Sridhar et al. observed that thyrotoxic patients primarily suffer from significantly increased sleep latency and referred to hyperkinetic disorders (tremors, bowel dysfunction and altered appetite) being intermediary in the effect of hyperthyroidism on sleep. [55] This was consistent with previous studies reporting sleep disruption in endogenous hyperthyroidism.

In summary, hyperthyroidism negatively impacts sleep and may reduce the efficiency and duration of sleep and increase latency through peripheral effects of TH. (Table 1) However, future studies are warranted to firmly establish the nature of sleep disruption in hyperthyroidism.

Thyroid nodules and thyroid cancer

Thyroid nodules are discrete masses within the thyroid parenchyma that may represent an abnormal proliferation of thyrocytes. A majority of thyroid nodules are benign, but about 5% on average may harbor thyroid cancer.[56] Notably, no direct link between structural thyroid disorders and sleep has been demonstrated to date, but it is widely speculated that there is an alteration in the circadian pattern of gene expression within the thyroid parenchyma. [57] This alteration of circadian gene expression has been previously demonstrated in a large number of cancers including leukemia, breast, endometrial, colorectal, lung, ovarian, pancreatic and prostate as well as other endocrine cancers. [58–60] Altered circadian genomics has been an area of active scientific interest, both from a carcinogenesis and a possible therapeutic perspective. [60] A deeper understanding of circadian clock dynamics in thyroid malignancies may facilitate the earlier molecular diagnosis of thyroid malignancies, while also providing insights into the effects of thyroid cancer on sleep. [56]

Conclusion

Sleep and the hypothalamic pituitary thyroid axis are closely interlinked in humans and are integrated at the level of the hypothalamic centers involved in the circadian clock. A deeper understanding of their mutual effects may provide credible insights into human adaptive behaviors and evolution. Moreover, the inter-relationships between the HPT axis and sleep architecture are important considerations in management of patients with thyroid and sleep disorders.

Supplementary Material

Supplement 1. Annotated bibliography of papers of special interest cited in this review.

Supplement 1: Annotated Bibliography

Highlights.

• Sleep and the hypothalamic pituitary thyroid (HPT) axis influence each other through the circadian clock.

• Sleep restriction attenuates the nocturnal rise and mean secretion of thyroid-stimulating hormone.

• Hypothyroidism results in poor sleep quality and architecture.

• Hyperthyroidism prolongs sleep latency, and reduces sleep efficiency and duration.

• HPT axis and sleep interdependence should be factored in the care of affected patients