Corticotropin-releasing hormone (CRH) is secreted by a hypothalamic region called the paraventricular nucleus (PVN) and acts on CRH receptors in the anterior pituitary to cause the release of adrenocorticotropic hormone (ACTH) into the blood. ACTH acts on the adrenal cortex, which produces and releases cortisol into the blood and participates in maintaining homeostasis throughout the body. CRH also activates the locus ceruleus (LC) which utilizes norepinephrine (NE) and causes further stimulation of the PVN and subsequent release of CRH. It also stimulates the amygdala, which is part of the limbic system.1,2 Elevated brain NE levels and CRH have been implicated in sleep disturbances, including primary insomnia.3,4 NE levels have also been shown to directly correlate to CRH levels, whereby elevated NE results in elevated CRH and low NE results in low CRH.5,6

Along with its numerous actions in the body, cortisol has feedback inhibition on the PVN and anterior pituitary to decrease CRH and ACTH production and release, respectively. Many areas of the brainstem, including the LC, are rich in cortisol receptors, indicating additional negative feedback mechanisms mediated by the cortisol- HPA axis.7,8 Furthermore, the PVN receives GABAergic innervations, which can also inhibit the release of CRH.9 These GABAergic neurons are chiefly opposed by the excitatory neurotransmitter glutamate.7 Therefore, in addition to negative feedback signaling by cortisol, HPA axis regulation also includes NE, GABA, and glutamate modulation.

Normal Sleep Physiology

Normal sleep architecture is characterized by cycles of light sleep, deeper slow-wave sleep, and REM sleep. Light sleep includes stages 1 and stages 2 in the sleep cycle. Stage 1 sleep, the beginning of the sleep cycle, is considered a transition period between wakefulness and sleep. This period of sleep lasts only 5-10 minutes and is characterized by mixed frequency theta waves (very slow brain waves); slow, rolling eye movements; and slightly reduced eye movement and chin electromyography (EMG). Stage 2 lasts for approximately 20 minutes and involves mixed-frequency brain waves with rapid bursts of rhythmic brain wave activity known as sleep spindles. During stage 2, body temperature starts to decrease and heart rate begins to slow. Deeper slow-wave sleep includes stages 3 and 4. Stage 3 sleep is characterized by 20%-50% slow brain waves known as delta waves. It is a transitional period between light sleep and very deep sleep. Stage 4 has greater than 50% delta waves and is sometimes referred to as delta sleep because of the slow brain waves that occur during this time. Stage 4 lasts approximately 30 minutes. The 5th stage of sleep, known as rapid eye movement (REM) sleep, is when most dreaming occurs. Stage 5 is characterized by increased respiration rate and brain activity. REM sleep has mixed frequency EEGs with theta waves in combination with rapid eye movements and nearly absent chin EMG. REM sleep occurs approximately every 90 minutes in adults, with a predominance of slow-wave sleep in the first half of the night and a predominance of REM sleep in the second half.10

Sleep starts out sequentially, but then it cycles through the stages in an out-of-sequence progression. It begins in stage 1 and progresses into stages 2, 3, and 4. After stage 4 sleep, stages 3 and then 2 are repeated before REM (stage 5) sleep begins. The body usually returns to stage 2 sleep after REM sleep is over. The first cycle of REM sleep is about 90 minutes after falling asleep and can last only a very short amount of time. With each cycle, REM sleep lasts longer.

The circadian rhythm of cortisol secretion has a waveform pattern with the nadir for cortisol occurring at about midnight. Cortisol levels start to rise approximately 2-3 hours after sleep onset and continue to rise into the early morning and early waking hours. The peak in cortisol is about 9 a.m.; as the day continues, levels decline gradually. With the onset of sleep, cortisol continues to decline until the nadir. Throughout the cycle, pulsatile secretions of cortisol of various amplitudes occur. Cortisol binds to mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) and causes either excitation or inhibition of the PVN depending on the location and type of receptors. Low levels of cortisol in the evening and night are associated with MR binding. When cortisol levels are higher, GRs are activated. In stressful times, NE and GRs may be activated preferentially and thereby increase CRH. This elevated CRH increases sleep EEG frequency, decreases short-wave sleep, and increases light sleep and frequent waking.

Sleep/HPA Axis and Cortisol Rhythm

The initiation of sleep occurs when HPA axis activity is lowest, and sleep deprivation is association with HPA activation. Nighttime awakening is associated with pulsatile cortisol, NE, and CRH release and is followed by a temporary inhibition of cortisol secretion. Cortisol begins to have a rapid rise upon the first morning awakening and continues to rise for about 60 minutes. This phenomenon is called the awakening response.

Dysfunctional HPA axis activity may play a role in some sleep disorders, but in other cases the HPA axis dysfunction is actually the result of a sleep disorder, as seen in obstructive sleep apnea. HPA axis hyperactivity can lead to fragmentation of sleep, decreased slow-wave sleep, and shortened sleep time. To complicate matters, sleep disturbances can worsen HPA axis dysfunction, thereby worsening the cycle. Both insomnia and obstructive sleep apnea are specific sleep disorders that are associated with HPA dysfunction.

Depression and other stress-related disorders are also associated with sleep disturbances, elevated cortisol,11 altered NE levels,12 and HPA axis dysfunction.13 Interestingly, chronic insomnia without depression occurs with elevated cortisol levels, particularly in the evening and the first part of the nighttime sleep period.14-17 This elevation in cortisol may be a primary cause of the sleep disturbance. In addition, the elevated cortisol may be a marker for increased CRH activity and CNS norepinephrine.18-20

In summary, HPA axis hyperactivity can have a negative impact on sleep, leading to sleep fragmentation, decreased deep slow-wave sleep, and shortened sleep time. In turn, sleep problems including insomnia and obstructive sleep apnea can further propagate HPA axis dysfunction.

Interventions to normalize HPA axis abnormalities, decrease nocturnal CRH hyperactivity, and decrease cortisol may be beneficial in treating insomnia and other sleep disorders.

Alternative Approach to Hypercortisol-Induced Sleep Problems

An effective way to manage chronically elevated cortisol levels is to ensure that the adrenal glands are supported by proper nutrition. Vitamin B6, vitamin B5 (pantothenic acid), and vitamin C often become depleted with prolonged hyperactivity of adrenal gland activity and increased production of cortisol.21 These nutrients play a critical role in the optimal functioning of the adrenal gland and in the optimal manufacturing of adrenal hormones. Levels of these nutrients can be diminished during times of stress. For instance, urinary excretion of vitamin C is increased during stress, which is evidence of vitamin C “dumping.” Consequently, additional symptoms may develop with these nutritional deficiencies. Observations and a rich tradition of anecdotal writings and reports supporting this claim have shown that deficiencies in pantothenic acid results in fatigue, headaches, and insomnia. L-tyrosine and L-theanine support the adrenal glands by supporting NE production and are beneficial in combating fatigue and anxiety symptoms related to stress. 22,23 In addition, the cortisol feedback mechanisms are dependent on adequate amounts of calcium, magnesium, potassium, manganese, and zinc. 24 Therefore, supplementation of these nutrients along with other supporting agents, such as L-tyrosine and L-theanine, may help ameliorate some symptoms as well as assist in proper HPA axis functioning.

Ashwagandha (Withania somnifera), also known as Indian ginseng, has been shown to reduce corticosterone, a glucocorticoid hormone present in amphibians, reptiles, rodents, and birds that is structurally similar to cortisol. 25,26 An array of clinical trials and laboratory research also support the use of ashwagandha in enhancing mood, reducing anxiety, and increasing energy. 27-30

Magnolia (Magnolia officinalis), was studied in a randomized, parallel, placebo-controlled study in overweight premenopausal women and resulted in a decrease in transitory anxiety, although salivary cortisol levels were not significantly reduced. 31 Magnolia has been demonstrated to improve mood, increase relaxation, induce a restful sleep, and enhance stress reduction. 32 In an unpublished study conducted at the Living Longer clinic, Cincinnati, Ohio, a proprietary blend of Magnolia officinalis and Phellodendron amurense was shown clinically to normalize the hormone levels associated with stress-induced obesity. It was demonstrated that this combination lowered cortisol levels by 37 percent and increased DHEA by 227 percent.

Phosphatidylserine (PS), also known as lecithin phosphatidylserine, is known to blunt the rise in cortisol and ACTH following strenuous training and significantly reduce both ACTH and cortisol levels after exposure to physical stress. 33,24 Phosphatidylserine also has been shown to improve mood. 35,36

Another approach to improving sleep is targeting GABA activity. Increasing GABA activity will decrease LC, PVN, and resultant HPA axis activity. One method to support GABA functioning is to decrease glutamate signaling. Glutamate and GABA activity oppose each other; therefore, decreasing glutamate activity will support healthy HPA axis activity. L-theanine is a glutamate receptor antagonist and has been shown to decrease brain NE levels secondarily to increasing GABA levels. 37,38 Interestingly, N-acetylcysteine (NAC) is a known precursor for cysteine, necessary for the synthesis of glutathione, 39,40 but also has been shown to decrease glutamate levels. NAC decreases glutamate by enhancing the activity of a cystine/glutamate antiporter. Glutamate is regulated by a cystine/glutamate antiporter that exchanges extraceullular cystine for intracellular glutamate. 41 Ultimately, the actions of this antiporter serve to lessen synaptic glutamate levels. Furthermore, glutamate is involved in immune-cell signaling to increase dendritic cell maturation following the exposure to antigens. To address elevated glutamate at its source, evaluation of intestinal permeabilities, food sensitivities/allergies, and bacterial and/or viral infections need to be considered due their relationship to dendritic cell maturation via increase antigen presence. 42

4-amino-3-phenylbutyric acid is a synthetic amino acid sold as a nutritional supplement that crosses the blood-brain barrier a nd is a GABA agonist. 43 Like many other GABA agonists, 4-amino-3-phenylbutyric acid can promote sleep by stimulating sleep-promoting centers in the brain. It also supports healthy cortisol levels by inhibiting the LC release of NE into the PVN.

Rhodiola rosea is an adaptogenic herb that modulates cortisol. 44 It reduces catecholamine release and prevents catecholamine depletion from the adrenal glands. In addition, research that was conducted in Russia indicates that it may stimulate opioid receptors, 45 which in turn can reduce NE excitability in the PVN and HPA axis activity. 46

Many traditional botanicals (eg, American ginseng, ashwagandha, Asian ginseng, astragalus, cordyceps, reishi, eleutherococcus, holy basil, rhodiola, schisandra, maca, licorice and common nutritional supplements (eg, phosphatidylserine, L-theanine, 4-amino-3-phenylbutyric acid, NAC) have been utilized for their stabilizing effects on the HPA axis. Combination/multi-ingredient formulations are common in a whole-system approach to restoring HPA axis dysfunction, whether to increase or decrease cortisol levels.

Conclusion

Reducing cortisol levels and stabilizing HPA axis dysfunction can be a very effective approach to addressing sleep disturbances, while also reducing the long-term risks associated with elevated cortisol levels.

**Sections of this article are reprinted with permission from Emerson Ecologics.

Disclosures

Tori Hudson, ND, is director of education/research at Vitanica and sits on the scientific advisory boards at ITI, Nordic Naturals, NHI, and Biogenesis.