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Adrenal hormones and adaptation to stress.

The phenomenon of stress, a now dominant constituent of our daily vocabulary, was coined over seventy years ago by Hans Selye. (1) Selye described the occurrence as nonspecific bodily changes that transpired in response to physically harmful stimuli. (2) In his reporting, Selye also indicated that although the adrenal glands are the first glands to respond to stress, they are also the first glands to fail under stressful conditions. The body possesses a complex system for adapting to stressful conditions, due primarily to the fact that the ability of an organism to adjust homeostasis, and in turn increase the chance of survival is dependent upon the activation of the stress system. This activation in turn leads to both behavioral and peripheral changes. (3)

The adrenal glands, a pair of triangular structures located atop each kidney, play a key role in stress adaptation and regulation. Not only are they necessary for life, but they also play an essential role in energy production, and in controlling the conversion of carbohydrate, protein and fat into glucose, as a source of fuel for the body. Moreover, they partake in the fluid and electrolyte balance of cells in both the interstitial fluids and in the blood stream, and are an important component in the production of sex hormones, especially following menopause. By virtue of the cortisol effect, the adrenals also play a role in the storage of fat, as cortisol has a direct effect on fat storage and weight gain in stressed individuals.

The adrenal glands are made up of two discrete parts, the inner adrenal cortex and the outer adrenal medulla. The adrenal cortex secretes four major groups of hormones, classified as the glucocorticoids, the mineralcorticoids, androgens and estrogens. The adrenal medulla is responsible for the secretion of the catecholamines, particularly epinephrine and norepinephrine. The secretion of all adrenal steroids, including the glucocorticord Cortisol, is under the control of the pituitary adrenocorticotropic hormone (ACTH), which functions by a negative feedback mechanism. Consequently, a high level of circulating Cortisol will suppress the secretion of ACTH, while a drop in cortisol will result in an increased ACTH secretion. (4) The action of the glucocorticoids is catabolic, stimulating the breakdown of protein and the inhibition of protein synthesis. Increased Cortisol in the circulation initiates fat deposition in adipose tissue, and consequently weight gain is common with cortisol excess. Blood glucose homeostasis is also affected by Cortisol, and its action is two-fold, via the stimulation of hepatic gluconeogenesis and via the inhibition of glucose uptake by tissues. Additionally, both the inflammatory and immune responses are suppressed by glucocorticoids. Thymic and lymph atrophy are known to develop in the presence of excess cortisol. (4)

Cortisol, the prototype of the glucocorticoids, is the hormone synthesized in the greatest quantity by the adrenal glands; approximately two hundred fold that of aldosterone. It exerts numerous physiologic actions on the body, including maintenance of normal blood pressure, regulation of fluid and electrolyte balance, protein metabolism, body fat distribution, glucose metabolism, and normal muscle formation. It also exerts action on both the hematopoietic system (blood cell formation) and on the lymphatic tissues. (4) The secretion of cortisol is executed in a diurnal pattern, with the highest value between 6 and 8 a.m., and the lowest normally around midnight. Cortisol also acts as an antiinflammatory signal, meaning that it acts as an "off switch" for the immune system, helping to prevent the inflammatory response. An elevation in cortisol has been demonstrated to contribute to insulin resistance, central obesity, dyslipidaemia and hypertension, and consequently a direct correlation between elevated cortisol and weight gain has been established. Regarding obesity, in female subjects with abdominal obesity, void of depression, it has been demonstrated that an exaggerated ACTH and cortisol response exists. (7)

Dysregulation of the stress system or a maladaptive neuroendocrine response has the potential to result in disturbances in growth and development, and may ultimately result in other health consequences including psychiatric, endocrine/metabolic, and/or autoimmune imbalances, as well as vulnerability to diseases. (8) It has been documented that stress-induced hypercortisolism and visceral obesity and their cardiovascular and other sequelae increase the all-cause mortality risk of affected subjects by 2-3-fold, and curtail their life expectancy by several years. (3) If not controlled ACTH hypersecretion frequently results in Cushing's disease. (9) Other diseases have been correlated to an excess production of adrenal androgen. For example, it has been estimated that in patients with polycystic ovarian syndrome, 20-30% produce an excess of adrenal androgen, resulting in elevated levels of dehydroepiandrosterone sulfate (DHEAS). Accordingly, in patients with PCOS, as a consequence of the response to ACTH stimulation a "generalized hypersecretion of adrenocortical products" has been observed. (10)

Nutritional Support for Healthy Adrenal Function

An extensive body of research provides important insights into nutritional support for optimal adrenal function. It is well accepted that stress increases the need for many nutrients, and a variety of factors affects the function of the adrenal glands. These may include dietary, environmental and/or innate mechanisms. Dietary factors are important contributors of adrenal stress. For example excess dietary carbohydrates or diets low in protein put additional stress on the adrenals. Inadequate or poor quality water also affects the adrenals due to inadequate oxygenation of the tissues. Prolonged or persistent hyperfunction may consequently result in unwanted health consequences, including Gushing syndrome, hyperaldosteronism, or adrenogenital syndromes. (11) A potential end result of adrenal hyperfunction is the excess production of one of the three corticosteroids; Cortisol, aldosterone or adrenal androgens.

In children and adolescents adrenal hyperfunction may ultimately result in stunted growth and short stature in adults. Growth hormone has also been observed to be decreased in patients with adrenal hyperfunction. (12), (13) Consequently, adrenal stress results in a greater need for many nutrients.

L-Tyrosinc for Catecholamine Synthesis

Dietary L-Tyrosinc is characteristically obtained via the metabolic conversion of phenylalanine. It functions as a key precursor in the synthesis of the catecholamines; epinephrine, norepinephrine and dopamine, and, coupled with iodine, functions as a key component in the production of thyroxine ([T.sub.4]) and triiodothyronine ([T.sub.3]). During stressful situations, catecholamine release is amplified, which over time may result in depleted levels. As a precursor of the catccholamics, alterations in L-tyrosinc availability may impact the synthesis of dopamine and norepinephrine. L-Tyrosine has been noted to have a beneficial effect during increased neuronal tiring rates, as in times of stress, and to prevent the decline in cognitive function associated with physical stress. (14) Thus, during times of stress, L-Tyrosine is considered a conditionally essential amino acid.

Vitamins associated with Adrenal Support Vitamin C. The concentration of vitamin C in the adrenal glands is among the highest in the body, being roughly 100 times that of blood plasma levels. (15) As such they are extremely sensitive to inadequacies in vitamin C. In catecholamine synthesis, vitamin C is required as a co-factor in the conversion of dopamine to norepinephrine. (16) In humans vitamin C secretion occurs as part of the stress response via hormone regulation, specifically in response to stimulation via the hormone adrenocorticotrophic (ACTFI). Following ACTH stimulation the mean adrenal vein vitamin C level increased approximately four fold, and then subsequently returned to near pre-stimulation levels approximately 15 minutes thereafter. Peak adrenal vitamin C and Cortisol concentrations have been strongly correlated ([r.sup.2] = 0.35, P<0.001), suggesting a local action of vitamin C on the adrenal glands. Additionally, it has been noted that, although being of unknown function, the increase in vitamin C secretion suggests that "adrenal vitamin C secretion is an integral part of the stress response." (17) Stress, fever and viral infections, as well as habitual actions, such as smoking and alcohol use, cause a rapid decline in the blood level of vitamin C. (18)

Pantothenic Acid. Pantothenic acid is a cofactor in the synthesis of coenzyme A (CoA). CoA plays an important part in cellular respiration, as well as in the biosynthesis of many important compounds including fatty acids, cholesterol and acetylcholine. (19) Animal studies have documented morphological damages in the adrenal cortex with pantothenic acid deficiency. (20), (21), (22), (23), (24), (25) Early experiments in animals also indicated that following prolonged pantothenic acid deficiency, extensive damage to the adrenals resulted, which was attributed to the adrenals inability to immediately utilize pantothenic acid. It was subsequently concluded that pantothenic acid deficiency results in an imposed stress upon the adrenal cortex, which in turn results in exhaustion, and consequently, adrenal hypofunction. (26) In spite of the fact that deficiencies are generally thought of as being rare, a deficiency in pantothenate results in fatigue and generalized malaise. (27)

Vitamin [B.sub.6]. Vitamin [B.sub.6] serves as a coenzyme in well over 100 reactions, most of which are transaminase (aminotransferase) reactions. It plays an important role in the synthesis of the neurotransmitters y-aminobutyric acid (GABA), serotonin, dopamine, norepinephrine and epinephrine. (28) As a physiological modulator of steroid hormone action, Vitamin [B.sub.6] has been associated with modulation of the expression of a diverse array of hormonally responsive genes. For efficient function, both the nervous and immune systems require an adequate supply of vitamin [B.sub.6]. (30), (31), (32), (33) Vitamin [B.sub.6] is also required for the conversion of tryptophan to niacin and serotonin, (34), (35) as well as for the conversion of tyrosine to dopamine. In one study, a deficiency in vitamin [B.sub.6] was correlated to a slower extracellular dopamine release (43% longer with deficiency). (36) Dopamine is known to be an active participant in the secretory modulation of both aldosterone and catecholamine from the adrenal gland. (37) Dopamine depletion is correlated with physical and/or psychological stress.

Vitamin E. Vitamin E is found in all cells in the human body, and functions primarily as an antioxidant. The adrenal cells, along with the pituitary, platelet and testicular cells, contain the highest cellular concentration of vitamin E. (28) In animal studies vitamin E deficiency was demonstrated to predispose tissues to lipid peroxidation. (38) Conversely, vitamin E consumption affords protection against the effects of mineral toxicity, attributed to reversing the alterations in adrenocortical activities brought on by toxic mineral levels. (39) In another study, the use of alpha tocopherol during times of significant stress was demonstrated to decrease lipid peroxidation in both the liver and the brain, while simultaneously preventing depletion in glutathione levels, which are routinely depleted by stress. Adrenal sensitivity to ACTH is also increased with vitamin E use. (41)

Thiamin. Thiamin, a water-soluble B-complex vitamin, is involved in many bodily functions, including its requirement in the metabolism of carbohydrates, as part of the coenzyme thiamin pyrophosphate (TPP). In the absence of thiamin, a slowing or complete blocking of enzymatic activity occurs. As part of the citric acid cycle, essential for energy production, thiamin functions as a component in the decarboxylation of a-ketoglutaric acid to succinyl CoA. (28) In animal studies corticosterone levels have shown to be significantly increased with thiamin deficiency. (42), (43)

Riboflavin. Like thiamin, riboflavin is also a water-soluble vitamin. It participates in normal cell function, growth and energy production. Riboflavin serves as a crucial component in converting food into energy via the manufacturing of flavin adenine dinucleotide (FAD). FAD is required for electron transport and ATP production in the Krebs cycle. Ariboflavinosis (riboflavin deficiency) is associated with weakness, cheilosis (fissures in the skin at the angles of the mouth), angular stomatitis (inflammation of the mucous lining of the mouth) and anemia. Individuals particularly susceptible to deficiency include the elderly, those with chronic illnesses or those with alcohol dependency. (44) Stress increases the need for riboflavin due to an increase in fatty acid oxidation. Riboflavin deficiency has been correlated to adrenal cortex dysfunction in animals. (45)

Niacin. Niacin's primary cellular function is as a coenzyme for [NAD.sup.+] and [NADP.sup.+], both of which function in the maintenance of cellular oxidation-reduction reactions. In addition to its varied cellular functions, NAD is used as a substrate for the production of poly-ADP-ribose (PARP). PARP is a nuclear enzyme activated by DNA strand breaks. It functions to synthesize polymers of ADP-ribose molecules, making it an important component in DNA repair. (46) Niacin intake has also been correlated with anxiety reduction.

Minerals associated with Adrenal Support

Minerals can also be beneficial components for adrenal support, functioning as aides in sustaining the adap-togenic response of the adrenals.

Zinc. Zinc participates as an active component in over 300 different enzymes, and plays a vital role in many biological processes. As a cofactor for the antioxidant enzyme superoxide dismutase (SOD) it is an important component in cellular protection. It also functions in enzymatic reactions in both carbohydrate and protein metabolism. (44) Zinc deficiency and adrenal stress have been associated. In one study a correlation between zinc deficiency and prostaglandin production was noted, demonstrating that with deficiency interference in the production and/or function of the prostaglandins ensued. (47)

Copper. Like zinc and iron, copper is also involved in gene regulation and expression, specifically for the metallothioneins, or metal-binding proteins. Studies have suggested that copper plays a role in mitochondrial gene expression, noting a decrease in oxidative phosphorylation with deficiency. A number of enzymes require copper as a cofactor, and copper is necessary to balance zinc.

Manganese. Manganese (Mn) is a required mineral for optimal adrenal glandular activity. It serves as a component for energy metabolism, as a cofactor for enzymes of the citric acid cycle, and as a functional cofactor as part of the enzymatic structure of several additional enzymes. As an essential cofactor for Mn superoxide dismutase (MnSOD), it is an important participant in the cellular antioxidant defense mechanism. (48) It also functions as an important modulator in signal transduction pathways. (49) Recent evidence has denoted a correlation between Mn deficiency and the balance of endothelium-derived prostanoids, indicating the presence of oxidative stress in Mn deficiency, as a result of reduced activity MnSOD. (50)

Lithium and Rubidium. Lithium and rubidium, in trace amounts, function as relaxant minerals. Lithium has been shown to have general neuroprotective effects, (51) to offer protection against glutamatc excitotoxicity, as well as to offer CNS neuroplasticity (changes in the brain organization as a result of experience). (52) The trace mineral rubidium (Rb) resembles potassium in terms of its method of absorption and excretion.

Acute stress impacts dopamine, increasing its release and metabolism. (53) Symptoms associated with neuropsychological issues have been coupled with disturbances in dopaminergic neurotransmission. (54) Dopamine, a known precursor to norepinephrine and epinephrine, also functions as a neurotransmitter. (55) Supplementation with lithium or rubidium was demonstrated to result in a decreased dopamine output. (56) Dopamine release in the brain has been shown to exert an important adaptagenic influence over specific behaviors, including emotion and cognition, as well as to affect mechanisms of reward and locomotional control.

Botanical Extracts for Adrenal Support

A number of botanicals have been identified as having adaptogenic properties with intake, along with a corresponding negligible disturbance in physiological function. In addition to established nutrients, several herbal extracts help support normal adrenal function. Many of these have their origins in Chinese or Ayurvedic traditions.

Achyranthes. In the Chinese pharmacology, the action of Achyranthes is said to invigorate the blood, and to expel blood stasis. (57) It is used in Yang tonic formulations. Its functionality is said to revolve around its ability to guide other herbs to the kidneys, genitals, and legs. (58)

Damiana (Turnera diffusa). Damiana is a small shrub with an aromatic leaf, found predominantly in Mexico, Southern and Central America. Like Achyranthes, Damiana is also designated as a yang tonic, and is suggested to aide with energy. It is considered a strengthener for the nervous system, and is viewed as a nervous restorative. (59), (60) Its properties are indicated as stimulating to the nervous system and as a diuretic, (61) while its traditional use is as a general tonic for the nervous, endocrine, and reproductive systems. (44)

Gotu Kola (Centella asiatica). - In Ayurvedic medicine Gotu Kola is an herb viewed as an important component in rejuvenation, as well as one of the chief herbs for revitalizing the nerves and brain cells. The following properties have been attributed to its actions; mildly antibacterial, anti-viral, anti-inflammatory, anti-ulcerogenic, anxiolytic, a cerebral tonic, a circulatory stimulant, a diuretic, nervine and vulnerary. (62) Punturee, et. al., demonstrated that C. asiatica has immuno-stimulating activity regarding both non-specific cellular immune responses and humoral immune responses. Additionally, they noted the inhibition of TNF-[alpha] with an ethanol extract of C. asiatica, implicating that it may be an important component in downregulating inflammation. (63)

Sichuan Teasel (Dipsacus asperoides). According to the Chinese tradition, Dipsacus asperoides (DA) is said to tonify the liver and kidneys, and to promote the movement of blood. (64) A crude polysaccharide fraction (DAP-1) from the root of DA has been shown to have a stimulating effect on the mitogenic activity of lymphocytes, as well as to suppress the phagocytic activity of macrophages. (65)

Asiatic Dogwood. (Cornus officinalis). Cornus officinalis (CO) is popular in traditional medicine, and is known for its tonic, pain-relieving, and diuretic properties. (66) In addition to its use as a tonifier for liver and kidney deficiency, indicated by such symptoms as lightheadedness and dizziness, it is also said to tonify the essence and assist the yang. (64) The aglycons of anthocyanins have been shown to possess strong antioxidant activities. (67), (68) Likewise, the anthocyanins of CO were confirmed to possess strong antioxidant activity. (69)

Basil (Ocimum basilicum). Basil is a popular culinary herb, as well as a medicinal herb in Thailand, India and Turkey. (70) It is said to affect the lungs and stomach meridians, and its actions are indicated as being stimulatory to the adrenal cortex. (71) The chief compounds isolated from basil include eugenol, citral and geraniol, (72) as well as rosmarinic acid, a natural phenolic compound shown to inhibit complement-dependent inflammatory processes. (73)

Schisandra (Schisandra chinensis). Schisandra chinensis (SC) has been utilized in traditional Chinese medicine (TCM) for over 2000 years, as both a tonic and a calmative. As a tonic, one of its uses is to support mental function. It is considered an adaptogenic herb, which functions in the harmonization of the system. More recently, SC has been utilized to increase resistance to disease and stress, boost energy levels (void of caffeine associated jitteriness), increase both mental and physical endurance, to improve vision, and to support both the musculoskeletal and immune systems. (74) Modern Chinese research suggests that SC may have a protective effect on the liver, as well as possessing immune accentuating properties. Gomisin A, an isolated component from SC was demonstrated to have relaxant properties, demonstrating an "anti-stress" effect.

Tinospora cordifolia. The use of Tinospora cordifolia (TC) for debility and dyspepsia in Ayurvedia is common. The root of TC is documented as having anti-stress properties, as well as immune supporting properties. (77), (78) In animal studies an aqueous extract of TC was demonstrated to have advantageous properties with adrenaline-induced hyperglycemia. (79), (80), (81)

Taken collectively, the components discussed above provide nutritional support for the adrenal glands, consisting of herbal adaptogens, and supportive vitamins and minerals. These components serve to aide in supporting bodily functions when the body is under stress, as well as in supporting normal Cortisol values, which may be especially important in certain conditions, such as obesity, Syndrome X and hyperinsulinism. Stress, a poor diet and environmental toxins are known contributors of adrenal malfunction, factors which have been termed "diseases of civilization." (82)

Rachel Olivier, MS, ND, PhD serves as a Physician Advisor for Biotics Research Corporation.

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by: Rachel Olivier, MS, ND, PhD

Submitted by: Biotics Research Corporation
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