The evolution of genomic stability to a mechanism in reproduction and psychiatry.

There are two forms of immune defense, the specific or adaptive immune defense and the unspecific innate immune defense. Vaccination is utilized against specific bacteria via the adaptive immune system. The innate immunity DNA stress defense is a non-toxic mechanism developed in yeasts and conserved in mammals and in plants. Although the steroidal hormone cascade has overtaken the stress response and allows superfast response via non-genomic receptors, the old innate immunity response is still mediated via the steroidal hormones cascade. The classical drug/receptor model has provided for many solutions, however, in antibiotics, cancer, and in severe mental diseases this model reaches to certain limits. The NIH/Department of Mental Health has developed a new model that shows severe mental diseases may be immune diseases that can be treated by replacing old diseased nerve cells by new healthy nerve cells, where the old innate immunity may be exploited. This means that severe mental diseases are physical diseases. A newly developed model, where modifications of the steroidal hormone cascade help to understand bipolarity, schizophrenia, and PTSD in men and women can be transferred to gynecological hormone modifications in women, where innate immunity is mediated via the same steroidal hormone cascade. Treatment via immune response via the DNA cascade should be developed in cancer, infections and severe mental disease, because foreign cells or diseased cells may be removed by the unspecific innate immunity.

Model approach for stress induced steroidal hormone cascade changes in severe mental diseases.

INTRODUCTION: Stress was described by Cushing and Selye as an adaptation to a foreign stressor by the anterior pituitary increasing ACTH, which stimulates the release of glucocorticoid and mineralocorticoid hormones. The question is raised whether stress can induce additional steroidal hormone cascade changes in severe mental diseases (SMD), since stress is the common denominator. METHODS: A systematic literature review was conducted in PubMed, where the steroidal hormone cascade of patients with SMD was compared to the impact of increasing stress on the steroidal hormone cascade (a) in healthy amateur marathon runners with no overtraining; (b) in healthy well-trained elite soldiers of a ranger training unit in North Norway, who were under extreme physical and mental stress, sleep deprivation, and insufficient calories for 1 week; and, (c) in soldiers suffering from post traumatic stress disorder (PTSD), schizophrenia (SI), and bipolar disorders (BD). RESULTS: (a) When physical stress is exposed moderately to healthy men and women for 3-5 days, as in the case of amateur marathon runners, only few steroidal hormones are altered. A mild reduction in testosterone, cholesterol and triglycerides is detected in blood and in saliva, but there was no decrease in estradiol. Conversely, there is an increase of the glucocorticoids, aldosterone and cortisol. Cellular immunity, but not specific immunity, is reduced for a short time in these subjects. (b) These changes are also seen in healthy elite soldiers exposed to extreme physical and mental stress but to a somewhat greater extent. For instance, the aldosterone is increased by a factor of three. (c) In SMD, an irreversible effect on the entire steroidal hormone cascade is detected. Hormones at the top of the cascade, such as cholesterol, dehydroepiandrosterone (DHEA), aldosterone and other glucocorticoids, are increased. However, testosterone and estradiol and their metabolites, and other hormones at the lower end of the cascade, seem to be reduced. 1) The rate and extent of reduction of the androgen metabolites may cause a decrease of cellular and specific immunity which can lead to viral and bacterial infections; joint and stomach inflammation; general pain; and allergic reactions. 2) The decrease in testosterone, and estradiol in SMD may have detrimental effects in cell repair as the estradiol metabolite, 2-methoxy-estradiol (2ME2), helps to transforms stem cells into functional cells. As dopamine and 2ME2 are inversely metabolized via various forms of catechol-O-methyl transferase (COMT), well-being and hypertension may be related. 2ME2 is related to vascular endothelial growth factor (VEGF), which regulates blood capillary growth and O2 supply. As reduced O2 is a key marker of stress, the increase of glucocorticoids in all forms of mental and physical stress cannot counterbalance the reduced 2ME2 in cellular and mental stress. The increased cholesterol and triglycerides are related to stroke and infarction, contributing to a reduced life expectancy in SMD between 14 and 20 years. The increase of aldosterone leads to increases in anxiety, edema, and lung infections. DISCUSSION: Increasing mental and physical stress is related to systematic deviations in the steroidal hormone cascade in the non-psychotic state, which then may cause life threatening co-morbidities in PTSD, SI, and BD.

The impact of testosterone imbalance on depression and women's health.

Women suffer more often from depression than males, indicating that hormones might be involved in the etiology of this disease. Low as well as high testosterone (T) levels are related to depression and well-being in women, T plasma levels correlate to depression in a parabolic curve: at about 0.4-0.6 ng/ml plasma free T a minimum of depression is detected. Lower levels are related to depression, osteoporosis, declining libido, dyspareunia and an increase in total body fat mass. Androgen levels in women decrease continuously to about 50% before menopause compared to a 20-year-old women. Androgen levels even decline 70% within 24 h when women undergo surgical removal of the ovaries. Conventional oral contraception or HRT cause a decline in androgens because of higher levels of SHBG. Hyperandrogenic states exist, like hirsutism, acne and polycystic ovary syndrome. Social research suggests high androgen levels cause aggressive behavior in men and women and as a consequence may cause depression. Higher androgen values are more pronounced at young ages and before and after delivery of a baby and might be responsible for the "baby blues". It was found that depression in pubertal girls correlated best with an increase in T levels in contrast to the common belief that "environmental factors" during the time of growing up might be responsible for emotional "up and downs". T replacement therapy might be useful in perimenopausal women suffering from hip obesity, also named gynoid obesity. Abdominal obesity in men and women is linked to type 2 diabetes and coronary heart diseases. Testosterone replacement therapy in hypoandrogenic postmenopausal women might not only protect against obesity but also reduce the risk of developing these diseases. Antiandrogenic progestins might be useful for women suffering from hyperandrogenic state in peri- and postmenopause. Individual dosing schemes balancing side effects and beneficial effects are absolutely necessary. Substantial interindividual variability in T plasma values exists, making it difficult to utilize them for diagnostic purposes. Therefore a "four-level-hormone classification scheme" was developed identifying when estradiol (E) and T levels are out of balance. (1) Low E-low T levels are correlated with osteoporosis, depression, and obesity; (2) high E-low T with obesity, decreased libido; (3) high T-low E levels with aggression, depression, increased libido, and substance abuse; (4) high E-high T with type II diabetes risk, breast cancer and cardiovascular risk. Testosterone delivery systems are needed where beneficial and negative effects can be balanced. Any woman diagnosed for osteoporosis should be questioned for symptoms of depression.

Melatonin deficiencies in women.

The pineal hormone melatonin is the mediator of external light to physiologic adaptation to day and night rhythms, it regulates reproduction in animals but attempts to utilize melatonin in women for contraception have failed. Melatonin seems to be the natural hormone to facilitate sleep in insomniac patients and causes no hang over. When applied together with benzodiazepine it allows reduction of benzodiazepine without withdrawal effects. It should be applied 2 h before sleeping time in doses between 3 and 5 mg. Melatonin acts via the gamma-aminobutyric acid- and benzodiazepine receptor explaining its success in treatment of seizures in children and in adults. Constant application of benzodiazepine reduced the production of natural melatonin in rats, supporting the evidence that long-term application of benzodiazepine in humans does not restore sleeping habits but reduces natural sleeping habits even more. Low melatonin levels were seen in bulimia or neuralgia and in women with fibromyalgia; replacement reduced pain, sleeping disorders, and depression in fibromyalgia and bulimia. Melatonin profiles are a diagnostic tool to distinguish between several forms of depression, like major depression, winter depression (SAD), unipolar depression, delayed sleep phase syndrome (DSPS). In patients with a major depression success with antidepressants correlated with an increase in their melatonin profiles but only patients suffering from DSPS can be successfully treated with melatonin. In perimenopausal women melatonin administration did produce a change in LH, FSH and thyroid hormones. Some oncostatic properties are supported by cell culture work and studies in animals. In Nordic countries indigenous people suffer less from breast and prostate cancer, winter darkness seems to protect. The supposedly increased melatonin levels created the 'melatonin hypothesis'. Epidemiological studies did show that blind people indeed have half the rate of breast cancers, supporting the hypothesis. Controversial results concerning melatonin and insulin resistance and glucose tolerance have been published. In postmenopausal women application of melatonin reduced glucose tolerance and insulin sensitivity. Pregnant women should avoid melatonin, since its teratogenic effect is not known. Patients suffering from non-hormone dependent tumors, like leukemia, should avoid melanin, since tumor growth was promoted in animal experiments. It can be expected that melatonin will receive wide consideration for treatment of sleeping disturbances, jet lag, and fibromyalgia once an oral formulation becomes available in Europe.

Progesterone increase under DHEA-substitution in males.

Two case reports of men suffering from excessive fatigue and depression are presented, both treated with 50 or 25 mg DHEA per day over a period of 1 year. Under DHEA treatment one subject reported being less tired and the other experienced improved well-being without depressive episodes and an increase in libido. Investigations of sex hormone parameters in plasma before and under treatment revealed a decrease of testosterone and an increase of progesterone in both, possibly dose-dependent to DHEA application. It is hypothesised that the increase of progesterone is parallel to an increase of its metabolite allopregnanolone (which was not determined), that might explain the improvement in well-being. The increase of progesterone under DHEA supplementation in males should receive further attention.

17beta-estradiol matrixpatch removal and reapplication in postmenopausal women: experimental results.

This study compares the pharmacokinetic performance of a matrix system for transdermal 17-beta-estradiol (E(2)) delivery using multiple consecutive dosing with a first application in postmenopausal women undergoing hormone replacement therapy. A clinical study (SI) was conducted over a treatment period of 11 days in 16 postmenopausal women receiving three consecutively applied matrix patches for the delivery of E(2). The first patch was worn for 4 days, the second for 3 days, and the third patch for 4 days. The E(2) plasma profiles determined during the third application were compared with results obtained by a published clinical study (SII) using the same patch in the same group of postmenopausal women without E(2) pretreatment. Additionally, the 24 h plasma profiles of E(2) and estrone were determined before and on day 4 during patch application of the third patch. Comparison of the mean pharmacokinetic parameters from the two studies showed no significant difference in E(2) plasma levels: AUC(0-->96h) [pg/mL h] SI: 4342 +/- 1513 and SII: 4512 +/- 1229; C(max)[pg/mL] SI: 51.3 +/- 28.8 and SII: 54.2 +/- 22.3; C(average) [pg/mL] SI: 45.0 +/- 13.2 and SII: 47.0 +/- 9.4; C(min) [pg/mL] SI: 31.4 +/- 5.9 and SII: 32.2 +/- 8.1. Over 96 h, fluctuation, f, defined as (C(max) - C(min)) / C(average), was 0.44 in SI and 0.47 in SII. Individual comparison of E(2)-C(max), -AUC, and -C(min) revealed that more than 87.5% of all patients showed a variation between SI and SII of less than 10%. The mean of the individual AUC(0-->96h) variation between the first and the third patch was only 4.7%. There was no significant drop in E(2) plasma values after patch removal and reapplication, and accumulation of E(2) did not occur after several patches were applied consecutively. Plasma E(2) showed a circadian rhythm that was lower in the morning and higher in the evening. No circadian rhythm was observed in untreated basal plasma E(2) in the group of postmenopausal women. The transdermal matrix system yielded sustained E(2) plasma levels in postmenopausal women in the initial application period. In long-term dosing there was no accumulation of E(2) in plasma and no significant drop after patch removal. It is presently not known why the circadian variation in the experimentally obtained E(2) plasma values exists.

17beta-estradiol matrixpatch removal and reapplication in postmenopausal women: theoretical predictions with an oscillating diffusion coefficient model.

The pharmacokinetic performance of a matrix system for transdermal beta-estradiol (E(2)) delivery after multiple consecutive dosing in postmenopausal women undergoing hormone replacement therapy was investigated. The E(2) plasma profiles determined during the third application in 16 postmenopausal women were compared with results obtained in a published clinical study using the same patch in 24 postmenopausal women without E(2) pretreatment; they were compared with a theoretical diffusion/pharmacokinetic model. A conventional theoretical model with constant model parameter (CPM) obtained from in vitro mass balance experiments in a Franz cell type set up described successfully the transdermal E(2) bioavailability parameter AUC(0-96h) (4341.9 +/- 1513.1; calculated 4250.8) and C(average) (45.0 +/- 13.2; calculated 41.2). Also, experimentally, there was no significant drop in E(2) plasma values after patch removal and reapplication; this was corroborated by calculations. Accumulation of E(2) did not occur when several patches were applied consecutively over a period of 3 weeks. Steady state was achieved following application of the first patch. However, the differences between recorded E(2) plasma profiles and theoretical results detected at specific measurement points cannot be explained by the CPM model. Experimentally obtained plasma profiles were always lower in the morning and higher in the evening than predicted on the basis of the model. Measurements of in vivo skin temperature in the postmenopausal women showed oscillating temperature profiles in the form of a cosinor function: The temperature mesor of untreated postmenopausal women was 34.8 degrees C with an acrophase at 17.0 o'clock (95% CI: 14.30-19.30) and an amplitude of +/- 0.4 degrees C (p = 0.1). During the application of the patch the average temperature next to a patch rose 0.3 degrees C, which was statistically significant (p = 0.1). In the skin under the application of the matrix patch a mesor temperature was detected as 35.6 degrees C with an amplitude of +/- 0.5 degrees C with an acrophase at 17.51 o'clock (95% CI: 14.30-21.00) (p = 0.05). The temperature period was 24 h for all measurements and the maximum temperature was observed at about 16.30 h, and a minimum at about 5.00 h. A linear dependency was detected in in vitro experiments between the log of E(2) permeability and the temperature for stripped skin, epidermis/dermis layer, as well as for the matrix. Modeling of E(2) plasma profiles with oscillating diffusion coefficients (ODM1) with a sine wave function results in this equation: D(1) = D(0x) + Da(x).sin(k.t). D(0x) is the diffusion coefficient determined at 35.6 degrees C, k is 1/24 h, D(a) is the diffusion coefficient of the temperature amplitude, h is hour, and x stands for the respective diffusion layer. It was shown that the experimental E(2) plasma profile variations are more pronounced than can simply be explained by skin temperature variations alone (ODM1 model). A simplex fit with an oscillating diffusion coefficient in the form of a sine wave function for the stratum corneum (ODM2 model) resulted in a temperature amplitude of 1.1 degrees C, about twice as high as was determined in the in vivo measurements (ODM2 model). Therefore, other circadian parameterlike blood flow might superimpose the temperature profile. The improvement in data analysis by incorporating oscillating diffusion coefficients (ODM1 and 2) over CPM was judged from a comparison of experimental data with the calculated plasma profiles with the AIC, Akaikes model selection criterion, which allows ranking between models because it is independent of the scaling of the data points. ODM1 and ODM2 improved the data analysis over CPM by allowing better calculation of experimental C(max), t(max), the time to reach to C(max), and the fluctuation, f. No difference between CPM, ODM1, or ODM2 was found for the bioavailability parameter C(average) and AUC(0-96h).

Comparison of steady state development and reduction of menopausal symptoms after oral or transdermal delivery of 17-ß-estradiol in young healthy symptomatic menopausal women.

OBJECTIVE: There is a renewed interest in the delivery of estradiol (E2) for the reduction of menopausal symptoms in young symptomatic menopausal women. This paper compares experimentally and theoretically obtained E2 plasma values by oral and transdermal delivery and compares them with relevant menopausal symptoms. STUDY DESIGN: Two independent previously published studies were compared, which each contained 42 young symptomatic menopausal women. Experimentally obtained plasma values at days 1, 7 and 21 were compared with a theoretical model, taken from the literature, for describing plasma values for an oral immediate release formulation, consecutively for 21 days. Menopausal symptoms were determined in the steady state for oral and transdermal delivery with the Kuppermann index, previously not reported. In the case of oral delivery, estradiol was compared with estradiol valerate. RESULTS: Previously published results for transdermal delivery of E2 showed that the matrix system establishes a steady state condition with the application of the first patch. Excellent agreement between theoretically predicted and experimentally obtained E2 plasma values for oral delivery in menopausal women was obtained. Circadian E2 plasma levels were observed continuously for transdermal delivery, were seen in oral delivery during first application and disappeared when steady state was achieved. Application of the prodrug E2-valerate delayed the maximum plasma peak from 1 pm to 4 pm, similar to the transdermal matrix patch. Investigating menopausal symptoms determined with the Kuppermann index did not reveal differences between oral or transdermal "E2 kinetic (hot flushes) relationship". This relationship was similar to symptomatic women suffering from hot flushes in untreated menopausal women or premenopausal women. Different menopausal symptoms required different E2 plasma levels: the average E2 levels higher than 23 pg/mL in plasma did abolish insomnia in 50% of postmenopausal women, with 28 pg/mL is needed to suppress 50% of dysthymia; however, rather high levels of 41 pg/mL are needed to suppress 50% of hot flushes, suggesting a rather complex mechanism beyond an E2 receptor mediated process. CONCLUSION: There is a difference in the steady state between oral and transdermal E2 delivery. Steady state condition is achieved in the first application of a matrix patch, whereas with the application of a tablet the steady state is achieved in transdermal delivery within 12-14 days. Our reported calculated missed intake of a E2 tablet shows that E2 plasma levels drop for 4 days consecutively. Our conducted study has several limitations: firstly, no cross-over was conducted, but a rather cumbersome mathematical modeling; secondly, healthy women with no accompanying severe diseases were included in this study. The higher the oral dose, the higher the E2 steady state levels, but the time to achieve steady state levels is independent from the E2 dose.

Balancing steroidal hormone cascade in treatment-resistant veteran soldiers with PTSD using a fermented soy product (FSWW08): a pilot study.

UNLABELLED: Abstract Introduction: A clinical study was conducted to determine steroidal hormone cascade in the blood to relate them to mental performance with the Clinician-Administered PTSD scale (CAPS), serum lipid concentrations, and steroidal hormones, particularly cortisol, testosterone, estradiol, dehydroepiandrosterone (DHEA), and pregnenolone, in treatment-resistant male veterans with combat-related chronic posttraumatic stress disorder (PTSD) before and after consumption of a special fermented soy formulation (FSWW08). Admitted veterans in the study were resistant to conventional psychological and pharmacological therapies. METHOD: Ten treatment-resistant soldiers with combat-related PTSD (according to the International Classification of Diseases, 10th Revision code) for ≤1.5 years were enrolled in this study. A specially formulated fermented soy product, FSWW08, was given to the veterans for 3 months and then extended to 6 months. CAPS was used to assess the severity of PTSD. Immunologic cytokines, triglycerides, and 16 steroidal hormones were also determined from the blood of the PTSD patients before, during, and after consumption of the FSWW08. RESULTS: FSWW08 increased blood levels of steroids, such as testosterone, estradiol, and particularly the adrenal hormones cortisol and androstenediol. Decreased steroidal hormones from the upper part of the hormone cascade, such as cholesterol, DHEA, and pregnenolone were experienced. The arteriosclerotic risk was reduced (cholesterol, 280±35 to 205±22 mmol/L, p<0.001; triglycerides, 645±267 to 161±22 mg/dL, p<0.001; very-low-density lipoprotein cholesterol, 312±112 to 151±20 mg/dL, p<0.001; homocysteine in serum (i.s.), 26±4 to 11.8±2.1 µmol/L, p<0.001). High-density lipoprotein cholesterol concentration was significantly lower after consumption of FSWW08 (51±15 to 89±7.8 mg/dL, p<0.001). FSWW08 significantly reduced mental symptoms according to CAPS after 7 days throughout the 6-month study. Insomnia (estradiol increased from 53±24 to 88±41 pg/L), breathing disorders (may be related to increased aldosterone) are hormone dependent and were corrected in those with insomnia. The increase in testosterone and decrease in prolactin was corroborated by an increase in sex drive and improved partner relationships. Common immunity disorders of the veterans, such as increased herpes labialis, flu-like syndromes, and stomach pain were resolved in all veterans and was corroborated by significant improvements in immunologic cytokines: tumor necrosis factor α was reduced (from 13.5±0.4 to 9.0±1.4 pg/mL, p<0.001) and interleukin ß (from 7.0±0.5 to 4.5±1.8 pg/mL) and interferon γ (from 10.4±2.4 to 6.3±1.5 pg/mL, p=0.001) were also detected. PTSD is associated with clinically elevated leukocytes and lymphocytes, which are reduced by FSWW08 as well. CONCLUSION: It is the first time that the normalization of the whole steroidal hormone cascade in the blood could be correlated with improvements in mental and physical parameters (especially metabolic and immunologic disorders) in veterans with combat-related and treatment-resistant PTSD. Studies of FSWW08 in larger cohorts and over longer periods of time, as well as dosing effects, have to be conducted to validate these results.

The effect of fermented soy (FSWW08) on blood hematology and cachexia in cancer patients.

Abstract In cancer patients, appetite and immune status are significantly weakened. Two experimental fermented formulations without (group A, named as FSWW08) and with (group B, FSWW08) an extract from yam root were investigated against a placebo formulation with casein (group C) in a clinical study conducted in six cancer hospitals where cancer patients underwent radio or chemotherapy (patients undergoing radiation therapy n=78, patients undergoing chemotherapy n=184, total 262). IgG and IgA were increased by formulation A in patients despite receiving radio- or chemotherapy. Group A experienced statistically significant increases in lymphocyte transformation rates, whereas group B and group C did not. Formulations A and B either inhibited or lessened statistically significant decreases in white blood counts, whereas the placebo group experienced substantial decreases. Hemoglobin and platelet decreases were inhibited in group A, although not statistically significantly. Patients in group A received no blood transfusions, whereas many patients from the placebo group received blood transfusions. Appetite loss was reduced in group A from 57.9% to 13.3% and in group B from 70% to 35.8%. In the placebo group, an increase in appetite loss was detected under chemo and radiation therapy from 41.8% to 70.9%.

Cancer protection of soy resembles cancer protection during pregnancy.

It has been established that carrying a pregnancy to full-term at an early age can protect against contracting cancer by up to 50% in later life. The trophoblast theory of cancer states that trophoblast and cancer tissue are very similar. New findings suggest that the loss of fetal cells during pregnancy resemble those cells responsible for causing metastasis in cancer. Fetal cells and spreading cancer cells are highly proliferative. They are similar to stem cells, exhibiting no or low hormone receptor expression, and require a hormone receptor independent mechanism for control. Control of membrane stability during pregnancy is of vital importance for a successful pregnancy and is mediated by androstenediol and 2-methoxyestradiol. 2-Methoxyestradiol has no hormone receptor affinity and elicits strong anticancer effects particularly against cancer stem cells and fetal cells, for which currently no treatment has yet been established. There is a discussion whether pregnancy reduces cancer stem cells in the breast. Soy isoflavones are structurally similar to both hormones, and elicit strong anticancer effects and antiangiogenesis via inhibition of NF-κB, even in hormone receptor independent breast cancers seen in epidemiologic studies. The trophoblast theory of cancer could help to explain why soy baby nutrition formulas have no effect on baby physiology, other than the nutritional aspect, although soy elicits many effects on the adult immune system. To survive the immune system of the mother, the immune system of the fetus has to be separated; otherwise, the reduction of the immune system in the mother, a necessary feature for the blastocyst to grow, would immediately reduce the immunity for the fetus and endanger its survival. Similar to a fetus, newly born babies show immune insensitive to Th1 and Th2 cytokines, which are necessary and crucial for regulating the immune system of the mother, thus raising the risk of the baby of developing allergies and neurodermatitis. Gene expression studies in vitro as well as in circulating tumor cells from patients consuming a fermented soy product support the antiangiogenic as well as antiproliferative effects of soy.