Клуб выпускников МГУ: AGEING Dr.Sula

Immunosciences Lab., Inc. (ISL) is a leading California-based and licensed clinical laboratory and research facility. Our laboratory analyzes complex diseases that directly or indirectly involve the human immune system. We offer a variety of tests scientifically designed to detect immune disorders caused by nutritional deficiencies, viruses and environmental factors like chemicals. Through its unique diagnostic testing, Immunosciences Lab helps physicians diagnose and treat diseases associated with immune function disorders such as AIDS, arthritis, Chronic Fatigue Syndrome, and diseases associated with aging.

For the past 10 years, the scientists at Immunosciences Lab have been committed to wellness testing. ISL's primary goal is to expand wellness testing in order to combat common diseases like cancer, Alzheimer's, osteoporosis, diabetes, and degenerative diseases of aging. These diseases are commonplace, difficult to treat, and often fatal when detected late. In order to treat them more effectively, it is imperative that wellness testing be continually expanded to help signal the occurrence of these diseases at their earliest stage of development. By doing so, ISL provides physicians with tools to inhibit disease progression and perhaps ultimately prevent certain occurrences.

Since increasing evidence suggests that some medications, nutritional supplements and hormones used by different clinicians to combat diseases associated with aging may have serious side effects, ISL developed various biomarkers to signal a greater risk of illness. We firmly believe that these and other laboratory tests, designed markedly for males and females, should be used on patients undergoing various therapies by treating physicians in order to monitor the risks/benefits of their treatments.

Biomarkers are physiological manifestations of changes that may occur during aging. If an intervention improves these markers in a population, chances are that the agent will improve the quality of life as well as longevity. These markers aid physicians in evaluating a patient's risk of developing diseases much as blood lipid levels are used in standard medical practice to monitor the risk of heart disease.

Michael B. Sporn, Professor of Pharmacology and Medicine at Dartmouth Medical School, has argued repeatedly that an "obsession" with curing advanced disease has blinded researchers to the promise of prevention. For example, "Like heart disease," he says, "cancer is the culmination of years of subtle pathology. It is never too soon to intervene - but it is often too late." Noting the success of cardiovascular intervention strategies in reducing morbidity rates from heart disease, he has long called for a revision in cancer research priorities that would emphasize the detection of signals (biomarkers) indicating the onset of cancer rather than an attempt to pursue radical treatment at its terminal stages.

Realizing the importance of degenerative disease prevention, we have developed several biomarkers capable of signaling a greater risk of illness. Using these techniques, it is possible to attain relatively quick answers by monitoring selected signs and damage in the body which prepare the environment for abnormal cell growth and differentiation. These molecular techniques aim to uncover critical illness events taking place inside the body and identify measurable biological flags signaling their occurrence. Some of these biological flags (biomarkers), in the form of lifespan panels one and two for both male and female, are presented here (please see pages 17 through 20). We cater to the specific needs of our clients. Specialized panels may therefore be designed to meet every physician’s requirements.

The aging process is characterized by a breakdown in abnormal homeostasis control mechanism and change in the function of immunoregulatory cells. The proper functioning of the immune system is necessary for protection against antigenic insults form the external and internal environments. With increased aging there is a decline in the ability of organisms to cope with these insults. Thus, with the development of age-related immunodeficiency, there is an increased frequency of infectious, autoimmune, and malignant diseases. The most widely documented age-related immunological abnormalities occur with T- and B-cell activities, NK cell function, and enhancement in programmed cell death and change in cell cycle progression. Therefore, natural killer cell activity and programmed cell death (apoptosis) are used as biomarkers of immune competence during aging.

It has been known that emotional distress such as anxiety, depression, academic stress, bereavement and aging has a negative impact on health in general and on the immune function in particular.

Although the main task of the immune system is to protect us against the multitude of external microorganisms and other foreign perils, some of its weapons are reserved for combating abnormal cells. Killer cells move constantly through the body's tissues, combing the tissues for deviant cells. NK cells play an important role in a variety of human diseases. Compromised or absent NK cell activity has been linked to development and progression of cancer, chronic and acute viral infections, chronic fatigue syndrome, various immunodeficiencies, and certain autoimmune diseases. Deficiencies or abnormalities in NK cell function may contribute to, or be a biologic marker for disease. The role of NK cells in health and diseases is summarized in the following table.

ROLE OF NK CELLS IN HEALTH AND DISEASE

Antitumor effects and elimination of cancer

Antiviral and antibacterial activity

· Regulation of the immune system

Regulation of hematopoieses

Interaction with the neuroendocrine system

Effects on reproduction

It has been well established that patients with a variety of solid malignancies and large tumor burdens have decreased NK activity in the circulation, and that this low NK activity may be significantly associated with the development of distant metastases. Furthermore, in patients treated for metastatic disease, the survival time correlates directly with the levels of NK activity. In patients with hematologic malignancies, there appears to be a correlation between NK activity and the status of disease; the more advanced the disease, the lower the NK activity. Decreased NK activity may also be an important risk factor for the development of malignancy in humans. The prognostic significance of low NK activity in patients with cancer has been recently emphasized; thus, low NK activity may have prognostic value in predicting relapses, poor responses to treatment and, especially, decreased survival time.

Growth hormone deficient patients show a significantly lower basal and interferon stimulated NK cell activity than matched controls with normal levels of growth hormone. Similarly IGF-1 levels show positive correlation with NK Cell activity. Growth hormone and IGF-1 appears to be a co-regulatory modulator of NK Cell activity.

For the above reasons, it is important to reliably detect abnormalities in NK cell function and monitor prognosis of chronic illnesses after therapy with biological response modifiers or other agents including antioxidants.

Apoptosis is a distinct form of cell death taking place in the majority of cells. It is common during embryogenesis, normal tissue, and cytotoxic immunological reactions. Also occurs naturally at the end of the lifespan of differentiated cells. Apoptosis can also be induced in cells by exposure to different agents including physiological activators, heat shock proteins, bacterial toxins, oncogene, chemotherapeutic drugs, a variety of toxic chemicals, ultraviolet and gamma radiation. The programmed cell death occurs due to activation of nucleases and protease's (enzymes) that degrade the DNA structure into smaller DNA pieces of about 200 base pairs. However, the stage that precedes nuclear disintegration is characterized by the breakdown of the mitochondrial membrane. Using special reagents, it is possible to tag the damaged DNA and identify the percentage of apoptotic cells with high accuracy.

Apoptosis and cell proliferation plays an important role in tissue development, differentiation, homeostasis, and aging. The balance established between these two processes depends on a variety of growth and death signals, which are in turn influenced by diet, nutrition, lifestyle, and other environmental factors. When the equilibrium between the life and death of a cell is disrupted, for example, due to lack of intracellular antioxidants, either tissue growth or atrophy may occur. With increased levels of antioxidants, this process may be returned to balance state.

Execution of a genetic program for apoptosis during development and aging is thought to be governed by sequential expression of specific genes. In aging, apoptosis is triggered by an internal signal that activates the cell death machinery, which includes proteases and endonuclease activities.

We postulated that increased concentrations of intracellular oxidant in aged cells, due to a deficiency in their hormonal and anti-oxidant machinery, might contribute to an enhanced rate of apoptosis. To test this hypothesis, venous blood (10 ml) was obtained from 15 individuals between the ages of two and eighty years of age. Peripheral blood mononuclear cells (PBMC) were isolated by Ficoll-Hypaque gradient centrifugation of heparinized blood. The lymphocyte ring was isolated and cultured for 24 hours in the presence of serially diluted vitamin C. Cells were collected, fixed, and analyzed for the presence of apoptotic cells and cell cycle analysis by flow cytometry.

The results indicated an increased apoptotic cell population and abnormal cell cycle progression in aged population (65-80 years old), as compared to a younger population (5-40 years old). Vitamin-C treatment of PBL isolated from the aged population decreased their apoptotic population by 30%. In addition, Vitamin C decreased the apoptotic cell population in a dose-dependent manner. These results indicate a novel mechanism for the control of cell death in an aging population, as well as a surrogate diagnostic marker for cellular integrity and health status.

Evidence presented here supports the thesis that the major histocompatibility complex (MHC) is a supergene system controlling immune regulation and aging through developmental pattern and biochemical pathways. Therefore, many or all aging diseases have an immunological component, which is shown in Figure 1.

Such immune function abnormalities are mainly due to increased exposure of genetic material to a variety of environmental and endogenous insults. Therefore, DNA repair is one mechanism in the molecular basis of protection against aging. Indeed, excision and repair capacity of DNA is directly proportional to the lifespan of the species. Inability to correct this DNA damage and formation of DNA and protein adducts by free radicals may on the one hand increase nuclear antigen and anti-DNA formation by initiating damage and, on the other, be particularly harmful to precursors of T-suppressor cells. Both effects would increase the probability or severity of autoimmune diseases. Furthermore, an increase in the inflammatory proteins and immune complex formation leads to further increase in free-radical production by aggregated granuocytes, which could aggravate the situation.

Other mechanisms responsible for cellular DNA damage and induction of programmed cell death are shortening of the telomeres (physical ends of human chromosomes) and induction of P53, the senescent cell antigen and IGF-BP3. Expression of these aging antigens which appear mainly in old cells, mark them for death by initiating the binding of IGF autoantibody and subsequent removal by phagocytes. Therefore, aging is associated with lymphopenia and progressive decline in immune function. It has been shown that in vivo manipulation of genes and diet can increase maximum lifespan in animal models.

Significant improvement in cell-mediated immune function, programmed cell death, cell cycle progression, DNA adduct, DNA repair enzymes and reduction in senescence proteins after antioxidant use may enable us to extend the maximum human lifespan and postpone or prevent the onset of diseases with aging. Mechanisms responsible for degenerative diseases of aging and strategies for their prevention are shown in Figures 2 & 3.

Deoxyribonucleic acid (DNA) is the genetic blueprint for all known life and serves as the template for the production of structural and regulatory proteins. DNA has a double-helix structure, with each helix consisting of a linear polymeric chain that incorporates alternating phosphate groups and deoxyribose sugar units. Chemical carcinogens or their metabolites can interact with DNA, resulting in the formation of covalently bonded DNA adducts. If these adducts are not enzymatically repaired, they may cause mutations and, in extreme cases, carcinogenesis.

Cancer causing chemicals or their metabolites which are formed in the body has the capacity to bind to DNA of different cells, form DNA adducts, DNA damage, and mutation that may finally lead to abnormal cell growth and differentiation. This abnormal cell growth if it is not controlled on time, may lead to altered functionality and disease. Nucleic acid adducts are released spontaneously by different DNA repair enzymes including Superoxide Dismutase, Catalase, and Glutathione Peroxidase, and are secreted in urine. Therefore urinary adducts such as 8-Hydroxy-2-DeoxyGuanosine are used as a measure of exposure to chemicals. However, we believe that urinary adducts reflect the function of DNA repair enzymes that are involved in releasing adducts from target tissue and not the direct level of adduct in the target tissue.

Thus, we have developed a very sensitive method for measuring the levels of adducts in the cellular DNA that is reflecting a better measure of exposure to chemicals and its bioaccumulation throughout life.

OXIDATIVE STRESS AND ITS ROLE IN CANCER, AGING, AND VARIETY OF NEURODEGENERATIVE DISEASES.

Although oxygen is essential to life as part of normal metabolism, its access can give rise to a variety of reactive oxygen species (ROS). Under normal conditions, the body is well-equipped with a variety of mechanisms that serve to inactivate the extra reactive oxygen species. However, under certain conditions when these mechanisms are faulty or the body has been exposed to environmental chemicals, irradiation, iron loading, and others, the elevated ROS can cause a variety of diseases and even death.

Superoxide Anion is one example of ROS that is formed when molecular oxygen is subjected to ionizing radiation and acquires an additional electron or xanthine oxidase converts xanthine to uric acid and by so produces superoxide radicals. Superoxide is also formed by the auto-oxidation of hydroquinones, cathecholamines, and thiols. Superoxide Anion is short-lived and is converted to Hydrogen Peroxide by the enzyme Superoxide Dismutase (SOD) which maintains the steady-state levels of superoxide. For this reason altered, SOD function has been linked to both Down’s Syndrome and Amyotrophic lateral sclerosis or Lou Gehrig’s disease.

Unsaturated lipids, proteins, and DNA are the components of the cell that are most sensitive to oxidative damage. This protein, DNA damage, and lipid peroxidation can end with membrane damage, altered receptor functionality and eventually to cell injury, which could be increased by metals such as iron or attenuated by antioxidant levels. Therefore, oxidant/antioxidant balance is the major factor in maintaining good cellular function and prevention of programmed cell death.

Two major mechanisms play a role in reducing the harmful effects of oxidants in the cell. Under normal conditions, these mechanisms maintain homeostasis and control the free radicals up to certain level. If these mechanisms are damaged or the endogenous level of antioxidants is low, a condition is formed which is referred to as oxidative stress. Due to oxidative stress, a variety of diseases can result.

The first protection mechanism against oxidative stress is enzymatic. These enzymes are:

      ROOH   +      2GSH ® GSSG + ROH + H₂O
(Glutathione Hydroperoxide    (reduced glutathione)
           Peroxidase)

    H₂O₂ + 2GSH ® GSSG + 2H₂O
          Hydrogen             (reduced glutathione)          oxidized
          Peroxide                                                           glutathione

Therefore, if the levels of superoxide dismutase, catalase, and glutathione peroxidase are elevated and the level of oxidized glutathione (GSSG) is twice or more than reduced glutathione (GSH), oxidative stress may be evident.

The second protection mechanism against oxidative stress depends on the intracellular level of antioxidants. A number of naturally occurring compounds has the ability of reacting with free radicals produced due to oxidative stress. These antioxidants are classified as water-soluble and fat-soluble vitamins. Ascorbic acid and glutathione are major water-soluble antioxidants.

Fat-soluble antioxidants: vitamin A (a -carotene, b -carotene), lycopene, coenzyme Q10 and Tocopherols (b and g ).

· The growth hormone and insulin-like growth factor are used by some clinicians for prevention of the decline of the immune system and development of different disorders during aging. The growth hormone (GH) and insulin-like growth factor (IGF) axis constitutes an integrated hormonal system, which along with insulin itself plays a major role in body anabolism. GH and IGF-1 have a major controlling influence on linear growth during childhood. However, the GH/IGF hormonal system also has well-defined effects on protein, carbohydrate, lipid, and mineral metabolism throughout life. Many of the growth-promoting and metabolic effects of GH are not direct actions of GH on its target tissues, but mediated by insulin-like growth factor-1.

· The interaction of IGF-1 with its specific receptor leads to a series of anabolic actions within the cell, including the synthesis of proteins and macromolecules that leads to cell division. For this reason, both GH and IGF-1 have been used as therapeutic agents in the treatment of growth disorders including growth hormone deficiency, Turner Syndrome, chronic renal failure in children.

· However, the therapeutic use of GH and IGF-1 is not limited to their growth-promoting properties. In fact, administration of GH to normal adults results in prompt and reproducible effects on metabolism, including protein synthesis, an increase in insulin resistance, and change in lipid, calcium, and mineral metabolism. Thus, GH continues to play an important role in metabolism long after linear growth has ceased. Many studies have shown that in adults the levels of GH and IGF-1 decline with aging. The circulating levels of GH and IGF-1 in an average 80-year old may be as low as in a child with classic growth hormone deficiency. For this reason many catabolic problems of aging such as a decrease in ability to synthesize proteins and repair DNA and tissues seems to be related to a decrease in GH and IGF levels and biological action.

· The therapeutic use of GH is not limited to its growth-promoting properties. The administration of GH to healthy adult subjects results in prompt and reproducible effects on metabolism including nitrogen retention, an increase in insulin resistance, total energy expenditure and body fat loss.

· Because of the relatively low levels of GH and IGF-1 in aging adults many people beyond the sixth decade of life are functionally GH deficient, and hence benefit from GH therapy.

· In controlled studies using GH therapy in aging adults, a number of investigators have shown definite changes in nitrogen retention, body composition, bone turnover, and bone density. However, it seems unlikely that GH therapy will be the universal rejuvenative agent for all the abnormalities of aging. growth hormone therapy may be useful in elderly patients as part of a multifaceted therapeutic approach involving exercise, nutritional and/or other therapeutic interventions. However, due to a narrow therapeutic window of GH in aging adults one should screen patients for baseline levels of GH and IGF-1 and, if qualified for treatment, they should be monitored for post-treatment levels of IGF-1 and IGF-binding protein-3. Other biomarkers should be performed in order to predict the incidence of GH and IGF-1 side effects.

· Increasing evidence suggests that IGFs may play a role not only in the normal development and function, but also in the growth and behavior of many cancer cell types. Therefore, male and females undergoing GH/IGF-1 therapy should be monitored for prostate, breast, and ovarian cancer, respectively.

· Death from breast cancer is due to unregulated cellular proliferation and progressive tumor growth at primary and metastatic sites. Several studies have demonstrated that IGF-1 and IGF-II are mitogens for breast cancer cells and hence their elevated levels may be the cause of unregulated cellular growth. Furthermore, the IGF binding proteins and receptors are expressed by virtually all breast cancer cell lines. Taken together, these data suggest that insulin-like growth factor could be an important growth regulatory factor for breast cancer. Therefore, individuals undergoing GH/IGF-1 therapy should be monitored by laboratory tests, which serves as biomarkers for cancer. Some of these markers are summarized below.

· A glycoprotein, normally present in serum at about 30 units/ml, is significantly elevated in serum of women with metastatic breast cancer. This is a powerful prognostic indicator in patients with advanced breast cancer.

· A cell surface glycoprotein widely used as a marker for ovarian epithelial cancer, this marker exists in serum and other fluids as a high molecular weight (> 100 kDa) complex. Significantly, higher levels are reported in patients with ovarian cancers. The CA 15-3 and CA-125 tests detect signals of cancers, which are already underway. However, the level of an oncoprotein (P185) in the serum of many breast cancer patients precedes the CA15-3 level; and hence, may provide a better means of early warning.

· DETECTION OF c-erbB-2/HER-2 OR NEU ONCOGENE PROTEIN PRODUCT (P185) IN BLOOD

· There is a large body of evidence in the literature, which examines the involvement of neu in tumorigenesis and disease progression. Like the EGF-R, neu gene amplification and/or protein expression has been identified in a number of cancers, most notably breast. In addition, elevated neu protein in tumors has been shown to coincide with elevated neu protein levels in serum. Therefore, detection of neu protein or p185 in serum may be an indication of breast cancer reaction.

· Prostate-specific antigen (PSA) is an antigen derived from prostatic tissue. A PSA level between 0-4 ng/ml is considered normal and higher levels are detected in benign prostate hypertrophy, prostate cancer, and prostate surgery.

· Carcinoembryonic antigen (CEA) is derived from gastrointestinal and adenocarcinoma tissue. Levels of 0-2.5 ng/ml are considered normal in non-smokers and up to 10 ng/ml in smokers. Levels higher than 10 ng/ml are found in colon, lung, metastatic breast, pancreas, stomach, prostate, ovary, bladder, limbs, neuroblastoma, leukemia, osteogenic carcinoma. Conditions other than cancer that are associated with abnormal values are inflammatory bowel disease, pancreatitis, gastritis, bronchitis, pulmonary infections, colonic polyps, chronic renal failure, and cirrhosis.

· Prostate cancer is the worst fear for most men. During the past twenty years, urologists, with the use of prostate-specific antigen (PSA) tests, have contributed significantly to the early detection and prevention of prostate cancer.

· The PSA test detects the signal of cancers that are already underway. However, a major drawback to the PSA test is that it is unable to identify men who are at high risk of getting prostate cancer before they develop the disease. This is unlike cholesterol, triglycerides, or homocysteine, which serves as a heads-up for heart disease. For this reason the American Cancer Society called for increased research and education for early detection and prevention of prostate cancer. Recent discoveries of a team from Harvard and McGill Universities may have provided a means of early warning via measurement of a molecule called Insulin-Like Growth Factor-1 (IGF-1) in the blood.

· IGF-1 is a peptide, which mediates the actions of growth hormone. This factor, which is secreted by the liver and other tissues, possesses metabolic and mitogenic activities. In laboratory studies, researchers have shown that the IGF-1 molecule is a powerful growth factor which stimulates the growth of both cancerous and normal prostate cells.

· In a report published in January 23, 1998 of Science, the investigators team studied nearly 15,000 men and were able to clearly show that men whose blood contained high levels of IGF-1 were four times more likely to develop prostate cancer than those men who had low levels of this growth factor.

· In most cases while the IGF-1 was elevated, the PSA levels were normal until seven years later when the cancer was diagnosed and the PSA test showed a positive diagnosis. This finding indicates that IGF-1 is telling us something before prostate cancer even occurs. This indication is much like having a cholesterol level of 300 or more and being more worried about heart disease than having a level of 180.

· Moreover, an IGF-1 test might be used to (1) identify high-risk men who need close monitoring or (2) to recognize potentially aggressive tumors while they are still small. This approach could lead to ways of lowering men’s risk for prostate cancer.

· In serum and other biological fluids, the IGF’s are carried by specific binding proteins (IGFBP’s). IGFBP-3 is the main IGF-binding protein in postnatal serum and its molar concentration is similar to the total combined concentration of IGF-I and IGF-II. IGF-I and IGFBP-3 are growth hormone-dependent and abnormally low IGF-I and IGFBP-3 levels are indicative of growth hormone insufficiency. Conversely, elevated levels indicate growth hormone excess, or acromegaly. Direct testing of GH may be difficult due to its episodic release from the pituitary and relatively short half-life in the circulation, whereas IGFBP-3 levels remain relatively stable throughout the day. These aspects of IGFBP-3 physiology and chemistry make the quantitative measurement of IGFBP-3 an extremely valuable tool for the assessment of the GH-IGF axis and GH-related disorders.

· Testosterone is a hormone responsible for the development of male secondary sexual characteristics. This substance is synthesized mainly in the leydig cells of the testes. It is secreted by the adrenal glands and testes in men and by the adrenal glands and ovaries in women. Excessive production induces premature puberty in men and masculinity in women. Routine testosterone measurements in men have been found useful in the assessment of hypogonadism, pituitary gonadotropin function, impotency, and crytorchidism; these measurements are also useful in the detection of ovarian and adrenal tumors in women.

· Testosterone circulates almost entirely bound to transport proteins but normally, less than one percent is free. The principal transport protein for testosterone is known as sex hormone binding globulin (SHBG). It carries, at least in females, a higher percentage of testosterone in circulation than either albumin or CBG. SHBG has a responsiveness, not associated with albumin, insofar as the SHBG level is sensitive to changes in the ratio of circulating estrogens to changes in the ratio of circulating androgens. SHBG thus plays a greater role in determining the level of free testosterone in circulation.

· The concentration of free testosterone in circulation is expected to increase if the testosterone level (T) increases or if the SHBG level decreases. The T/SHBG ratio thus serves as a rough guide to the concentration of free testosterone. It also increases in severe acne, male androgenic alopecia (balding), hirsuitism, and other conditions.

· Estradiol (estradiol-17b , E2) is a steroid hormone with a molecular mass of 272.3 Daltons, which circulates predominantly protein-bound. In addition to estradiol, other natural steroidal estrogens include estrone, estriol, and their conjugates. Natural estrogens are hormones secreted principally by the ovarian follicles and also by the adrenals, corpus luteum, placenta and, in males, by the testes. Exogenous estrogens (natural or synthetic) elicit, to varying degrees, all the pharmacologic responses usually produced by endogenous estrogens.

· Estrogenic hormones are secreted at varying rates during the menstrual cycle throughout the period of ovarian activity. During pregnancy, the placenta becomes the main source of estrogens. At menopause, ovarian secretion of estrogens declines at varying rates. The gonadotropins of the anterior pituitary regulate secretion of the ovarian hormones, estradiol, and progesterone; hypothalamic control of pituitary gonadotropin production is in turn regulated plasma concentrations of the estrogens and progesterone. This complex feedback system results in the cyclic phenomenon of ovulation and menstruation.

· Estradiol determinations have proved of value in a variety of contexts, including the investigation of precocious puberty in girls and gynecomastia in men. Its principal uses have been in the differential diagnosis of amenorrhea and in the monitoring of ovulation induction.

· Progesterone is a steroid hormone, which plays an important role in the preparation for and maintenance of pregnancy. It is synthesized from cholesterol via pregnenolone - then rapidly metabolized to pregnanediol, for the most part, in the liver. The ovary and placenta are the major production sites; but a small amount is also synthesized by the adrenal cortex in both men and women.

· Circulating progesterone levels, which are characteristically low during the follicular phase, increase sharply during the luteal phase of menstrual cycles, reaching a maximum some 5 to 10 days after the midcycle LH peak. Unless pregnancy occurs, a steep decline to follicular levels sets in about 4 days before the next menstrual period. This pattern constitutes the rationale behind the well-established use of serum progesterone measurements as a simple and reliable method for ovulation detection.

· Measurements of serum progesterone have also been used to check the effectiveness of ovulation induction, to monitor progesterone replacement therapy and to detect and evaluate patients at risk for abortion during the early weeks of pregnancy

· Measurement of Dehydroepiandrosterone Sulfate (DHEA-SO4, DHEA) an adrenal steroid, is important to investigations of abnormal hair growth (Hirsutism) and balding (Alopecia) in woman. It is also of value in the assessment of adrenarche and delayed puberty.

· The DHEA-SO4 in circulation originates almost entirely from the adrenals, though in men some may also derive from the testes, partly accounting for the sex difference which emerges at about age 15. On the other hand, this hormone is not produced by the ovaries, even under pathological conditions. In itself, DHEA-SO4 is only weakly androgenic like androstenedione and testosterone, and this be indirectly a cause of hirsutism or virilization.

· Plasma levels of DHEA-SO4 increase steadily from about the seventh year of life, then gradually decline after the third decade. Pregnancy and oral contraceptives induce a moderate increase.

· DHEA-SO4 is secreted into the bloodstream at a rate only somewhat greater than DHEA, but because of its much slower turnover - DHEA-SO4 has a half-life of nearly a full day - it maintains a plasma level almost a thousandfold higher. Unlike cortisol, DHEA-SO4 does not exhibit significant diurnal variation. Unlike testosterone, it does not circulate bound to sex hormone-binding globulin ad hence is not influenced by alterations in the level of this carrier protein. Its abundance, together with its within-day and day-to-day stability, makes it an excellent direct indicator of adrenal androgen output - superior, certainly, to the measurement of urinary 17 - ketosteroids in this context.

· High DHEA-SO4 levels is often encountered in the polycystic ovary syndrome. Extremely high levels (greater than 800 m g/dl) in women are suggestive of a hormone-secreting adrenal tumor.

· Cortisol (hydrocortisone, compound F) is the major glucocorticoid, which is secreted by the adrenal cortex. Among its physiological effects are anti-inflammatory activity, blood pressure maintenance, and synthesis of carbohydrate from protein.

· Glucocorticoids are synthesized in response to adrenocorticotropic hormone (ACTH) which is secreted by the anterior lobe of the pituitary gland. To the normal individual, cortisol participates in a negative feedback loop with ACTH through the hypothalamus-pituitary-adrenal cortex axis (HPA axis). Pituitary ACTH is, in turn, regulated by corticotropin-releasing factor (CRF) which is secreted by the hypothalamus. The hypothalamic CRF is responsive to cortisol levels and to stress. Physical and psychological stress, diurnal variation, and low blood sugars will affect the rate of cortisol secretion.

· Malfunction of any organ in the HPA axis will result in alteration of cortisol levels. The evaluation of adrenal gland function by measurement of plasma or serum cortisol levels aid in the diagnosis of normal and abnormal states. Combinations of morning and evening measurements and stimulation and suppression tests can offer strong evidence for diagnosis of specific adrenal-related diseases. The diagnosis of Addison’s disease (chronic adrenal insufficiency) and Cushing’s syndrome (adrenal overproduction) are two examples for which the specific assay of circulating cortisol levels is helpful in patient evaluation

The measurement of T3 (Triiodothyronine) is a quantitative determination of the Total T3 concentration in the blood and is the test of choice in the diagnosis of T3 Thyrotoxicosis. It is not the same as the T3 uptake test that measures the unsaturated TBG in serum. It can also be very useful in the diagnosis of hyperthyroidism. T3 thyrotoxicosis refers to a variant of hyperthyroidism in which a thyrotoxic patient will have elevated T3 values and normal T4 values. It is of limited value in diagnosing hypothyroidism.

T4 (Thyroxine) is one of the thyroid panel tests used in the evaluation of thyroid function. It is a direct measurement of the concentration of T4 in the blood. It is also a good index of thyroid function when the TBG is normal. The increase in TBG levels normally seen in pregnancy and with estrogen therapy will increase the Total T4 levels. The decrease of TBG levels in persons receiving anabolic steroids, in chronic liver disease and in nephroses will decrease the total T4 value. This test is done commonly to rule out hyperthyroidism and hypothyroidism. The T4 test can also be used as a guide in establishing and following maintenance doses of thyroid in the treatment of hypothyroidism. In addition, it also can be used in hyperthyroidism to follow the results of antithyroid drugs.

The measurement of TSH (Thyroid-Stimulating Hormone) is used in the diagnosis of primary hypothyroidism when there is thyroid gland failure due to intrinsic disease, and it is used to differentiate primary from secondary hypothyroidism by determining the actual circulatory level of TSH. In prinicple, it is the same as the neonatal T4 test. It is not the same measurement as the TSH stimulation test, in which the thyroid uptake of radioiodine is measured before and after the injection of TSH.

Armed with these results, clinicians can attempt to use different strategies to intervene in the early pre-cancerous stage before the invasive disease begins and hopefully reverse the course of disease development.

AGEING Dr.Sula - General Overview 2008