| 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
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.
Estradiol
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.
Homocysteine
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
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. |