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Section 1

SECOND-TIER NATURAL ANTIDEPRESSANTS: REVIEW AND CRITIQUE

A PRACTICAL APPROACH TO CIRCADIAN RHYTHM SLEEP DISORDERS

INTERACTIONS OF TAURINE WITH GABAB BINDING SITES IN MOUSE BRAIN

TAURINE HELPS WITH BOTH SLEEP AND ANXIETY THROUGH REDUCING EXCITATORY NEUROTRANSMISSION

UBIQUINONE SUPPLEMENTATION DURING LOVASTATIN TREATMENT: EFFECT ON LDL OXIDATION EX VIVO

HIGH-DOSE STATINS AND SKELETAL MUSCLE METABOLISM IN HUMANS: A RANDOMIZED, CONTROLLED TRIAL

MENAQUINONE-4 ENHANCES TESTOSTERONE PRODUCTION IN RATS AND TESTIS-DERIVED TUMOR CELLS

VITAMIN D IS AN IMPORTANT FACTOR IN ESTROGEN BIOSYNTHESIS OF BOTH FEMALE AND MALE GONADS

ASSOCIATION BETWEEN PLASMA 25-OH VITAMIN D AND TESTOSTERONE LEVELS IN MEN

LEVELS OF DHEA AND DHEAS AND RESPONSES TO CRH STIMULATION AND HYDROCORTISONE TREATMENT IN CHRONIC FATIGUE SYNDROME




SECOND-TIER NATURAL ANTIDEPRESSANTS: REVIEW AND CRITIQUE

Both supplements of L-tryptophan and 5-HTP have been used in the treatment of depression, but the use of 5-HTP may offer the advantage of bypassing the conversion of L-tryptophan into 5-HTP by the enzyme tryptophan hydroxylase, which is the rate-limiting step in the synthesis of serotonin.

Tryptophan hydroxylase can be inhibited by numerous factors, including stress, insulin resistance, vitamin B6 deficiency, and insufficient magnesium... Moreover, 5-HTP easily crosses the blood-brain barrier, and unlike L-tryptophan, does not require a transport molecule to enter the central nervous system (Green et al., 1980; Maes et al., 1990).

Besides serotonin, other neurotransmitters and hormones, such as melatonin, dopamine, norepinephrine, and beta-endorphin have also been shown to increase following oral administration of 5-HTP. All of these compounds are thought to be involved in the regulation of mood as well as sleep and may represent mechanistic pathways stimulated by 5-HTP administration.

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A PRACTICAL APPROACH TO CIRCADIAN RHYTHM SLEEP DISORDERS

Light suppresses melatonin while darkness stimulates its synthesis. Many people have trouble falling asleep. Delayed sleep phase syndrome results in late sleep onset, despite normal sleep architecture and total sleep duration.

Melatonin has been shown to improve sleep latency (the time it takes to fall asleep) in several randomized controlled studies. Rather than immediately prior to sleeping, melatonin works best when given two hours before sleeping. Melatonin is also useful for jet lag, irregular sleep-wake rhythms, and shift work sleep disorder. Exogenously administered melatonin has phase shifting properties, and the effect follows a phase- response curve (PRC) that is about 12 h out of phase with the PRC [phase response curve] of light Melatonin administered in the afternoon or early evening will phase advance the circadian rhythm, whereas melatonin administered in the morning will phase delay the circadian rhythm (Fig. 2). The magnitude of phase shifts is time-dependent, and the maximal phase shifts result when melatonin is scheduled around dusk or dawn. The effect of exogenous melatonin is minimal when administered during the night, at least during the first-half of the night.

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INTERACTIONS OF TAURINE WITH GABAB BINDING SITES IN MOUSE BRAIN

The interactions of taurine with GABAB receptors were studied in membranes from the brain of the mouse by measuring the binding of [3H]baclofen and that of [3H]GABA in the presence of isoguvacine.

Taurine displaced ligand binding to GABAB receptors concentration-dependently with an IC50 in the micromolar range. The effects of baclofen on the release of taurine and GABA from slices of cerebral cortex of the mouse were assessed using a superfusion system. Potassium-stimulated release of both [3H]taurine and [3H]GABA was unaffected by baclofen but potentiated by delta-aminovalerate.

The enhancement of release of [3H]taurine by delta-aminovalerate was partially antagonized by baclofen, suggesting that baclofen-sensitive receptors could modify the release.

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TAURINE HELPS WITH BOTH SLEEP AND ANXIETY THROUGH REDUCING EXCITATORY NEUROTRANSMISSION

Anxiety and Sleep: Taurine helps with both sleep and anxiety through reducing excitatory neurotransmission. It increases GABA in the brain, can bind to GABA receptors, and indirectly suppresses NMDA signaling. It also acts on glycine receptors, which contributes to its anti-anxiety effects.

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UBIQUINONE SUPPLEMENTATION DURING LOVASTATIN TREATMENT: EFFECT ON LDL OXIDATION EX VIVO

The statins or 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) inhibitors are the most effective drugs in lowering serum low density lipoprotein (LDL) concentration. They decrease cardiovascular morbidity and mortality of hypercholesterolemic patients, even in primary prevention. Large controlled prospective studies have shown that statins as a group improve the prognosis of coronary heart disease (CHD) patients.

The HMG-CoA reductase inhibitors affect competitively the early key enzyme of the mevalonate pathway (Fig. 1), thus inhibiting the synthesis of cholesterol and other non-sterol end products. One of them is coenzyme Q10 (2,3-dimethoxy-5-methyl-6-decaprenyl benzoquinone), also known as ubiquinone. It may be estimated that on a normal diet, 60% of plasma ubiquinone is endogenous.

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HIGH-DOSE STATINS AND SKELETAL MUSCLE METABOLISM IN HUMANS: A RANDOMIZED, CONTROLLED TRIAL

High-dose statin treatment leads to changes in the skeletal muscle sterol metabolism. Furthermore, aggressive statin treatment may affect mitochondrial volume.

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MENAQUINONE-4 ENHANCES TESTOSTERONE PRODUCTION IN RATS AND TESTIS-DERIVED TUMOR CELLS

MK-4 stimulates testosterone production in rats and testis-derived tumor cells via activation of PKA. MK-4 may be involved in steroidogenesis in the testis, and its supplementation could reverse the downregulation of testosterone production in elders. More ...
VITAMIN D IS AN IMPORTANT FACTOR IN ESTROGEN BIOSYNTHESIS OF BOTH FEMALE AND MALE GONADS

In the present study, the role of vitamin D in the regulation of estrogen synthesis in gonads was investigated. Vitamin D receptor null mutant mice showed gonadal insufficiencies. Uterine hypoplasia and impaired folliculogenesis were observed in the female, and decreased sperm count and decreased motility with histological abnormality of the testis were observed in the male.

The aromatase activities in these mice were low in the ovary, testis, and epididymis at 24%, 58%, and 35% of the wild-type values, respectively. The gene expression of aromatase was also reduced in these organs. Elevated serum levels of LH and FSH revealed hypergonadotropic hypogonadism in these mice. The gene expressions of estrogen receptor alphaand beta were normal in gonads in these mice.

Supplementation of estradiol normalized histological abnormality in the male gonads as well as in the female. Calcium supplementation increased aromatase activity and partially corrected the hypogonadism. When the serum calcium concentration was kept in the normal range by supplementation, the aromatase activity in the ovary increased to 60% of the wild-type level, but LH and FSH levels were still elevated.

These results indicated that vitamin D is essential for full gonadal function in both sexes. The action of vitamin D on estrogen biosynthesis was partially explained by maintaining calcium homeostasis; however, direct regulation of the expression of the aromatase gene should not be neglected.

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ASSOCIATION BETWEEN PLASMA 25-OH VITAMIN D AND TESTOSTERONE LEVELS IN MEN

A small randomized controlled trial suggested that vitamin D might increase the production of testosterone in men, which is supported by experimental studies in animals and a cross-sectional study showing positive associations between plasma 25-hydroxyvitamin D [25(OH)D] and testosterone and concordant seasonal variation of both biomarkers.

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LEVELS OF DHEA AND DHEAS AND RESPONSES TO CRH STIMULATION AND HYDROCORTISONE TREATMENT IN CHRONIC FATIGUE SYNDROME

DHEA levels are raised in CFS and correlate with the degree of self-reported disability. Hydrocortisone therapy leads to a reduction in these levels towards normal, and an increased DHEA response to CRH, most marked in those who show a clinical response to this therapy.

On the other hand, there have been a number of recent studies that have investigated the role of DHEA supplementation in patients with adrenal insufficiency. In this condition, DHEA(-S) levels appear to be reduced in parallel to the reduction in cortisol, and replacement therapy with DHEA appears to give additional benefits over and above that seen with cortisol replacement (Arlt et al., 1999; Hunt et al., 2000).

It is also of interest to note the recent literature regarding the importance of the cortisol/DHEA ratio in major depression, where an emerging literature suggests that it is a high cortisol/DHEA ratio that may be the most important indicator of excessive physiological effects of cortisol on the brain (Goodyer et al., 2001; Young et al., 2002). In other words, either low DHEA or high cortisol could contribute to the excess cortisol effect on the brain. Hydrocortisone may reduce elevated DHEA in chronic fatigue patients. On the other hand, low DHEA in adrenal insufficiency may improve with DHEA supplementation.

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Section 2

LOW-DOSE HYDROCORTISONE IN CHRONIC FATIGUE SYNDROME: A RANDOMISED CROSSOVER TRIAL

THE HYPOTHALAMO-PITUITARY-ADRENAL AXIS IN CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA SYNDROME

THE THERAPEUTIC POTENTIAL FOR TRYPTOPHAN AND MELATONIN: POSSIBLE ROLES IN DEPRESSION, SLEEP, ALZHEIMER'S DISEASE AND ABNORMAL AGING

EFFECTS OF L-TRYPTOPHAN ON SLEEPINESS AND ON SLEEP

MELATONIN IN NONAPNEA SLEEP DISORDERS

TAURINE INDUCES ANTI-ANXIETY BY ACTIVATING STRYCHNINE-SENSITIVE GLYCINE RECEPTOR IN VIVO

EVALUATION OF ANTIOXIDANT SYSTEMS IN PITUITARY-ADRENAL AXIS DISEASES

REDUCTION OF SERUM UBIQUINOL-10 AND UBIQUINONE-10 LEVELS BY ATORVASTATIN IN HYPERCHOLESTEROLEMIC PATIENTS

ASSOCIATION OF HIGH VITAMIN D STATUS WITH LOW CIRCULATING THYROID-STIMULATING HORMONE INDEPENDENT OF THYROID HORMONE LEVELS IN MIDDLE-AGED AND ELDERLY MALES

ASSOCIATION OF VITAMIN D STATUS WITH SERUM ANDROGEN LEVELS IN MEN




LOW-DOSE HYDROCORTISONE IN CHRONIC FATIGUE SYNDROME: A RANDOMISED CROSSOVER TRIAL

Studies of the hypothalamo-pituitary adrenal (HPA) axis in chronic fatigue syndrome show a mild hypocortisolism of central origin, in contrast to the hypercortisolism of major depression. In some patients with chronic fatigue syndrome, low-dose hydrocortisone reduces fatigue levels in the short term. Treatment for a longer time and follow-up studies are needed to find out whether this effect could be clinically useful.

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THE HYPOTHALAMO-PITUITARY-ADRENAL AXIS IN CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA SYNDROME

The hypothalamo-pituitary-adrenal (HPA) axis plays a major role in the regulation of responses to stress. Human stress-related disorders such as chronic fatigue syndrome (CFS), fibromyalgia syndrome (FMS), chronic pelvic pain and post-traumatic stress disorder are characterized by alterations in HPA axis activity. However, the role of the HPA axis alterations in these stress-related disorders is not clear.

Most studies have shown that the HPA axis is underactive in the stress-related disorders, but contradictory results have also been reported, which may be due to the patients selected for the study, the methods used for the investigation of the HPA axis, the stage of the syndrome when the tests have been done and the interpretation of the results. There is no structural abnormality in the endocrine organs which comprise the HPA axis, thus it seems that hypocortisolemia found in the patients with stress-related disorder is functional.

It may be also an adaptive response of the body to chronic stress. In this review, tests used in the assessment of HPA axis function and the HPA axis alterations found in CFS and FMS are discussed in detail.

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THE THERAPEUTIC POTENTIAL FOR TRYPTOPHAN AND MELATONIN: POSSIBLE ROLES IN DEPRESSION, SLEEP, ALZHEIMER'S DISEASE AND ABNORMAL AGING

Evidence suggests that stress and/or a dietary lack of tryptophan may make deficiencies of serotonin and melatonin common. In addition, older animals and human beings have a reduced ability to synthesize melatonin.

Disorders of melatonin levels and rhythms are suggested to be a cause of affective disease, abnormal sleep, Alzheimer's disease, and some age related disorders. If these ideas prove to be true, then preventive measures are possible.

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EFFECTS OF L-TRYPTOPHAN ON SLEEPINESS AND ON SLEEP

Over the past 20 yr, 40 controlled studies have been described concerning the effects of L-tryptophan on human sleepiness and/or sleep. The weight of evidence indicates that L-tryptophan in doses of 1 g or more produces an increase in rated subjective sleepiness and a decrease in sleep latency (time to sleep).

There are less firm data suggesting that L-tryptophan may have additional effects such as decrease in total wakefulness and/or increase in sleep time. Best results (in terms of positive effects on sleep or sleepiness) have been found in subjects with mild insomnia, or in normal subjects reporting a longer-than-average sleep latency.

Mixed or negative results occur in entirely normal subjects--who are not appropriate subjects since there is no room for improvement. Mixed results are also reported in severe insomniacs and in patients with serious medical or psychiatric illness.

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MELATONIN IN NONAPNEA SLEEP DISORDERS

Nonapnea sleep disorders: Nonapnea sleep disorder In humans, melatonin secretion increases soon after the onset of darkness, peaks in the middle of the night (between 2 and 4 a.m.), and gradually falls during the second half of the night

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TAURINE INDUCES ANTI-ANXIETY BY ACTIVATING STRYCHNINE-SENSITIVE GLYCINE RECEPTOR IN VIVO

Taurine has a variety of actions in the body such as cardiotonic, host-defensive, radioprotective and glucose-regulatory effects. However, its action in the central nervous system remains to be characterized. In the present study, we tested to see whether taurine exerts anti-anxiety effects and to explore its mechanism of anti-anxiety activity in vivo.

The staircase test and elevated plus maze test were performed to test the anti-anxiety action of taurine. Convulsions induced by strychnine, picrotoxin, yohimbine and isoniazid were tested to explore the mechanism of anti-anxiety activity of taurine. The Rotarod test was performed to test muscle relaxant activity and the passive avoidance test was carried out to test memory activity in response to taurine. Taurine (200 mg/kg, p.o.) significantly reduced rearing numbers in the staircase test while it increased the time spent in the open arms as well as the number of entries to the open arms in the elevated plus maze test, suggesting that it has a significant anti-anxiety activity.

Taurine's action could be due to its binding to and activating of strychnine-sensitive glycine receptor in vivo as it inhibited convulsion caused by strychnine; however, it has little effect on picrotoxin-induced convulsion, suggesting its anti-anxiety activity may not be linked to GABA receptor. It did not alter memory function and muscle activity. Taken together, these results suggest that taurine could be beneficial for the control of anxiety in the clinical situations. Copyright (c) 2007 S. Karger AG, Basel.

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EVALUATION OF ANTIOXIDANT SYSTEMS IN PITUITARY-ADRENAL AXIS DISEASES

Adrenal Fatigue / Hypoadrenalism - Low CoQ10 has been shown to lead to hypoadrenalism. The role of adrenal steroids in antioxidant regulation is not known. Previously, we demonstrated some Coenzyme Q(10) (CoQ(10)) alterations in pituitary diseases, which can induce complex pictures due to alterations of different endocrine axes.

Therefore we determined CoQ(10) and Total Antioxidant Capacity (TAC) in pituitary-dependent adrenal diseases: 6 subjects with ACTH-dependent adrenal hyperplasia (AH); 19 with secondary isolated hypoadrenalism (IH), 19 with associated hypothyroidism (multiple pituitary deficiencies, MPH). CoQ(10) was assayed by HPLC; TAC by the system metmyoglobin-H(2)O(2), which, interacting with the chromogenous 2,2(I)-azinobis-(3-ethylbenzothiazoline-6-sulphonate), generates a spectroscopically revealed radical compound after a latency time (Lag) proportional to the antioxidant content. CoQ(10) levels were significantly lower in IH than AH and MPH, with a similar trend when adjusted for cholesterol.

Also TAC was lower in IH than in AH and MPH, suggesting that adrenal hormones can influence antioxidants. However, since thyroid hormones modulate CoQ(10) levels and metabolism, when thyroid deficiency coexists it seems to play a prevalent influence.

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REDUCTION OF SERUM UBIQUINOL-10 AND UBIQUINONE-10 LEVELS BY ATORVASTATIN IN HYPERCHOLESTEROLEMIC PATIENTS

CoenzymeQ10 is a cofactor produced by the body that aids in energy production in the Krebs cycle and mitrochondrial electron transport chain. It is converted into the antioxidant ubiquinol following ingestion: Dyslipidemia, High Cholesterol, Current statin use. CoQ10 levels decrease with age and have also been observed to be low in patients with certain disorders (e.g. cardiovascular diseases, diabetes).

CoQ10 supplementation has been shown to offset some negative side effects of statin medications. Statins + CoQ10 - HMG-CoA reductase inhibitors (lovastatin, pravastatin, rosuvastatin, and simvastatin) decrease the concentration of CoQ10 in the human body.

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ASSOCIATION OF HIGH VITAMIN D STATUS WITH LOW CIRCULATING THYROID-STIMULATING HORMONE INDEPENDENT OF THYROID HORMONE LEVELS IN MIDDLE-AGED AND ELDERLY MALES

Vitamin D is recognized to be an essential element for bone metabolism and skeletal health; however, its deficiency can cause rickets in children as well as an increased propensity for osteoporosis. In addition, it may also affect extraskeletal health. Indeed, vitamin D deficiency has been identified as a risk factor for diabetes mellitus, cancers, multiple sclerosis and other autoimmune diseases, atherosclerosis, and infectious diseases. Few past studies have reported the impact of vitamin D deficiency on autoimmune thyroid disease and demonstrated inconclusive results.

Besides affecting the thyroid gland through immune-mediated processes, vitamin D has been shown to influence rat thyroid follicular cells by directly inhibiting thyrotropin-stimulated iodide uptake in a dose-dependent manner. Recently, a population-based study has reported that high vitamin D status in younger individuals is associated with low circulating thyroid-stimulating hormone (TSH). However, it remains unknown as to why no relationship between vitamin D status and serum TSH levels in middle-aged and elderly individuals was found in this study.

Therefore, in the present study, we examined the relationship between vitamin D status and circulating TSH levels in middle-aged and elderly individuals with thyroid autoimmunity, while taking thyroid function into consideration in addition to the relationship between vitamin D insufficiency and thyroid autoimmunity, the presence of thyroid nodule(s) and thyroid volume in a cross-sectional study.

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ASSOCIATION OF VITAMIN D STATUS WITH SERUM ANDROGEN LEVELS IN MEN

Men with sufficient 25(OH)D levels (?30 μg/l) had significantly higher levels of testosterone and FAI and significantly lower levels of SHBG when compared to 25(OH)D insufficient (20?299 μg/l) and 25(OH)D-deficient (<20 μg/l) men (P < 005 for all). In linear regression analyses adjusted for possible confounders, we found significant associations of 25(OH)D levels with testosterone, FAI and SHBG levels (P < 005 for all). 25(OH)D, testosterone and FAI levels followed a similar seasonal pattern with a nadir in March (122 ?g/l, 159 nmol/l and 408, respectively) and peak levels in August (234 μg/l, 187 nmol/l and 497, respectively) (P < 005 for all).

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