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Research in Review Summer 2003 - Testosterone Aeron LifeCycles Clinical Laboratory applies salivary analysis to the life long hormonal needs of women and men. As a tool for both interest and education, Aeron is compiling a quarterly review for clinicians, which will report short synopses of current findings in hormone science. Validation of Salivary Testosterone as a Screening Test of
Male Hypogonadism. This study compared salivary bioavailable testosterone
(through Aeron Laboratory - SBA-T) to ancilating bioavailable testosterone (BT)
and total testosterone (TT) levels in serum for 127 men aged 23 to 80 years.
SBA-T was highly significantly correlated with BT. SBA-T was also correlated
with the calculated free T index of Vermeulen and Kaufman. They then examined
the ability of SBA-T to predict symptoms using the ADAM questionnaire (Androgen
Deficiency in the Aging Male) and the Aging Male Survey (AMS). SBA-T was
significantly related to a positive ADAM score and to a total AMS score. SBA-T
was highly predictive of hypogonadal symptoms such as sleep problems, physical
exhaustion, sexual dysfunction, and decrease in sexual desire. Based on these
findings, they suggest that salivary testosterone is an acceptable measure for
diagnosing hypogonadism.
Evaluation of Assays Available to Measure Free Testosterone.
This study compared the results of various testosterone assays in a
cross-sectional study of 50 male subjects age 28 to 90 years. The following
assays were undertaken: total testosterone (T), free testosterone by equilibrium
dialysis (FT(D)), bioavailable testosterone (BT), free testosterone by
ultracentrifugation (FT(U)), and direct estimation of serum free T by an analog
ligand radioimmunoassay (FT(A)). In addition, using total T and sex
hormone-binding globulin (SHBG), we calculated the free androgen index (FAI) and
the free testosterone index (FTI) using the method of Vermeulen. If T was used
to classify hypogonadism in comparison to BT, it resulted in misclassification
in 42% of cases. Based on these data, they suggest that the FTI or BT is the
most practical methods to determine hypogonadism.
Diagnosis of Hypogonadism in the Aging Male.
The
diagnosis of hypoandrogenism in the aging male is still difficult, since the
symptomatology is aspecific and multifactorial, and it is unknown whether the
androgen requirements of the elderly men are the same as those of the young men.
In the absence of convincing arguments for the altered requirements with age,
they considered that the normal ranges of (free) testosterone levels in young
adults is also valid for elderly men. The diagnosis of hypoandrogenism in
elderly males requires both the presence of clinical symptoms and decreased free
testosterone levels. The best methods for determining free or bioavailable
testosterone, are equilibrium dialysis and ammonium sulfate precipitation,
respectively. They are, however, time-consuming techniques, which are not easily
automated. An Integrative Review on Current Evidence of Testosterone
Replacement Therapy for the Andropause.
This paper examines the evidence
supporting testosterone replacement in aging males. In general, most
investigators agree with short-term safety but long-term safety is unknown.
Testosterone therapy in aging males improves body composition, certain domains
of brain function and may also decrease cardiovascular risk in biological
models. Potential risks include erythrocytosis, edema, gynecomastia, and
prostate stimulation. The possibility of increased risk if clinically
significant prostate cancer and cardiovascular disease has been considered. Testosterone Supplementation Therapy for Older Men: Potential
Benefits and Risks. A structured, qualitative review was performed of
placebo-controlled trials that included men aged 60 and older and evaluated one
or more physical cognitive, affective, functional, or quality-of-life outcomes.
In healthy older men with low-normal to mildly decreased testosterone levels,
testosterone supplementation increased lean body mass and decreased fat mass.
Upper and lower body strength, functional performance, sexual functioning, and
mood were improved or unchanged with testosterone replacement. Variable effects
on cognitive function were reported, with improvements in some cognitive domains
(spatial, working, and verbal memory). In a few studies, men with low
testosterone levels were more likely to experience improvements in lumbar bone
mineral density, self-perceived functional status, libido, erectile function,
and exercise-induced coronary ischemia with testosterone replacement than men
with less marked testosterone deficiency. No major unfavorable effects on lipids
were reported, but hematocrit and prostate specific antigen levels often
increased. Impact of Obesity on Hypogonadism in the
Andropause.
Overall, there seems to be an inverse relationship between body mass index and
testosterone levels, as is also demonstrated in this cross-sectional study.
Obesity seems to depress the production of testosterone. It has been
hypothesized that there is increased aromatization of testosterone to estradiol
and alteration of the hypothalamic-pituitary-adrenal axis in obese older men. Prostate-Specific Antigen Changes in Hypogonadal Men Treated
with Testosterone Replacement. The effect of parenteral testosterone
replacement therapy on the development or growth of prostate cancer was assessed
by looking at serum prostate-specific antigen levels of hypogonadal men with
erectile dysfunction. Patients received intramuscular injections every 2 to 4
weeks, allowing for dose titration. 54 hypogonadal men were included, with a
mean age of 60.4 and a mean follow-up of 30.2 months on testosterone therapy. Of
the 54 men, 6 (11%) required prostate biopsy while on testosterone therapy
because of a rise in serum PSA above 4.0 ng/mL. One patient (2%) was diagnosed
with prostate cancer. They concluded that testosterone replacement therapy in
men with erectile dysfunction and hypogonadism is associated with a minor PSA
elevation, but there does not appear to be a short-term increase in risk for the
development of prostate cancer. Androgens and Cardiovascular Disease.
Observational studies show that blood testosterone concentrations are
consistently lower among men with cardiovascular disease, suggesting a possible
preventive role for testosterone therapy, which requires critical evaluation by
further prospective studies. Short-term interventional studies show that
testosterone produces a modest but consistent improvement in cardiac ischemia
over placebo, comparable to the effects of existing antianginal drugs. By
contrast, testosterone therapy has no beneficial effects in peripheral arterial
disease but has not been evaluated in cerebrovascular disease. Androgens and Coronary Artery Disease.
Hypoandrogenemia in men and hyperandrogenemia in women are associated with
visceral obesity; insulin resistance; low high-density lipoprotein (HDL)
cholesterol (HDL-C); and elevated triglycerides, low-density lipoprotein
cholesterol, and plasminogen activator type 1. The effects of exogenous T on
cardiovascular mortality or morbidity have not been extensively investigated in
prospective controlled studies; preliminary data suggest there may be short-term
improvement in electrocardiographic changes in men with coronary artery disease.
Exogenous androgens induce both apparently beneficial and deleterious effects on
cardiovascular risk factors by decreasing serum levels of HDL-C, plasminogen
activator type 1 (deleterious), lipoprotein a, fibrinogen, insulin, leptin, and
visceral fat mass (beneficial) in men as well as women. The decrease in HDL-C
may instead reflect accelerated reverse cholesterol transport. Based on current
evidence, the therapeutic use of T in men need not be restricted by concerns
regarding cardiovascular side effects. Androgen Effects on Bone and Muscle.
Both sex steroids - estrogen (E) and testosterone (T) - have receptors on all
bone cells, with androgen dominance on osteoblasts and osteocytes. Specific
receptors for the weaker androgens, such as DHEA have also been identified.
Endogenous androgens increase bone mineral density (BMD) in both adolescent and
adult premenopausal women. Women with excess endogenous androgen-for example,
those with hirsutism and polycystic ovary syndrome (PCOS) - have increased BMD
compared with normal young women. E and androgen therapy increases BMD to a
greater degree than does E therapy alone. This is true for both oral
combinations of esterified E and methyltestosterone and for subcutaneous T
implants. Defining “Relative” Androgen Deficiency in Aging Men: How
Should Testosterone be Measured and What are the Relationships Between Androgen
Levels and Physical, Sexual and Emotional Health? In men, bioavailable
and free testosterone levels decline by about 1.0 and 1.2% per year,
respectively, after the age of 40. The definition of clinically relevant
androgen deficiency in the aging male remains uncertain. The maximum benefit of
testosterone replacement occurs in those men with the lowest testosterone
levels. Population Variation in Age-Related Decline in Male Salivary
Testosterone. Mean bioavailable testosterone level differences between
populations (USA, Congo, Nepal, and Paraguay) were greatest for young men (aged
15-30) and insignificant for older men (aged 45-60). The slope of age related
decline in testosterone was significant in the USA and Congolese participants
only. Age patterns of testosterone decline vary between populations primarily as
a result of variation in the peak levels attained in young adulthood. Female Androgen Insufficiency: the Princeton Consensus
Statement on Definition, Classification, and Assessment. The term “female
androgen insufficiency” was defined as consisting of a pattern of clinical
symptoms in the presence of decreased bioavailable T and normal estrogen status.
Currently available serum assays were found to be lacking in sensitivity and
reliability at the lower ranges, and the need for an equilibrium dialysis
measure was strongly emphasized. Causes of androgen insufficiency in women were
classified as ovarian, adrenal, hypothalamic-pituitary, drug-related, and
idiopathic. A simplified management algorithm and clinical guidelines were
proposed to assist clinicians in diagnosis and assessment. Potential risks
associated with treatment were identified, and the need for informed consent and
careful monitoring was noted. Androgen Deficiency: Menopause and Estrogen-Related
Factors.
Estrogen depletion and replacement therapy at menopause can have clinically
significant effects on bioavailability of endogenous androgens. Androgens
complement the actions of estrogens in symptom control and disease prevention in
postmenopausal women. Although androgen effects on sexual function are
important, effects of androgens in many body systems should be considered in
future research to determine optimal postmenopausal hormone replacement therapy. Secreting Ovarian Tumors May Protect Women from
Osteoporosis.
Hyperandrogenism in premenopausal women, mainly in polycystic ovarian syndrome,
has been reported to have a protective effect on bone mass. A total of 14
patients with ovarian tumors were studies. Steroid levels were measured prior to
and after surgery. Bone mineral density by DEXA as assessed. In 7 women, bone
measurement was repeated after 1-year follow-up. All patients showed increased
levels of testosterone, androstenedione, and free testosterone prior to surgery.
BMD was also in the normal-upper range or over normal in all of them. As
expected in the subjects with a second DEXA (a year after surgery), a decrease
in bone mass was noted. Risk Factors and Endogenous Sex Hormones for Prediction of
ER+ and ER- Breast Cancer in Older Women: Findings from the study of
osteoporotic fractures. Baseline serum estradiol and testosterone levels
from 7721 women aged 65 and older who participated in the Study of Osteoporotic
Fractures were followed for 10.5 years. It was discovered that women with serum
testosterone concentrations in the highest versus lowest quintile had a 5.1 fold
increased risk of ER+ but a lesser increased risk of ER- breast cancer. In older
women, high serum T and advanced education (>16years) were strong risk
factors for ER+ cancer while family history and weight were strong risk factors
for ER- breast cancer. Measuring testosterone levels may help identify high risk
individuals. Androgens and Estrogens Modulate the Immune and Inflammatory
Responses in Rheumatoid Arthritis. Generally, androgens exert
suppressive effects on both humoral and cellular immune responses and seem to
represent natural anti-inflammatory hormones; in contrast, estrogens exert
immunoenhancing activities, at least on humoral immune response. Low levels of
gonadal androgens and adrenal androgens, as well as lower androgen/estrogen
ratios, have been detected in body fluids (blood, synovial fluid, smears,
salivary) of both male and female rheumatoid arthritis patients, supporting the
possibility of a pathogenic role for the decreased levels of the
immune-suppressive androgens. Sex hormone balance is a crucial factor in the
regulation of immune and inflammatory responses, and the therapeutic modulation
of this balance should represent part of advanced biological treatments for
rheumatoid arthritis and other autoimmune rheumatic diseases. Bioavailable Testosterone in Men with Rheumatoid
Arthritis-High Frequency of Hypogonadism. The bioavailable T levels (non-SHBG
bound Testosterone) of men with Rheumatoid Arthritis (RA) was compared with
those of 99 age-matched healthy men. The RA men had lower NST levels than
healthy men in all age groups. T levels and the T/SHBG ratio were lower only in
the age group 50-59yr.Thirty-three of the 104 patients were considered to have
hypogonadism compared with seven of the 99 healthy men. Longitudinal Assessment of Serum Free Testosterone
Concentration Predicts Memory Performance and Cognitive Status in Elderly Men.
Participants were volunteers from the Baltimore Longitudinal Study of Aging,
aged 50-91 yr. at baseline T assessment. Four hundred seven men were followed
for an average of 10yr, with assessments of multiple cognitive domains and serum
total T, SHBG, and a free T index (FTI). Higher FTI was associated with better
scores on visual and verbal memory, visuospatial functioning, and visuomotor
scanning and a reduced rate of longitudinal decline in visual memory. Men
classified as hypogonadal had significantly lower scores on measures of memory
and visuospatial performance and a faster rate of decline in visual memory. No
relations between total T or the FTI and measures of verbal knowledge, mental
status or depressive symptoms were observed. Testosterone Deficiency and Mood in Aging Men: Pathogenic and
Therapeutic Interactions. There is a progressive reduction in
hypothalamic-pituitary-gonadal (HPG) function in aging men; testosterone (T)
levels decline through both central (pituitary) and peripheral (testicular)
mechanisms and there is a loss of the circadian rhythm of T secretion. Overall,
data suggest that although hypogonadism is not central to major depressive
disorder (MDD), HPG hypofunction may have aetiological importance in mild
depressive conditions, such as dysthymia. Lifestyle and Nutritional Determinants of Bioavailable
Androgens and Related Hormones in British Men. The study was based on a
sample of 696 men with a wide range of nutrient intakes and lifestyle
characteristics who were assessed with a questionnaire and serum sex hormones
using immunoassays. Men aged 70 years or older had 12% lower testosterone and
40% lower free-testosterone than men who were 20-29 years of age. Men who had a
BMI of 30+ kg/m2 had a 30% lower testosterone, 45% lower SHBG. Compared with no
exercise, vigorous exercise of 3+ hours a week was associated with 11% higher
testosterone and 16% higher SHBG concentrations. No dietary factors were
associated with testosterone or Free-T. The Clinical Relevance of Sex Hormone Levels and Sexual
Activity in the Aging Male. Serum total and free testosterone,
sex-hormone binding globulin levels were measured, and they completed the
International Index of Erectile Function (IIEF) questionnaire. The total and
free testosterone levels decreased and SHBG increased with age, but only the
change in free testosterone and SHBG were statistically significant. Total
testosterone levels showed no significant correlation with any of the five
domains of the IIEF. Of the sex hormone levels, the change in free testosterone
correlated most closely with aging and had the closest correlation with sexual
activity. Free testosterone and SHBG levels were significantly correlated with
orgasmic function and/or erectile function rather than sexual desire. Effects of Prohormone Supplementation in Humans: a
Review.
Existing data suggest that acute oral ingestion of > or =200mg
androstenedione or androstenediol modestly and transiently increases serum
testosterone concentrations in men; however, this is accompanied by greater
increases in circulating estrogen(s). At doses <300mg/d, oral supplementation
for as long as 12-weeks and androstenedione or androstenediol has no effect on
body composition or physical performance and decreases high-density lipoprotein
cholesterol. Oral supplementation with norandrostenedione and nor androstenediol
for up to eight weeks has no effect on body composition or physical performance. Oral Andro-Related Prohormone Supplementation: Do the
Potential Risks Outweigh the Benefits?
Androstenedione, 4-androstenediol, 5-androstenediol, 19-norandrostenediol and
19-norandrostenedione are commonly referred to as “Andro” prohormones.
Supplement manufacturers often claim that Andro use improves serum Testosterone
concentrations, increases muscular strength and muscle mass, helps to reduce
body fatness, enhances mood, and improves sexual performance. Several studies
using oral Andro related prohormones show that Andro use can abnormally elevated
estrogen, which is thought to increase a person’s risk for developing prostate
or pancreatic cancers. In addition, most studies also indicate that significant
declines in high-density lipoproteins occur leading to an increased
cardiovascular disease risk. |