Introduction

There is a strong association between histamine level and age; as age increase the histamine level decrease. Also between sun sensitivity and histamine level there is a strong association. The lower the histamine level the higher the percentage of sun sensitivity patients. This suggests there should be a metabolic explanation for the association between histamine level, sun sensitivity and age. In this report we try to give a explanation for sun sensitivity in HPU-patients.

Results

Looking at the results over the past ten years, the one association that is striking, is the inverse relationship between histamine level and age. This is not a new finding. But within the group of HPU-patients it is clear from the present study that this relationship is much stronger in a statistical sense than in open population.
Looking at a sub-group of controls, almost all of the people with very low histamine levels had poor folic acid status. Even where this did not show as a low red-cell folate, there was an increase in FIGLU-excretion (Formiminoglutamic acid) after histidine loading. When the really low folate controls are removed from the forementioned statistics, the relationship between histamine and age strengthens to a very high statistical significance.
Further investigation according to Howard MacLaren Howard (pers. comm.), although it is so far that the complete research has been carried out on a relatively small group, shows that extreme low histamine level and FIGLU excretion correlates very well for around 85% of the patients. In general, as FIGLU increases (reflecting poor folate status) histamine decreases.
It is very clear from the findings that the poor folate status is not be the only reason for low histamine levels. FIGLU excretion after amino acid loading, being the most reliable predictor of folate deficiency and low histamine is only true for young female patients with very low hitamine levels. However, the relationship between the age of the patient, poor folate status and lowered histamine is statistically of very high significance. On the other hand high copper levels tends to decrease the histamine levels too. Copper tends to activate MAO and DAO enzymes that will break down histamine. This shows to be the other main reason for low histamine levels in HPU-patients. This is not influenced by using a copper containing birth control device.

Histamine is formed from histidine by histidine decarboxylase. All decarboxylation reactions are pyridixal-5-phosphate dependent. Because of the deficiency of pyridoxal-5-phosphate in HPU-patients histidine is not converted to histamine but the concentration of histidine is increased. This histidase is both induced by high histidine levels, hormones like estrogens and other porfyrinogens. Histidine will be converted, as age increases, very rapidly in trans-urocanic acid.

The pathway of FIGLU-formation

If histidine is not converted to histamine by decarboxylase, histidine will converted to FIGLU and if there is no folate deficiency into glutamic acid and formyl-THFA. The first reaction in this pathway is the nonoxidative deamination of L-histidine to trans-urocanic acid by histidase (histidine ammonia-lyase). In this reaction ammonia is released.^1,2 This enzyme is expressed with high activity in the liver and in the skin.^3,4 Histidase is regulated in a complex developmental, hormonal, and tissue-specific manner.^5-8
In contrast, hepatic activity is not detectable until four days after birth, and subsequently increases gradually until puberty. Adult females have a twofold higher level of hepatic histidase than males, owing to estrogen induction.^5-7 Other hormones, including glucocorticoids, glucagon, and triiodothyronine, also regulate hepatic histidase, albeit to a lesser extent than estrogen.^5,6,8 Dietary regulation of hepatic histidase has been demonstrated. High-protein diet show increased hepatic histidase activity^.9,10
However, the differences between the developmental programs of histidase in liver and epidermis could reflect differences in the metabolism of urocanic acid in these two tissues. In the liver, urocanic acid is an intermediate in the conversion of histidine to glutamic acid, whereas in the epidermis, it accumulates and may be both a UV protectant and an immunoregulator.
Urocanase catalyses the nonoxidative conversion of trans-urocanic acid to imidazolonepropionic acid. Imidazolonepropionic Acid Hydrolase converts imidazolonepropionic acid to formiminoglutamic acid (FIGLU), an important intermediate that links histidine catabolism to folate metabolism. FIGLU is a donor of formyl groups to tetrahydrofolic acid and is a marker for folic acid deficiency.¹¹
Formiminotransferase catalyses the formation of formiminotetrahydrofolic acid from FIGLU. Tetrahydrofolic acid is required for this reaction, and glutamic acid is liberated. Folic acid deficiency results in a strikingly increased excretion of FIGLU in response to loading with L-histidine, presumably due to the reduction in available tetrahydrofolic acid.¹² Trans-urocanic acid is formed from the deamination of L-histidine by histidase in the liver and in the stratum corneum.¹³ In the epidermis, trans-urocanic acid (lmax = 275 nm) undergoes an isomerization to cis-urocanic acid in UV light,¹⁴ the proportion of cis and trans isomers varying according to the UV light exposure.^15,16
Epidermal urocanic acid probably acts as natural sunscreen ^17,18 led to the hypothesis that the deficiency of urocanic acid in the skin causes more sensitivity to sunlight and more susceptible to sunburn than others. The ability of urocanic acid to protect skin from sunburn has been demonstrated by a number of investigators.^19-23 A study of skin erythema in histidinemic children suggested increased sensitivity to UV light.24 Urocanic acid in the skin may also reduce photomutagenesis, since the absorption spectra of both the cis and trans isomers of urocanate overlap with the absorption spectrum of DNA.¹⁴

Discussion

In HPU-patients the histamine level is not only decreased because of the deficiency of folic acid by also by the induction of the enzyme activity of MAO and DAO enzymes by copper. Even more than in open population the association between age and histamine level is very strong. But even at very young age (18-25 years) some women with HPU shoes markedly decreased histamine levels. In almost al these patients a certain amount of sun sensitivity excists.
In HPU-patients which strongly decreased histamine levels, histidase activity is strongly increased. This probably shows an induction mechanism on liver histidase. This is not only caused by estrogen in birth control pills, but also by porfyrinogenic substances with cannot be excreted by HPU-patients.Birth control pills are used on very young age (from 13 years and older) because of the severe menstrual problems which starts because of the deficiency of pyridoxaal-5-phosphate. Estrogen happens to be one of the main porfyrinogens in these young girls. Histadine levels are in fact low in plasma and urine of HPU-patients. HPU-patient are sun sensitive as well. In the questionnaires of HPU-patients there was a striking association between sun sensitivity and low histamine levels. Probably there is hardly enough histidine in the epidermis to be converted by the epidermal-histidase in the skin in trans-urocanic acid. That’s why the UV-screen is hardly build up and probably sun sensitivity develops.

Literature

1. Peterkofsky A: The mechanism of action of histidase: Amino-enzyme formation and partial reactions. J Biol Chem 237:787, 1962.
2. Furuta T, Takahashi H, Shibasaki H, Kasuya Y: Reversible stepwise mechanism involving a carbanion intermediate in the elimination of ammonia from L-histidine catalyzed by histidine ammonia-lyase. J Biol Chem 267:12600, 1992.
3. Dhanam M, Radhakrishnan AN: Comparative studies on histidase: Distribution in tissues, properties of liver histidase and its development in rat. Indian J Exp Biol 14:103, 1976.
4. Bhargava MM, Feigelson M: Studies on the mechanisms of histidase development in rat skin and liver. I. Basis for tissue specific developmental changes in catalytic activity. Dev Biol 48:212, 1976.
5. Feigelson M: Multihormonal regulation of hepatic histidase during postnatal development. Enzyme 15:169, 1973.
6. Lamartiniere CA, Feigelson M: Effects of estrogen, glucocorticoid, glucagon, and adenosine 3´:5´-monophosphate on catalytic activity, amount, and rate of de novo synthesis of hepatic histidase. J Biol Chem 252:3234, 1977.
7. Lamartiniere CA: Neonatal estrogen treatment alters sexual differentiation of hepatic histidase. Endocrinology 105:1031, 1979.
8. Armstrong EG, Feigelson M: Effects of hypophysectomy and triiodothyronine on de novo biosynthesis, catalytic activity, and estrogen induction of rat liver histidase. J Biol Chem 255:7199, 1980.
9. Kang-Lee YAE, Harper AE: Effect of histidine intake and hepatic histidase activity on the metabolism of histidine in vivo. J Nutr 107:1427, 1977.
10. Cedrangolo F, Illiano G, Servillo L, Spina AM: Histidine degradation enzymes in rat liver: Induction by high protein intake. Mol Cell Biochem 23:123, 1979.
11. Rao DR, Greenberg DM: Studies on the enzymic decomposition of urocanic acid. IV. Purification and properties of 4(5)imidazolone-5(4)propionic acid hydrolase. J Biol Chem 236:1758, 1961.
12. Luhby AL, Cooperman JM, Teller DN: Histidine metabolic loading test to distinguish folic acid deficiency from vit. B12 in megaloblastic anemias. Proc Soc Exp Biol Med 101:350, 1959.
13. Scott IR: Factors controlling the expressed activity of histidine ammonia-lyase in the epidermis and the resulting accumulation of urocanic acid. Biochem J 194:829, 1981.
14. Morrison H, Avnir D, Bernasconi C, Fagan G: Z/E photoisomerization of urocanic acid. Photochem Photobiol 32:711, 1980.
15. Norval M. Simpson TJ, Bardshiri E, Crosby J: Quantification of urocanic acid isomers in human stratum corneum. Photodermatology 6:142, 1989.
16. Pasanen P, Reunala T, Jansen Jansén CT, Rasanen Räsänen L, Neuvonen K, Ayras P: Urocanic acid isomers in epidermal samples and suction blister fluid of non-irradiated and UVB-irradiated human skin. Photodermatology 7:40, 1990.
17. Zenisek A, Kral JA The occurrence of urocanic acid in human sweat. Biochim Biophys Acta 12:479, 1953.
18. Zenisek A, Kral JA, Hais IM: “Sun-screening” effect of urocanic acid. Biochim Biophys Acta 18:589, 1955.
19. Everett MA, Anglin JH Jr, Bever AT: Ultraviolet induced biochemical alterations in skin. I. Urocanic acid. Arch Dermatol 84:717, 1961.
20. Baden HP, Pathak MA: The metabolism and function of urocanic acid in skin. J Invest Dermatol 48:11, 1967.
21. Zenisek A, Hais IM, Strych A, Kral JA: Does solar irradiation affect the natural antisunburn properties of the skin? Fr Ses Parfums 12:131, 1969.
22. Wadia AS, Sule SM, Mathur GP: Epidermal urocanic acid and histidase of albino guineapig following total body UV-irradiation. Indian J Exp Biol 13:234, 1975.
23. Ohnishi S, Nishijima Y, Hasegawa I, Futagoishi H: Study of urocanic acid in the human skin surface (II). Geometrical isomers and sunscreen effect. J Soc Cosmet Chem Jpn 13:61, 1979.
24. Baden HP, Hori Y, Pathak MA and Levy HL: Epidermis in histadinemia. Arch. Dermatol 100:432. 1969

Introduction

There is a big difference between the occurrence of burnout in men and women. These burn burnout symptoms are associated with the occurrence of specific autoimmune diseases. In the open population, Bechterev’s disease, Hashimoto’s thyroiditis, systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis are two to ten times more common in women than in men. Autoimmune diseases, which are more common in women, usually occur during sexual maturity. It is remarkable that not all autoimmune diseases are equally well represented in burnout and certainly not in HPU. Since HPU is also much more common in women and there are large differences in the symptoms between women and men, this must have something to do with the difference between men and women. If so, it means not only that there is a difference in the incidence of autoimmune diseases between men and women, but perhaps there should also be a difference in treatment. The underlying mechanisms regarding the differences in the incidence of burnout and the possibilities of specific treatment for women with burnout and autoimmune diseases are discussed. There are a number of factors that can explain a difference between men and women:

The pro-inflammatory effect of estrogens

Besides the pro-inflammatory effect of estrogens, progesterone and testosterone has an anti-inflammatory effect of [5,8]. Many authors describe the influence of sex hormones on the immune system and the stress regulation system. It appears that estrogens mainly have a pro-inflammatory effect, while testosterone and dihydrotestosterone are more anti-inflammatory[5]. Testosterone seems to shift from Th2 to Th1, while estrogens have a stimulating effect on the Th2 system. Most people with HPU have Th1 dominance.

It appears that both men and women who suffer from autoimmune diseases or stress or burn out have free and total testosterone plasma levels that are significantly lower than in healthy control groups.2,7

Programmed sexual hormone sensitivity at the beginning of life

In women there is a programmed sexual hormone sensitivity at the beginning of life till 18 year.⁴ Another factor is the change in regulation due to early exposure to steroids.⁴ In the eighteenth year, lymphocytes have both estrogens and androgenic receptors. After the eighteenth year, all androgen receptors of lymphocytes disappear and are only sensitive to estrogen. The programming of estrogen sensitivity can therefore influence the development of stress processing and the development of autoimmune diseases after the age of eighteen. This increased sensitivity to estrogen occurs early in life during pregnancy when the unborn child is exposed to obesogens and organotins. Women who have taken the pill also have children who are sensitive to estrogens.

Production of large amounts of prolactin in women

The production of higher levels of prolactin in women is also a possible factor in the occurrence of stress, burnout and autoimmune diseases in women.¹⁰ If you want to measure prolactin, you have to be careful; it has a circadian rhythm; it is high in the late night and low during the day. Prolactin has a pro-inflammatory effect at high concentrations. Hyperprolactinemia has been associated with the occurrence of several autoimmune diseases. The exact mechanism of action is unclear, but measures to reduce the amount of prolactin seem to improve autoimmune diseases.^1,9 Estrogens stimulate the production of prolactin in women. But the difference in stress response between men and women also leads to increased prolactin production in women. When a stress response occurs in a man, it primarily means increased activation of the right orbital frontal lobe in the brain and reduced third activation of the left orbital frontal lobe. In women, however, the stress response has a completely different effect. In women, a stress response does not significantly alter the frontal lobe but leads to a limbic, dopaminergic, oxytocin-, angiotensin- and prolactin-containing response. Women therefore produce more prolactin than men, not only because of the higher production of estrogens, but mainly because of the higher production of prolactin during the stress response. Prolactin increases the adhesion of leukocytes to tissue. Oxidative stress causes prolactin to be proteolytically degraded to a factor that, among other things, is strongly pro-inflammatory.¹¹
Another factor is the change in regulation due to early exposure to steroids.⁴ In the eighteenth year, lymphocytes have both estrogens and androgenic receptors. After the eighteenth year, all androgen receptors of lymphocytes disappear and are only sensitive to estrogen. The programming of estrogen sensitivity can therefore influence the development of stress processing and the development of autoimmune diseases after the age of eighteen. This increased sensitivity to estrogen occurs early in life during pregnancy when the unborn child is exposed to obesogens and organotins. Women who have taken the pill also have children who are sensitive to estrogens.
Young girls who do top-class sports have elevated prolactin levels in their blood. These increased levels are accompanied by a stronger development of the breasts, which is an undesirable situation. This increase in prolactin is accompanied by a sharp increase in testosterone and estrogen. This often prevents menstruation, which is a welcome side effect. In young men who exercise at the top of their game, prolactin increases much less, but testosterone decreases and estrogen increases. That female athletes are more or less male is what we expect from their appearance, but that male athletes are more female is often denied or wrongly attributed to the use of stimulants.

Prolactin is produced both in the pituitary gland and in the body. Prolactin is produced by the activation of histamine receptors, among other things. The binding of antihistamines to H1 receptors such as cimetidine ensures an additional release of prolactin.
Prolactin inhibits the release of GnRH and reduces LH (luteinizing hormone) and FSH (follicle stimulating hormones). Prolactin lowers hepcidin, causing the free iron level in the blood to rise, but ferritin falls. In addition, prolactin with Parathormoon stimulates serotonin production in the breast to bone loss.

Prolactin and celiac disease

Celiac disease is a gluten-sensitive autoimmune enteropathy in which both adaptive immunity and innate immunity are involved in its development (111). Serum prolactin levels were positively correlated with disease activity, degree of mucosal atrophy and serum concentration of anti-endomysial antibodies. Recently, a longitudinal study showed that prolactin decreased 6 months after a gluten-free diet. The evidence that prolactin decreases at the same time as the decrease in antibodies to transglutaminase indicates a direct association with a gluten-free diet and hormone levels (112).
In fact, women have improved immune reactivity: they have a better ability to express antigens and mitogenic reactions, increased antibody production, higher immunoglobulin levels (Ig) and the ability to reject antigens more quickly (5). The immune and neuroendocrine systems are closely linked and participate in dynamic two-way communication. Prolactin has a recognized immunostimulatory effect, in particular it inhibits the negative selection of autoreactive B lymphocytes and promotes autoimmunity. Therefore, hyperprolactinemia is associated with several autoimmune diseases. Note that prolactin stimulates immunoglobulin production. It also stimulates the development of antigen-presenting cells, the richest class II histocompatibility complexes and stimulation molecules (CD86, CD80 and CD46) (24).

Prolactin and thyroid autoimmune diseases

Autoimmune thyroid diseases consist mainly of two diseases, Graves’ disease and Hashimoto’s thyroid inflammation (113). Hyperprolactinemia was found in 20% of patients with autoimmune thyroid disease and was twice as frequent in patients with hypothyroidism. About 90% of Hashimoto’s inflammatory thyroid patients showed significantly higher PRL levels associated with decreased cortisol titers (114). The role of dopamine agonists in the treatment of autoimmune thyroid disease is not yet known. There is a theory whereby Candida antigens responsible for the incidence of autoimmune thyroid disease, gluten sensitivity and diabetes must be attributed. In the context of this discussion, the answer could also be prolactin cytokine.

Hyperprolactinemia as a consequence of D2 receptor blocking by antipsychotics

D2 receptor blocking antipsychotics cause hyperprolactinemia in 60% of children and adolescents, 40% of men and 60% of women. Longstanding hyperprolactinemia in adults leads to reduced bone density and a double increase in the risk of hip and thigh fractures. In addition, women with hyperprolactinemia have a 16% higher risk of developing breast cancer- Activation of the HPA axis by estrogens that produce more cortisol[6,3].
The increase in cortisol production is often attributed to the stress response, but it is precisely the continuous stress response that causes less and less cortisol to be produced and this production to be maintained initially by the sacrifice of DHEA and Pregnenolone Steal Syndrome. DHEA inhibits cortisol production, so sacrificing DHEA for cortisol production is the beginning of a major problem.

.A fourth factor is therefore the activation of the HPA axis (hypothalamic-pituitary-adrenocortical cortex), the activation of the HPA axis produces more cortisol. Normally, this increase is regulated by increased production of cortisol binding globulins (CBG) and DHEA. However, if the HPA axis remains (over)active for a prolonged period of time, there is a prolonged (over)production of cortisol, which causes the change in sensitivity to cortisol and thus reduces the immunoregulatory effect. This can lead to a further shift from Th1 to Th2.

Activation of estrogen receptors by organotins and obesogens

Last, but not least, is the increased activation of estrogen receptors by the presence of organotins and obesogens.⁷ Organotins are harmful to the visceral organs and obesogens make fat. Both substances are contained in the daily diet (as pesticide and herbicide residues), are used in plastics, are contained in hormone preparations in animal husbandry (e.g. chickens and cows), are used as fungicides in paints and reduce textile abrasion. Organotins and obesogens are considered to be one of the major factors in endocrinological, neurological and immunological disorders. They have a high affinity for estrogen receptors and a half-life that is at least ten times longer than that of natural sex hormones. This means that organotins and obesogens pathologically prolong the activation of estrogen receptors. This activates a large number of genes with anti-inflammatory and fat-producing effects. Due to the increased presence of estrogen receptors, women therefore have an increased risk of developing autoimmune diseases. The overactivity of the estrogen receptor indicates, among other things, reduced insulin sensitivity, increased cholesterol levels and reduced production of vitamin D, which further promotes pro-inflammatory activation.
HPU vitamin D receptor, Borrelia and prolactin production in HPU, Borrelia infections often have a different course after a tick bite and the clinical picture ends with a post-lymph. The possible cause can be a decrease in the zinc content of the tissue and a disturbance in vitamin D metabolism. Borrelia burgdorferi acts on the vitamin D receptor. The VDR (vitamin D receptor) must ensure that vitamin D reaches the cell from the blood. Borrelia reduce the function of the vitamin D receptor (in monocytes) by half. As a result, more 1.25 vitamin D remains in the bloodstream. The virus Epstein Barr also attacks the VDR in the same way. Like hormones, vitamin D has a feedback cycle. This means that if the values in the blood become too high, a process begins to normalize the values.

The VDR plays an important role in the body and is found in almost all body tissues and has numerous functions. The VDR would play a role in the production of insulin, prolactin, muscle function, immune and stress response, melanin synthesis and differentiation of skin and blood cells. Since the Borrelia directly influence the function of the VDR, many body processes are disturbed in their function. Many, if not all, tissues contain an intracellular receptor for 1,25-dihydroxyvitamin D. 6 When 1,25-dihydroxyvitamin D is introduced into the cell and has formed a complex with the receptor, a combination with a vitamin A-containing complex is formed. This combination binds to a vitamin D response element in the genes involved, whereupon the gene can be expressed. About 3% of our genes contain a vitamin D response element, which means that the synthesis of many proteins in our body depends on vitamin D status. Research in recent decades has provided increasing evidence of a role of vitamin D in immunological defense, autoimmune processes, muscle function, cell differentiation, and inhibition of tumor cell proliferation. The question now is whether the additional intake of vitamin D helps if the cause of the deficiency lies in a reduced effect of the vitamin D receptors. In this case, there is no vitamin D deficiency, the activated vitamin D3 will be bound in the tissue to copper-calcitriol.

The vitamin content in the bloodstream increases, which triggers the feedback cycle. Blood values then show a vitamin D deficiency, which often occurs in chronic infectious diseases. In this way, vitamin A and vitamin D are kept in balance in the body. And an excess of vitamin D reduces the amount of vitamin K in the body without sufficient vitamin A. Vitamin K deficiency can lead to arteriosclerosis, blood clotting problems, kidney stones, osteoporosis and the like.

Reduced sensitivity of the receptors due to a lack of ATP

The mechanisms described above not only show why women are more sensitive to stress, but also give us tools to treat it. In addition to the use of resoleomics, there are interventions that influence the above factors. It is important to regulate sex hormones, desensitize estrogen receptors and free them from obesogens and organotins. Curcumin regulates both the HPG axis (hypothalamic-pituitary-gonadal axis) and the HPA axis and regulates both sex hormones, prolactin and cortisol. Panax ginseng and ginkgo biloba are another way to regulate the HPA axis. The further regulation of prolactin can be achieved with dopamine. The use of Mucuna pruriens can make a good contribution to this. Soy extracts and red clover desensitize the estrogen receptors and increase SHBG production in the liver. In order to push organotins and obesogens out of the estrogen receptors, it is important to use natural ligands with a higher affinity to the estrogen receptors than organotins and obesogens. Instead of organotins and obesogens, they occupy the estrogen receptors, but only for a short physiological period.

These natural ligands are: Phyto-oestrogens from soy products, other isoflavones from e.g. red clover, lucerne, curcumin, peas and other legumes. Organotins and obesogens are broken down by glutathione-dependent detoxification organisms, which are activated by sulphurous amino acids, proteins and selenium. Cysteine, methionine and glutathione can be used to stimulate these detoxification mechanisms. It is also important to reduce the absorption of organotins and obesogens, e.g. by consuming organic food and avoiding plastic packaging and preservatives for food and beverages.

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