A Comprehensive Guide to Preventive Blood TestingMay 2004
By Penny Baron
Total and free testosterone
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).
DHEA-S (dehydroepiandrosterone sulfate)
C-reactive protein (CRP)
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
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.
Systemic inflammation and tests for proinflammatory cytokines TNF-a, IL-6, IL-1b and IL-8
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
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.