As I often prescribe both substances (hormones) to my patients, generally obtaining excellent results (of course, when the clinical history and tests indicate the need), it's important to remember that the beneficial effects can vary from one patient to another, as each organism has its own particularities. In addition, the levels of both substances tend to decrease progressively from the age of 30, especially in individuals with poor lifestyle habits, such as poor nutrition and a lot of stress. Here are some details about these substances:
DHEA:
“To date, conventional medical societies related to endocrinology have not recognized the need and clinical importance of treating and replacing adrenal dehydroepiandrosterone (DHEA) deficiency. A few conventional medical societies around the world have occasionally and timidly expressed the importance of DHEA replacement. In general, they conclude that there is still not enough data to support the replacement of this hormone. These societies are of the opinion that the scientific literature on DHEA is still scarce and its clinical efficacy has not yet been sufficiently proven. In addition, they express concern that DHEA replacement may be associated with a higher incidence of genital cancer and a reduction in HDL-cholesterol.”
After a careful and exhaustive review of the current scientific literature, as well as reading and discussing the institutional negative reports, we have concluded that there is still no reasonable scientific database to support the idea that the use of DHEA could pose any risk to human health.
We recognize and corroborate a large number of studies in which men and women with DHEA deficiency have been treated and have shown a significant improvement in various physical and mental aspects.
When we look at the studies that show “minor” effects of DHEA treatment, we can see that an important design flaw is often noticeable: the excessively short time that these people have spent receiving the hormone, periods of less than two weeks in most cases, which is notoriously insufficient time for consistent results to be achieved.
Alongside a minority of studies that show negative or non-significant results, there are a large number of studies that unquestionably attest to the importance and, even more so, the multitude of benefits of DHEA replacement. What's more, these studies not only confirm its efficacy, but also conclude that DHEA replacement, the most abundant steroid hormone produced in the human body, is one of the safest and most effective forms of replacement available. Randomized, placebo-controlled and double-blind studies confirm that there are no harmful effects on human health when physiological levels of DHEA are supplemented. Any side effects that do exist are completely linked to the use of excessive doses. The most characteristic signs of excessive doses of DHEA are oily skin, acne and mild hirsutism, all of which can be reversed by adjusting the dosage.
In many studies analyzing DHEA replacement, significant benefits have been obtained in terms of bone mass gain, skin quality, the immune system, glucose sensitivity, insulin sensitivity and lipid profile. Benefits have also been shown in mental and emotional performance, quality of life, fatigue, depression, cardiovascular risk reduction, diabetes and obesity.
It is the opinion of this group that the following arguments support and fully justify replacement treatment with DHEA in adults with low serum levels:
- DHEA is a hormone that is natural to humans, is fully configured to meet our metabolic demands and, in fact, is the hormone present in the greatest quantity in the human body.
- DHEA performs more than 150 anabolic functions in human metabolism.
- It has a multitude of benefits when used in adult individuals who have low levels, making it a valuable tool in the fight against age-related diseases.
- DHEA replacement is safe.
- DHEA replacement is affordable.
In order to improve the safety of DHEA replacement treatment, we recommend that doctors subject their clients to a program of periodic evaluations, including anamnesis, physical examination and complementary laboratory tests every 3 to 12 months, depending on their individual needs. We believe it is equally important to promote a routine of clinical and laboratory evaluations for prostate and breast cancer, at an interval of six to 12 months, depending on each case.
In our experience, the best methods for diagnosing DHEA deficiency are serum assessment of dehydroepiandrosterone sulphate levels and assessment of the excretion of 17-ketosteroid-DHEA metabolites in 24-hour urine using the gas chromatography technique.
The safe doses for DHEA replacement are the so-called physiological doses, between 20 and 100 mg/day for men and 5 to 50 mg/day for women.
In cases where it is clinically important to avoid converting DHEA to Testosterone or Estradiol, you can use 7-Keto-DHEA, DHEA's main active metabolite, which has exactly the same properties as DHEA, but is not converted to other hormones. In this case, the recommended doses can be up to 50 mg/day for women and 100 mg/day for men.
CONCLUSION OF THE CONSENSUS:
Based on the current scientific literature, there is no plausible justification to contraindicate or discourage DHEA replacement treatment in adults with low levels, except for postmenopausal women who are not undergoing menopausal hormone replacement. On the contrary, benefits in sufficient quantity and intensity have already been demonstrated and serve as a basis to allow us to recommend the use of physiological doses of DHEA to correct well-established and previously diagnosed deficiencies in adults, subjecting them thereafter to a regular program of clinical and laboratory monitoring. DHEA replacement is especially justified in individuals with health conditions treated with corticosteroids, since its use can safely counteract the excessive catabolic effects of corticosteroid therapy.” (source: “Consensus #9 - Healthy Longevity Group - Healthy Longevity Group Consensus Group - Healthy Longevity Group Scientific Council”) http://www.longevidadesaudavel.com.br/consensosDetalhes.asp?cod=15#.UUxVB7muB8 )
Still on DHEA (technical text but easy to understand for the attentive reader):
Dehydroepiandrosterone (DHEA) and its active ingredient, DHEA sulfate (DHEAS), are endogenous hormones, synthesized and excreted by the zona reticularis of the adrenal cortex in response to adrenocorticotropic hormone (ACTH). They are produced in the testes and ovaries, with DHEA and DHEAS serving as precursors to approximately 50% of androgens in men and 75% of active estrogen in premenopausal women and 100% of active estrogens after the menopause. They are derived from cholesterol, which is metabolized by cytochrome P450, producing pregnenolone, which gives rise to DHEA and progesterone. During pregnancy, a large amount of DHA and SDHEA is produced by the fetal adrenal glands. After birth, it decreases, remaining stable for up to 5-7 years. At adrenarche, the adrenal glands increase DHEA production again, accelerating at puberty. It peaks between the ages of 20 and 30 and then declines, decreasing by 2% per year. By the age of 80, there are only 10 to 20% of the peak production of youth. Its mechanism of action and clinical role are still unclear. Epidemiological data indicate an inverse relationship between DHEA and DHEAS levels in the frequency of cancer, cardiovascular disease (in men only), Alzheimer's disease and other age-related disorders, changes in immune function, progression of HIV infection, diabetes, obesity.
DHEA on immunity
DHEA is a powerful modulator of the immune response, both through its stimulatory effect on the immune system and its anti-glycocorticoid action. Some of DHEA's functions in the immune system:
- Cytokine production: DHEA regulates the production of cytokines in myeloid and lymphoid cells, increasing the production of IL-2 in T helper (Th1) cells. It negatively controls the production of IL-6 and IL-10 from Th2 cells. Thus, the drop in DHEA seen in the elderly contributes to cytokine imbalance (reduced Th1 production and increased Th2). Dysregulation of IL-6 and IL-10 is associated with autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus.
- Immune cell cytotoxicity: it seems that lymphocytes, in the presence of physiological concentrations of DHEA, mediate a more potent cytotoxicity, followed by antigenic stimulation, attributed to increased IL-2 secretion.
- Monocytes have receptors for DHEA, increasing the production of IL-1, tumor necrosis factor and nitric oxide synthase activity.
Prospective studies in premenopausal women have shown an inverse correlation between the DHEA/cortisol ratio and the risk of developing rheumatoid arthritis before the age of 50. DHEA-S is also low in patients with inflammatory diseases such as Crohn's disease, ulcerative colitis and lupus erythematosus. DHEA has been shown to have an effect on homeostasis by increasing the immune response, accompanied by up-regulation of immunity to different pathogens, viruses, parasites and bacteria. By influencing the rate of cell proliferation and viability of cytokine production, DHEA may be one of the regulators of IgE synthesis and eosinophil proliferation in patients with atopic dermatitis.
In aging, while DHEA decreases, glucocorticoids increase. DHEA reverses the changes associated with glucocorticoids after hemorrhagic trauma in rats, leading to normalization of corticoid levels, suggesting an autoregulatory effect of 11β-HSD1 by DHEA. Thus, it seems that ageing increases the action of glucocorticoids on the immune system (via activation of 11β-HSD1) with less positive action by DHEA, due to its decline. In stressful situations, the hypothalamic-pituitary-adrenal (HHA) axis is activated, releasing adrenocorticotropic hormone (ACTH) via specific peptides, stimulating the release and biosynthesis of glucocorticoids, in this case cortisol. Consequently, there is an increased risk of disease for the body, as there is suppression of anabolic and immunological processes, which can lead to diseases such as diabetes, hypertension, hyperlipidemia, hypercholesterolemia, amenorrhea, sexual impotence, deficits in growth and tissue repair, as well as CNS disorders, causing pathologies associated with mood swings. Since DHEA has a negative relationship with cortisol, i.e. it has an anti-glycocorticoid effect, the question arises as to whether modulating cortisol through specific nutrients and foods could also normalize DHEA levels and, consequently, stimulate one of its actions, which is to modulate the immune system.
The Role of Nutrients and Foods in Hormone Modulation
It is important to administer all the nutrients needed to maintain adequate levels of cortisol and therefore DHEA: this includes high-quality proteins, complex carbohydrates, essential fatty acids, vitamins and minerals.
It's important to avoid severe calorie restriction, as a decrease of 50% can contribute to an increase of 38% in cortisol levels. Fasting and malnutrition also increase cortisol levels. Vitamin E, when administered to exercised rats, together with DHEA, has been shown to attenuate the formation of TBARS in the heart, as well as minimizing the formation of catalases. DHEA and exercise are stressors in exercise, however, with the administration of vitamin E, this process is mitigated. The β-sitosterol found in fruits, vegetables and nuts has been shown to reduce cortisol. It is abundant, especially in avocados, accounting for 83.3% of the fat composition of this food, and avocado oil has 25 times more β-sitosterol than the fruit. In a study with marathon runners, a mixture of β-sitosterol and its glycosides (BSS:BSSG) was shown to inhibit immunosuppression, with changes in the decrease in IL-6 levels and in the cortisol:DHEA ratio, with a decrease in cortisol and an increase in DHEA levels. There was promotion of Th1 and Th2 balance, lymphocyte proliferation and an increase in Natural Killer cells. In a study of patients with depression, omega-3, alone or in combination with fluoxetine, was shown to reduce cortisol and inflammatory cytokines by regulating the HHA axis. Phosphatidylserine, according to a double-blind study with administration doses of 50 and 75 mg in healthy, exercising men, was shown to reduce ACTH and cortisol levels during physical stress. Caffeine also has an effect on cortisol, increasing it as it increases ACTH production. Dark chocolate was shown in a study to reduce the urinary excretion of cortisol and catecholamines when administered 40g a day for 14 days, as well as normalizing stress-related metabolic differences in energy metabolism (glycine, citrate, trans-sconitate, proline and β-alanine).
Vitamin C supplementation also lowers cortisol levels. In one study, supplementation with 1000 mg reduced post-competition cortisol levels in athletes by 30%. This is probably due to the inhibition of enzymes involved in steroidogenesis. By reducing cortisol during strenuous exercise, vitamin C plays an important role in preventing transient immune dysfunction in athletes. Another study of ultramarathon runners supplemented with 500 and 1500 mg of vitamin C showed a decrease in cortisol concentrations in the group with the highest supplementation, and in this group there was also a statistically significant decrease in IL-10 and IL-1 Ra levels. Rhodiola rosea extract also has the ability to increase resistance to chemical, biological and physical stress. In a study of rats subjected to stress, when supplemented with Rhodiola rosea, there was a small increase in ß-endorphins or no increase at all, showing a decrease and prevention of disturbances in the HHA axis.
Conclusion: Although DHEA's exact biological role is unknown, studies show its importance in immunity and disease prevention. It is important to note that DHEA supplementation should only be prescribed by a doctor” (source: “Nutrients and foods enhancing the immunological effects of DHEA” - Text prepared by the Scientific Department of VP Consultoria Nutricional - VP Consultoria Nutricional). https://vponline.com.br/ - dozens of bibliographical references at the link).
MELATONIN
The table below says a lot about her:
“Melatonin is a neurohormone produced by the pineal glands and is believed to have the main function of regulating sleep. This hormone is produced from the moment we close our eyes. In the presence of light, however, a neuroendocrine message is sent blocking its formation, so the secretion of this substance is almost exclusively determined by photosensitive structures, especially at night.”
Melatonin is a substance classified as an indolamine and its precursor is serotonin, an important neurotransmitter. It is speculated that the photoreceptive structures of the retina and pineal gland produce melatonin by modifying the serotonin synthesis pathway through an enzyme, serotonin-N-acetyltransferase. Circulating melatonin acts on the body's various systems to prepare for and induce sleep. This apparatus for producing melatonin is present in vertebrates in general.
It is also believed that maternal melatonin can help control the infant's sleep cycle. Research has shown that babies are in sync with their mothers. As Melatonin is present in breast milk and its concentration is higher at night, babies sleep more with milk offered at night.
In order to have a restful sleep, Melatonin needs to be secreted properly by the pineal gland, and it is assumed that other functions are carried out by Melatonin, such as the body's thermal regulation and changes in sexual behavior.
Production and Action
As with serotonin, melatonin is also produced from an amino acid called tryptophan, which is normally ingested in a balanced diet. Thus, the sequence would be for tryptophan to be transformed into serotonin, and the latter into melatonin. This is why the concentration of serotonin is increased in the pineal gland during the day, while there is light, contrary to what happens with melatonin.
As we have seen, melatonin production is directly linked to the presence of light. When light hits the retina, the optic nerve and other neuronal connections carry this information to the pineal gland, inhibiting the production of melatonin. The highest production of melatonin occurs at night, between 2:00 and 3:00 am, in a normal rhythm of life, and this increased production produces sleep.
During normal sleep, where a large part of the body's energy and balance is restored, in addition to the adequate production of melatonin, other concomitant phenomena take place:
- Significant decrease in cortisol and adrenaline production.
- Restoration of damaged DNA molecules
- Calcium channel blockade
Melatonin production peaks at the age of 3 and declines significantly between the ages of 60 and 70, resulting in poor quality sleep for the elderly. By the age of 60, we have half the amount of melatonin we had at 20, and by 70, levels are very low in many people, almost zero.
| MELATONIN CONCENTRATION IN THE BLOOD IN ng/ml | ||
| AGE | DAYTIME | NIGHT |
| PRE-PUBERTY | 21,8 | 97,2 |
| ADULT | 18,2 | 77,2 |
| SENIL | 16,2 | 36,2 |
| Melatonin concentration in the blood at different stages of life in Chinese men. There is a significant difference between nocturnal and diurnal production, as well as variations in nocturnal production between the pre-puberty, adult and senile groups. | ||
In view of melatonin's effect of causing drowsiness and a feeling of relaxation when released, after 1994 it became more indicated among people who travel internationally in order to adjust their biological time to time zones. Despite inducing sleep, melatonin is not addictive
Melatonin can also be secreted, causing drowsiness and relaxation, when you eat a meal high in carbohydrates, take a long hot bath or are exposed to the sun.
As well as inducing sleep, melatonin is a powerful antioxidant which, like other antioxidants, can slow down the ageing process. As an antioxidant, melatonin possibly reduces the level of the catabolic hormone cortisol. There is also evidence that melatonin stimulates the production of growth hormone.
The Pineal Gland
In animals, the pineal gland determines much of their seasonal behavior, according to the seasons. Thanks to this pineal activity, they migrate in winter, hibernate, mate and, in short, maintain typical behaviors that are repeated every year.
Melatonin is the most important hormone produced by our pineal gland, a tiny gland in the brain, located approximately behind the eye area, responsible for controlling the rhythm of harmony between day and night, light and dark.
In children, the pineal gland is very small and melatonin secretion is not regularized. Perhaps this is one of the explanations for children's unpredictable sleep. Melatonin production is at its best in adolescence and young adulthood, and begins to decline after the age of thirty or forty. By the age of seventy or eighty, secretion of the hormone is severely diminished.
Recent studies have shown that melatonin levels are higher in women, making them more sensitive to seasonal changes in light than men. In the fall and winter, women are more exposed to seasonal mental disorders and weight gain than in the summer. However, the hormonal supplement for both men and women is similar: it decreases and becomes similar in losses around the same age.
The functioning of the pineal gland is important for the body to remain adapted to the conditions of need, such as activity during the day and rest at night.
Consequences of Melatonin Decline
A person under stress normally produces more adrenaline and cortisol. For every molecule of adrenaline formed, four molecules of free radicals are produced, increasing the likelihood of cell damage. In addition, adrenaline and cortisol induce the formation of a tryptophan pyrolase enzyme capable of destroying tryptophan before it reaches the pineal gland. As a result, neither melatonin nor serotonin is produced (which can lead to carbohydrate cravings, weight gain and depression).“
Melatonin is an anti-free radical substance and therefore an antioxidant. It is able to cross the blood-brain barrier (the membrane that protects the brain) and is therefore able to perform functions at the neuronal level. This action is of fundamental importance in protecting neurons from free radical damage. Our brain tissue is much more susceptible to the action of free radicals than any other part of our body and, as Melatonin levels fall, there can be a concomitant decline in brain function.
Sleep disorders could also be one of the effects of a decrease in melatonin. As we get older, the pineal gland functions less and there is a drop in melatonin production. This causes some elderly patients to complain about the quality of their sleep or insomnia, but it may be that they sleep easily when they shouldn't, during the day, watching television, etc.
As we get older, our immune system loses its vigilant performance, decreasing our defenses and allowing our body to become more vulnerable to constant aggressions. Current research suggests that there is an important relationship between certain hormones (oestrogen, testosterone, DHEA, melatonin, pregnenolone and growth hormone) and the immune system. At this point, melatonin has been highlighted as an agent for maintaining the harmony and functioning of the immune system.
It seems to be able to increase the mobility and activity of defense cells, strengthen the formation of antibodies, facilitate defense against viruses, moderate the overproduction of corticoids generated by prolonged or repetitive stress and balance thyroid function, which acts directly on the production of very important defense cells, the T lymphocytes” (source: “Melatonin - Ballone GJ, Moura EC - Melatonin - in. PsiqWeb, Internet” - http://www.psiqweb.med.br/site/?area=NO/LerNoticia&idNoticia=113)
MELATONIN - A little more about it (technical text but easy to understand):
“The behavioral changes that occur according to the 24-hour rhythm in living beings are one of the most prominent features of life on planet Earth. The nervous system, in both simple and complex organisms, has developed over the millennia to meet the demands of time-dependent variations related to the light-dark cycle.”
The pineal gland and melatonin are of fundamental importance in the body's adaptation mechanisms to the environment, the insufficiency of which may be related to the genesis of various pathological processes, including neurological diseases. Melatonin acts as a neuroendocrine transducer, transforming external information about the night-day cycle into biochemical signals that modulate the time-dependent organization of autonomic, neuroendocrine and behavioural functions.
Melatonin (N-acetyl-methoxytryptamine) was characterized in 1958; it is an indoleamine known today as the main product secreted by the pineal gland, which is a midline organ in the brain, approximately 8 mm long, located below the splenium of the corpus callosum.
The regulation of melatonin secretion in the pineal gland is unique; unlike other glands, it is not influenced by other hormones secreted by other glands or cells, but rather the major regulator of melatonin production is the light-dark cycle, day-night environment, being a final organ of the visual system.”
Melatonin is only produced at night; light has a paradoxical effect on its production, stimulating it when it is received during the day and inhibiting it at night. The suprachiasmatic nucleus in the hypothalamus (which is the biological clock) receives light information via axons from the retinohypothalamic tract and, through norepinephrine, via beta-adrenergic receptors, stimulates the production of melatonin in the pinealocyte.
Melatonin secretion decreases with age; therefore, a series of biological events linked to aging may be related to this decrease. Other important aspects of melatonin include its oncostatic effect, its interaction with the immune and gonadotrophic systems, its potent antioxidant effect, its modulation of the dopaminergic and serotoninergic systems, its potentiation of opioid analgesia and GABA neurotransmission, its involvement in nitric oxide production and neurovascular control.
There are many biological rhythm disorders, also known as dyssynchronosis. They can be of external or environmental origin, due to the individual's lifestyle, as in the case of shift worker syndrome, jet lag (a disorder secondary to rapid time zone changes) and poor adaptation to the change in daylight saving time. Delayed and advanced sleep phase syndrome, rhythm disturbances in the blind and Smith-Magenis syndrome have an endogenous origin. Other diseases such as seasonal depression, bipolar depression, multiple sclerosis, premenstrual syndrome, migraine and cluster headaches have a marked chronobiological component, with a clear variation in their signs and symptoms according to circadian or circannual rhythms
Several neurological diseases, in addition to sleep disorders, are clinically influenced by biological rhythms, such as headaches, epilepsy, dementia, neurovascular, extrapyramidal, neuromuscular, demyelinating diseases and neoplasms.
Some headaches have a clear circadian rhythmicity, such as hypenic headache and cluster headache; others have a circannual variation, such as cluster headache and cyclical migraine; and finally menstrual migraine has a monthly rhythmicity.
Many biological effects of melatonin characterize it as a potential candidate for the pathophysiology and treatment of migraine. Its effects are to potentiate GABA, inhibit glutamate, sweep away nitric oxide, modulate the action of serotonin, dopamine and opioid analgesia, act as an anti-inflammatory, as well as having a similar molecular structure to indomethacin, a molecule of great interest in the field of headaches.
Recently, we showed that melatonin 3 mg was effective in preventing migraines. In migraine, decreased levels of melatonin and changes in its secretion curve have been detected. Clinically, attacks can occur at night, changes in sleep rhythm trigger migraine attacks, migraine patients sleep less, have longer latency and more nocturnal awakenings.
In a study carried out by us, altered melatonin levels were observed in patients with chronic migraine, with an increase in its peak and lower levels in cases of insomnia, indicating a chronobiological dysfunction(3). In another study of 200 patients with episodic and chronic migraine, it was found that 93 patients (46.5%) reported crises after changing their sleep schedule, 28 patients (14%) reported working a changed shift, resulting in 86% of them having worsening headaches. In addition, 86 patients (43%) reported frequent travel across time zones, of whom 79% had worsening headaches.
Headache after working shifts was correlated with fatigue and memory complaints. Headache after traveling across time zones was correlated with concentration and memory complaints. The sleep phase (22:22 h + 01:17) was significantly delayed (22:46 h + 01:20 h) p < 0.001, with 108 patients (54%) changing their sleep phase, ranging from -02:30 h to + 05:00 h. The majority of patients (75,69%) delayed, while 33 (31%) advanced their sleep phase. Delays or advances of more than 2:00 h accounted for 12.5% of the patients(4).
In cluster headaches, the importance of melatonin and rhythmicity is well established. A double-blind placebo-controlled study shows that melatonin is superior to placebo in episodic and chronic cluster headaches. Melatonin levels are decreased in patients with cluster headaches. The relationship between cluster headache and increased temperature is probably mediated by altered melatonin secretion.
In epilepsy, circadian variation is also important. In general, generalized seizures tend to occur more during the day, while secondarily generalized seizures occur more during sleep. The time dependency of seizures decreases with age, along with a decrease in melatonin secretion.
Melatonin shows antiepileptic action in both experimental models and humans, with a probable gabaergic mechanism. In patients with dementia, the appearance of agitation at the end of the day, the “sundowning” phenomenon, has been successfully treated with melatonin. Abnormal levels of melatonin can appear as early as the pre-clinical phase. In experimental models of Alzheimer's, an increase in survival and a reduction in pathological lesions were observed.
Melatonin has a powerful free radical scavenging action and is important as a neuroprotective substance. In experimental models of ischemia, there was a reduction in the affected area with its administration, as well as a reduction in edema and better recovery from neurological deficits. There is also a seasonal and circadian variation in stroke events.
Melatonin modulates the action of dopamine, inhibiting its release and thus potentially interfering with movement disorders. There are studies showing changes in melatonin levels in Parkinson's disease, benefit in tardive dyskinesia, and due to its neuroprotective action, it can act as an adjuvant in the treatment of Parkinson's disease. Behavioral REM disorders in Parkinson's disease and Lewy body dementia have improved with the use of melatonin.
The interaction of neurological diseases with the biological effects of melatonin is an avenue for scientific research, with the potential prospect of a better understanding of pathophysiological mechanisms and more appropriate therapeutic management
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