Total and free testosterone
Free testosterone is included in both the male and female panels.
Testosterone is produced in the testes in men, in the ovaries in women, and in the adrenal glands of both men and women. In men, testosterone production is stimulated by luteinizing (LH), which is produced by the pituitary gland and by Leydig cells in the testes. Testosterone levels normally decline with age, dropping to approximately 65% of young adult levels by age 75. This drop in testosterone is partially responsible for the significant physiologic changes seen in aging men.
Less than 2% of testosterone is typically found in the “free” (uncomplexed) state in the serum of both men and women. Approx-imately 50% is bound to sex hormone-binding globulin (SHBG) and the remainder to albumin. In men, free testosterone (an androgen, or “male hormone”) levels may be used to evaluate impotence or infertility. In women, high levels of free testosterone may indicate hirsutism (excessive hair growth, especially on the face and chest), which is often indicative of polycystic ovaries and, less commonly, ovarian cancer. Increased testosterone in women also suggests low estrogen levels. Low levels of free testosterone in women can lead to loss of libido, depression, and increased risk of heart disease.
Total testosterone (complexed and uncomplexed) is useful for assisting with differential diagnosis in males (LH secretion and Leydig cell function, gonadal and adrenal function, diagnosis of hypogonadism, hypopituitarism, Klinefelter syndrome, and impotence) and in females (Stein-Leventhal syndrome, masculinizing tumors of the ovary, tumors of the adrenal cortices, and congenital adrenal hyperplasia).
Pregnenolone is made directly from cholesterol within the mitochondria, and in turn is the substance from which the body manufactures DHEA and other steroid hormones, including testosterone, estrogens, cortisol, and aldosterone. It converts to DHEA and progesterone; in women, this conversion to progesterone is especially important, as it creates a balance with estrogen to reduce the risk of certain cancers. With the advent of degenerative disease, pregnenolone levels are generally suppressed.
DHEA-S (dehydroepiandrosterone sulfate)
DHEA measures adrenal cortical function. Elevated levels of this hormone, which peaks during one’s twenties, may be indicative of CAH (congenital adrenal hyperplasia), a group of disorders that result from the impaired ability of the adrenal glands to produce corticosteroids. Low levels of DHEA may predispose a person to memory loss, depression, excess fat accumulation, increased risk of heart attack, Alzheimer’s disease, and a host of chronic inflammatory disorders. DHEA is part of the Male and Female test panels that are described at the end of this article.
In non-pregnant women, estradiol is the most commonly measured type of estrogen; levels vary throughout the menstrual cycle, and are reduced to low but constant levels after menopause. Increased levels of estradiol in women indicate an increased risk of breast or endometrial (lining of the uterus) cancer. In men, estradiol is produced in amounts far lower than in women, and indicates hypothalamic and pituitary function. Increased levels of estradiol along with decreased levels of testosterone may indicate de-creased sex drive and ability to urinate. In men, estradiol and testosterone levels should be tested together. Aging males often have too much estradiol. This test is included in the Male and Female panels.
Elevated levels of the amino acid homocysteine have been shown to be an independent risk factor for development of coronary artery disease and thrombosis (stroke). Data also indicate that homocysteine levels may be elevated in patients with depression if folic acid (which normally helps to break down homocysteine) levels are depressed. Homocysteine levels increase with concomitant depression.20 The homocysteine test is included in the Male and Female Panels.
C-reactive protein (CRP)
Inflammation is a key pathogenic mechanism for development and progression of atherosclerosis and heart disease. Atherosclerosis is essentially an inflammatory response to an injury, such as hypertension, cigarette smoking, a diet rich in low-density lipoproteins (LDL), and hyperglycemia, among others. These stimuli elicit secretion of molecules that, along with uptake of cholesterol lipo-proteins, most likely form the basis for the atherosclerotic “fatty streak” along arterial walls.
These risk factors continue to facilitate the attraction and accumulation of inflammatory cells—macrophages, mast cells, and activated T-lymphocytes—within the atherosclerotic plaque. Disruption of this plaque, caused by chronic inflammation, may cause a heart attack as oxygen-deprived blood vessels become clogged with pieces of dislodged plaque material.
C-reactive protein is a very sensitive marker of systemic inflammation, and has emerged as a powerful predictor of coronary heart disease21 and other cardiovascular diseases.
The highly sensitive CRP test is able to measure the presence of C-reactive protein in the blood, even at very early stages of vascular disease, allowing for appropriate intervention with diet, supplements, or anti-inflammatory therapy.
Elevated levels of C-reactive protein have also been found to be associated with risk of developing type II diabetes,22 loss of cognitive ability in seemingly healthy people,23 Alzheimer’s disease, and depression in the elderly. Furthermore, risk factors for atherosclerosis and heart disease, such as smoking and high blood pressure, elevate blood levels of C-reactive protein that can be detected by the high-sensitivity CRP test,24 which is part of the Male and Female Panel tests.
PSA (prostate-specific antigen)free and complexed
Offered as part of the Male Panel, PSA is a very sensitive marker that may suggest prostate cancer. It may also be used to monitor efficacy of therapeutic regimens associated with the prostate.
Risk of prostate cancer may be assessed by determining absolute amounts of total PSA or by calculating the percent of free PSA compared to total PSA (complexed plus uncomplexed). A study in the New England Journal of Medicine found that 25% of patients with normal digital rectal exams (DRE) and total PSA levels of 4.0–10.0 ng/ml had prostate cancer.25 In the same study group, researchers calculated that risk of prostate cancer increased with decreases in the percentage of free PSA in the serum.
It should be noted that elevated levels of PSA may not necessarily signal prostate cancer, and prostate cancer may not always be accompanied by expression of PSA. Levels may be elevated in the presence of a urinary tract infection and an inflamed prostate.
In another study published in the New England Journal of Medicine, investigators recommended lowering the PSA cutoff from 4.1 ng/ml (the threshold at which biopsy is currently recommended). At the current threshold, it was determined that “82 percent of cancers in younger men and 65 percent of cancers in older men would be missed.”26,27 But levels below the currently recognized cutoff of 4.1 ng/ml may not distinguish between prostate cancer and benign prostate disease.
A PSA level over 2.5 ng/ml, or a PSA doubling time that occurs in less than 12 years, may be a cause for concern.
Progesterone levels, included in the female testing panel, may track menstrual/ovulation cycles (levels are highest during mid-cycle, the time of ovulation) and may be used as a marker for ovarian and adrenal tumors, and for leuteal ovarian cysts (increased levels). Decreased levels are associated with amenorrhea (lack of menstruation), fetal death, and toxemia in pregnancy. Adelaide’s Exercise Physiology Laboratory in Australia recently reported that women who exercised during times when progesterone and estrogen levels were at their highest (mid-month) had increased rates of fat metabolism as well as lower perceived exertion levels, suggesting more benefit from exercise during times of peak hormone levels.28
Systemic inflammation and tests for proinflammatory cytokines TNF-a, IL-6, IL-1b and IL-8
While the presence of C-reactive protein indicates inflammation, tests for specific proinflammatory cytokines (which regulate C-reactive protein) may identify the underlying cause of inflammation.
Cytokines are cellular growth factors that are synthesized by nearly every cell of the body and are generally produced only in response to “stress.” Secreted primarily from leukocytes (white blood cells), cytokines regulate the hosts’ response to infection, immune responses, inflammation, and trauma. Cytokines may be either proinflammatory (worsen disease) or anti-inflammatory (reduce inflammation and promote healing). Some studies suggest that susceptibility to disease may result from an imbalance between pro- and anti-inflammatory cytokines.29
There is also mounting evidence that depression may directly stimulate the production of proinflammatory (primarily IL-6) cytokines or indirectly stimulate production by down-regulating the cellular immune response (i.e., prolonged infection and delayed healing fuel sustained cytokine release).30
The pro-inflammatory cytokine panel detects abnormally high levels of the most dangerous inflammatory cytokines in the blood: tumor necrosis factor-a (TNF-a), interleukin-1 beta (IL-1b), interleukin-6 (IL-6), and interleukin-8 (IL-8).
Tumor necrosis factor-alpha
TNF-a has a wide range of biological action, and receptors for TNF-a may be found on nearly all cells. Produced primarily by activated macrophages, TNF-a has cytolytic (destructive) and cytostatic (suppressive) effects on tumor cells, and shows chemotactic (responsive) activity towards neutrophils. High levels may be seen in cases of sepsis, autoimmune disease, various infectious diseases, rheumatoid arthritis, inflammatory bowel disease, and transplant rejection.
Elevated levels of TNF-a have also been found in people with high blood pressure,31 and together with IL-6 may be associated with risk of heart disease.32 In a study by Verdeccia et al, levels of TNF-a were measured in persons with or without high blood pressure to ascertain if arterial flow-mediated dilation was affected by hypertension and chronic inflammation. Investigators found that regardless of whether blood pressure was controlled with antihypertensive medication, arterial flow-mediated dilation was significantly impaired in the hypertensive group. This group also showed higher levels of TNF-a, indicating persistent inflammation despite controlling blood pressure. This study showed that even when blood pressure is under control, hypertensives still suffer from continuous damage (endothelial dysfunction) to the inner lining of the arterial wall caused by a chronic inflammatory insult. These findings indicate that hypertensives should have their blood tested for TNF-a to assess how much inner wall (endothelial) arterial damage is occurring. If the level of TNF-a is high, aggressive therapies to suppress the inflammatory cascade should be considered.