Chronic insomnia can be one of the most challenging problems in a primary care practice. Inadequate or dissatisfying sleep is the most common sleep disturbance in the US. As many as 40% of adult Americans report at least occasional insomnia, and of those, nearly 20% have severe insomnia. Severe insomnia is defined as difficulty initiating or maintaining sleep at least three times a week for 1 month or more, with the problem being bad enough to cause fatigue during the day or impaired functioning.

Women are 30% more likely than men to report their insomnia, and it is more likely to be more severe. Sleep problems are especially common in perimenopausal women and increase after age 40 and plateau by age 50. Sleep problems are also more concomitant with medical and psychiatric disorders, which are more prevalent, or at least more reported, in women. Twenty-nine percent of women report that medications are needed to improve their sleep. Of those, nearly one-third rely on over-the-counter drugs, 13% use prescription drugs, and others use both.

The hypothalamic-pituitary-adrenal (HPA) axis interacts with sleep in a multiplicity of ways, and a growing body of research suggests reciprocal associations between sleep and activity of the HPA axis. That is the focus of this month's column.

A normal sleep architecture is characterized by cycles of light sleep, deeper slow-wave sleep, and rapid eye movement (REM) sleep. Light sleep includes stage 1 and stage 2. Stage 1 sleep has mixed frequency theta, slow rolling eye movements, and slightly reduced eye movement and chin electromyography (EMG). Stage 2 has mixed frequency electroencephalogram (EEG). Deeper slow-wave sleep includes stages 3 and 4. Stage 3 sleep is characterized by 20% to 50% delta EEG, and stage 4 has greater than 50% delta EEG. The REM cycles have mixed-frequency EEG with theta waves in combination with rapid eye movements and nearly absent chin EMG. REM occurs approximately every 90 to 110 minutes, with a predominance of slow-wave sleep in the first half of the night and a predominance of REM sleep in the second half.¹ Corticotropin releasing hormone (CRH) is secreted by the hypothalamus, in particular the paraventricular nucleus (PVN), which 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. Along with its numerous actions in the body, cortisol has feedback inhibition on the PVN and the anterior pituitary to control CRH or synthesis and release of ACTH. Other areas of the brain also impart feedback to the HPA axis.

The circadian rhythm of cortisol secretion has a waveform pattern, with the nadir for cortisol occurring at about midnight. Cortisol levels start to rise about 2 to 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., and as the day continues, there is a gradual decline in levels. With the onset of sleep, there is a continued decline until the nadir. Throughout the cycle, there are pulsatile secretions of cortisol of various amplitudes. Cortisol binds to mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs), and feedback onto the PVN is excitatory or inhibitory depending on the location and type of receptor. 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, 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.

The initiation of sleep occurs concurrent with a low HPA axis activation, and sleep deprivation is association with HPA activation. Nighttime wakenings are associated with pulsatile cortisol release and are followed by a temporary inhibition of cortisol secretion. Cortisol begins its rapid rise after the first morning awakening, continues for about 60 minutes, and is called the awakening response.

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

Depression and stress are associated with sleep disturbances and elevated cortisol.² Chronic insomnia without depression is also associated with elevated cortisol levels, particularly in the evening and the first part of the nighttime sleep period.^3-5 This elevated cortisol may be the primary cause of the sleep disturbance, or it may be a marker for increased CRH activity or for increased central norepinephrine.⁷

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

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

Alternative Approach to the Hypercortisol-Induced Sleep Problems
An effective way to manage chronically elevated cortisol levels is to ensure that the adrenal glands are supported by the proper nutrients. Vitamin B6, pantothenic acid, and vitamin C often become depleted when the demands on adrenal gland cortisol production are continuous.⁸ These nutrients play a critical role in the optimal function of the adrenal gland and in the optimal manufacture of adrenal hormones. Levels of these nutrients can be diminished during times of stress. Urinary excretion of vitamin C is increased during stress. A deficiency of pantothenic acid results in fatigue, headaches, insomnia, and more. L-tyrosine and L-theanine support the adrenal glands by combating fatigue and anxiety related to stress.⁹ In addition, the cortisol feedback control mechanism depends on adequate amounts of calcium, magnesium, potassium, manganese, and zinc.¹⁰

Ashwagandha (Withania somnifera), also known as Indian ginseng, has been shown to reduce corticosterone, a glucocorticoid hormone structurally similar to cortisol.^11,12 An array of clinical trials and laboratory research also support the use of Ashwagandha in enhancing mood, reducing anxiety, and increasing energy.^13-16

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.¹⁷ Magnolia can improve mood, increase relaxation, induce a restful sleep, and reduce stress.¹⁸ In an unpublished study conducted at the Living Longer Clinic in 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% and increased DHEA by 227%.

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.^19,20 Phosphatidylserine also has been shown to improve mood.^21,22

In a recent unpublished study of a proprietary formula, study subjects took a product containing Ashwagandha, phosphatidylserine, magnolia, and L-theanine. The nutritional/botanical supplement consistently decreased salivary cortisol levels in relation to baseline levels. In addition, participants reported increased relaxation, improved sleep, deeper sleep, and reduced stress levels.²³

Many traditional botanicals have been utilized for their stabilizing effect on the HPA axis, including American ginseng, Ashwagandha, Asian ginseng, astragalus, Cordyceps, reishi, eleutherococcus, holy basil, rhodiola, schisandra, maca, and licorice. Combination/multi-ingredient formulations are common in a whole-system approach to restoring HPA axis dysfunction, whether elevated or low cortisol levels.

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

Tori Hudson, ND
womanstime@aol.com

Notes
1.   Carskadon M, Dement W Normal human sleep: an overview. In: Kryger M, Dement W, eds. Principles and Practice of Sleep Medicine. Philadelphia: Saunders; 2000:15-25.
2.   Arborelius L, Owens M, Plotsky P, Nemeroff C. The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol. 1999;160:1-12.
3.   Vgontzas A, Tsigos C, Bixler E, et al. Chronic insomnia and activity of the stress system: a preliminary study. J Psychosom Res. 1998;45:21-31.
4.   Vgontzas A, Bixler E, Lin H, et al. Chronic insomnia is associated with nyctohemeral activation of the hypothalamic-pituitary-adrenal axis: clinical implications. J Clin Endocrinol Metab. 2001;86:3787-3794.
5.   Rodenbeck A, Hajak G. Neuroendocrine dysregulation in primary insomnia. Rev Neurol. 2001;157:S57-S61.
6.   Rodenbeck A, Huether G, Ruther E, Hajak G. Interactions between evening and nocturnal cortisol secretion and sleep parameters in patients with severe chronic primary insomnia. Neurosci Lett. 2002;324:159-163.
7.   Wong M, Kling M, Munson P, et al. Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone. Proc Natl Acad Sci USA. 2000;97:325-330.
8.   Patak P, Willenberg H, Bornstein S. Vitamin C is an important co-factor for both adrenal cortex and adrenal medulla. Endoc Res. 2004;30:871-875.
9.   Barliner S. An introduction to amino acids. Adv Nurse Pract. 2006;14:47-48,82.
10. Nutall F, Gannon M. The metabolic response to a high-protein, low-carbohydrates diet in men with type 2 diabetes. Metabolism. 2006;55:243-251.
11. Begum V, Sadique J. Effect of Withania somnifera on glycosaminoglycan synthesis in carrageniin-induced air pouch granuloma. Biochem Med Metab Biol. 1987;38:272-277.
12. Sudhir S, Budhiraja R, Migiani G, et al. Pharmacological studies on leaves of Withania somnifera. Planta Med. 1986;52:61-63.
13. Naidu P, Singh A, Kulkami S. Effect of Withania somnifera root extract on reserpine induced orofacial dyskinesia and cognitive dysfunction. Phytother Res. 2006;20:1406.
14. Kumar A, Kalonia H. Protective effect of Withania somnifer Dunal on the behavioral and biochemical alterations in sleep-disturbed mice (and over water suspended method). Indian J Exp Tiol. 2007;45:524-528.
15. Rasool M, Varalakshmi P. Protective effect of Withania somnifera root powder in relation to lipid peroxidation, antioxidant status, glycoproteins and bone collagen on adjuvant-induced arthritis in rats. Fundam Clin Pharmacol. 2007 Apr;21(2):157-164.
16. Sankar S, Manivasagam T, Krishnamurti A, Ramanathan M. The neuroprotective effect of Withania somnifera root extract in MPTP-intoxicated mice: An analysis of behavioral and biochemical variables. Cell Mol Biol Lett. 2007;12(4):473-481. Epub 2007 Apr 6.
17. Kalman D, Feldman S, Feldman, et al. Effect of a proprietary Magnolia and Phellodendron extract on stress levels in healthy women: a pilot, double-blind, placebo-controlled clinical trial. Nutr J. 2008;7:11:1-6.
18. Kuribara H, Stavinoha W, Maruyama Y. Behavioural pharmacological characteristics of honokiol, an anxiolytic agent present in extracts of Magnolia bark, evaluated by an elevat3ed plus-maze test in mice. J Pharm Pharmacol. 1998;50:819-826.
19. Benton D. The influence of phosphatidylserine supplementation on mood and heart rate when faced with an acute stressor. Nutr Neurosci. 2001;3(3):169-178.
20. Slater S, Kelly M, Yeager M, et al. Polyunsaturation in cell membranes and lipid bi-layers and its effects on membrane proteins. Lipids. 1996;31(suppl):S189-S92
21. Hellhammer J. Effects of soy lecithin phosphatidic acid and phosphatidylserine complex (PAS) on the endocrine and psychological responses to mental stress. Stress. 2004;7(2):119-126.
22. Monteleone P, Boinat L, Tanzillo C, et al. Effects of phosphatidylserine on the neuroendocrine response to physical stress in humans. Neuroendocrinology. 1990;52:243-248.
23. An open label pilot study of the safety and effectiveness of a cortisol-reducing combination in healthy adults. 2006. Unpublished.