Low Serum Testosterone and Mortality - Part 2

Low Serum Testosterone

In the industrialized world, men experience an earlier onset of cardiovascular disease and a life expectancy 5 to 10 years shorter than women.  Another study evaluated 4152 men and women, the evaluating “Low testosterone concentrations in men contribute to the gender gap in cardiovascular morbidity and mortality”.

The results indicated that men were uniformly at higher risk of incidence for cardiovascular morbidity, including being overweight, hypertension, high cholesterol, metabolic syndrome, and type II diabetes than women.

One particular study examined the association between serum testosterone and estradiol and all-cause mortality in elderly men.  In the conclusion of this study, which included a mean follow-up of 4.5 years, 383 deaths occurred.  Risk of death nearly doubled in subjects with low levels of both testosterone and estradiol compared with other subjects.  In conclusion, it was noted that elderly men with low serum testosterone and estradiol have increased risk of mortality.

The study noted that circulating estradiol levels in older men are low but measurable, exceeding the levels found in postmenopausal women.  It was noted that approximately 80% of circulating estradiol in men derived from androgens and therefore serum levels of estradiol and testosterone were significantly associated.  Studies investigating aromatase or estrogen receptor deficiency in males demonstrated that estradiol had important physiological effects on bone maturation and peak bone mass in younger men.  The role of estradiol in a Swedish Osteoporotic study revealed that low serum estradiol was associated with an increased risk of fracture.

In this study testosterone levels as well as estradiol levels in men were assessed.  Low levels of both testosterone and estradiol independently predicted all-cause mortality in these models.  In subjects with low levels of both testosterone and estradiol, risk of death approximately doubled when adjusted for age, BMI, physical activity and smoking.

The result of the study indicated that risk of death increased in elderly men in the lowest quartile of both testosterone and estradiol levels.  It was also noted that testosterone and estradiol predicted death independently of each other, and risk for death nearly doubled (96% increase) in subjects with both low testosterone and low estradiol compared with subjects within other quartiles of both hormones.

Two major hypotheses regarding the association between low sex steroid levels and mortality were put forward:

± Low sex steroid levels caused or worsened disease and thereby caused death.

± Low sex steroid levels are a result of disease and therefore associated with death.

In this case the second hypothesis, that is the low testosterone/low estradiol levels, is supported by evidence that both acute and chronic illnesses reduce testosterone production.  In acute illness, testosterone is often profoundly depressed at the testicular level and indirectly through gonadotropin suppression.  Therefore, low serum sex steroids may be considered a general marker of poor health and associated with increased mortality risk.

In this study, the association between estradiol/testosterone and mortality remained significant even after deaths were excluded that had occurred within the first 3 years of follow-up, thus arguing against a substantial role of prevalent diseases that otherwise might have been observed during observation.  Therefore, low testosterone levels contribute to frailty that affects the individual’s capability to recover after any disease and thereby affects survival.

In conclusion, low serum testosterone and estradiol were associated with increased risk of death in older Swedish men.  Subjects with low testosterone and estradiol were found to have an increased risk of mortality. Thus, both low testosterone and low estradiol may serve as markers of mortality risk in elderly men.

For more information, please visit us at the Southwest Age Intervention Institute blog.

Low Serum Testosterone and Mortality - Part 1

Low Testosterone

Low serum testosterone is a common condition in aging associated with decreased muscle mass and insulin resistance.  Studies reveal that low testosterone levels are a risk factor for mortality in male veterans.  Declining testosterone levels in elderly men are thought to underlie many of the symptoms and diseases of aging.

One study evaluated testosterone levels in men older than 40 years.  Initial results of this study revealed that mortality was 34.9% higher in men with low testosterone levels.  After adjusting for age, medical morbidity, and other clinical factors, low testosterone levels continued to be associated with increased mortality.

In contrast to menopause, in which all women undergo a nearly complete cessation of gonadal estrogen production, in men, gonadal testosterone decreases progressively at a rate of 1.5% after the age of 30.  Manifestations of low testosterone include:

± Decreased muscle mass

± Declining bone mineral density (BMD)

± Increased fat mass and central obesity

± Insulin resistance

± Decreased libido and performance

± Decreased energy

± Increased irritability

Approximately 30% of men 60 years and older are believed to have low testosterone which is often accompanied by undesirable signs and symptoms such as low bone density and muscle mass, increased fat mass (especially central obesity), low energy, impaired physical, sexual and cognitive function.

Furthermore, other studies have revealed men with low testosterone are at increased risk of falls, low BMD, hip fracture, anemia, type-2 diabetes, depressive illness, systolic and diastolic blood pressure, fasting plasma glucose and serum insulin, triglycerides, an adverse metabolic risk profile, atherosclerosis and Alzheimer’s disease.  Low testosterone was found with some acute and chronic illnesses and certain medications.  Low testosterone predicted increased risk of cardiovascular and respiratory disease and mortality but was not significantly related to cancer deaths.

Total testosterone did not differ by smoking habits or exercise but was slightly lower among men who consumed at least 1 alcoholic drink daily.  Levels of testosterone were higher in men who lost 10 pounds or more in the past 10 years and low in men who had gained at least 10 pounds.  Total testosterone was 8% lower for men who had hypertension and 22% lower for men who had metabolic syndrome compared with men who did not.

One study revealed that low testosterone precedes the development of central obesity, metabolic syndrome and diabetes.  This study also revealed that lower total testosterone levels were associated with insulin resistance, altered lipid profile and high blood pressure.

Some of the adverse affects of male aging are attributed to the decrease in testosterone stimulating a surge of interest in testosterone therapy for middle-aged and older men.  Testosterone sales in the U.S. increased 20 fold in the 1990’s.

In a separate study, men in a geriatric rehabilitation unit with low testosterone were found to have an increased 6‑month mortality compared with men with normal testosterone levels who were of comparable age with comparable medical morbidity.

One particular study was based upon the evaluation of 794 men, aged 50–91 with a median age of 73.6 who had serum testosterone measurements between 1984 and 1987 and followed for mortality through July 2004.  The results revealed that in the 11.8 year follow-up, 538 deaths occurred.  Men whose total testosterone levels were in the lowest quartile (<241 ng/dL) were 40% more likely to die than those with higher levels, independent of age, adiposity, and lifestyle.  Additional adjustment for health status markers, lipids, lipoproteins, blood pressure and insulin, and estradiol levels had minimal effect on results.

Reviewing age, adiposity, and lifestyle-adjusted factors of cause-specific mortality, low and bioavailable testosterone were each significantly associated with an elevated 20-year risk of cardiovascular disease morbidity and death due to respiratory disease.

For more information or to read Part 2 of the series, please visit us at the Southwest Age Intervention Institute blog.

Hormonal Decline and Osteoporosis in Men and Women - Part 2

Hormonal Therapy Men

Another study evaluated an oral low-dose estrogen therapy on bone mineral density in osteopenic postmenopausal women.  This study investigated 120 postmenopausal hysterectomized women.  The change in BMD differed significantly after 24 months.  Women on estrogen therapy showed significant increase in spine and hip Z-scores whereas the placebo control group showed significant decreases in spine and total hip BMD.  The results indicated the positive effect of an oral low-dose estrogen therapy on bone mineral density.

A further study was to reviewed osteopenia and male hypogonadism from primary testicular failure due to a prior lymphoma in addition to osteopenia.  The patient received supplementary calcium, vitamin D and testosterone.  Improvement in serum testosterone level was noted within six weeks along with increased energy, libido, and erectile function.  A dual-energy x-ray absorptiometry (DEXA) scan showed improvement in bone status also.  Therefore, male hypogonadism was associated with increased risk for osteopenia as well as osteoporosis.  It was noted that supplemental testosterone therapy, because of its direct effect and its aromatization to estrogen, could directly improve bone mineral density in patients suffering from hypogonadism.  One of the primary treatment regimens for hypogonadism is testosterone replacement and this helped increase bone mineral density.

According to the third National Health and Nutrition Examination Survey, between 3% and 6% of U.S. men have osteoporosis in the hip while 28% to 47% have osteopenia.  Prior to the age of 50 years, most fractures are traumatic in origin and are not caused by osteoporosis.  Fractures caused by osteoporotic fragility gradually increase in men from 60 to 80 years of age when testosterone levels are significantly reduced.  Osteoporotic fractures commonly occur about the femoral neck and the vertebra of the spine.  Vertebral fractures in men are found along the entire spine however the majority are in the lower thoracic area.  African-American men have significantly less incidents of hip fractures compared to Caucasian men.

More than 95% of circulating testosterone is bound to albumin and sex hormone-binding globulin (SHBG) leaving only a small amount of biologically active free testosterone to mediate androgen effects.  Although total testosterone does not always decrease in all men, there is commonly an increase in concentration of SHBG, resulting in a decline of free, biologically active testosterone.

Furthermore, testosterone is locally converted to dihydrotestosterone which more aggressively binds to the androgen receptors or aromatized to estradiol.  The incidence of osteoporosis in men is directly correlated to the reduction in circulating testosterone.  Because androgens promote an increase in osteoblasts, while inhibiting osteoclastic activity, decreasing bone density may ensue.  When discussing male osteoporosis secondary to hypogonadism, the direct effect of testosterone is likely 25% of its effectiveness, whereas its aromatization to estrogen contributes to the remaining 75%.

One study in question showed how estrogen may have regulatory effects on bone turnover in functional hypogonadal men and women.  In the study in question, endogenous estrogen and testosterone were suppressed.  Exogenous estrogen and testosterone were then administered.  Markers of bone turnover were then measured to determine which sex hormones were dominant in regulating bone resorption.  In patients with suppressed testosterone and estrogen, but no replacement, there was an increase in urinary excretion of particular markers suggesting increased bone turnover in the absence of sex hormones.

When estrogen alone was suppressed, there was still a high level of bone turnover marker excretion but not as significant as when both androgens were suppressed.  The changes seen when testosterone alone was suppressed and estrogen was not replaced, indicate the crucial role of estrogen on BMD.  Estrogen and testosterone were determined to have an additive effect on maintaining BMD.  Estrogen also not only enhanced bone mass but also retarded bone loss.  Furthermore, testosterone therapy was beneficial because of its action on osteoblast proliferation and osteoclast inhibition plus its aromatization to estrogen, resulted in improved bone density.

Furthermore, long-term treatment with testosterone replacement therapy has been shown to be well tolerated in men with osteoporosis.  In one particular study of testosterone treatment in hypogonadal men, it was found that bone mineral density increased approximately 7.5% in the L2 through L4 vertebra of the lumbar spine and by 5% in the femoral trochanter region.

One further study revealed that using testosterone replacement for 18-30 months resulted in a 3.1% increase in BMD.  Mean estrogen levels were also higher after treatment with testosterone.  Serum markers of bone turnover in turn were all decreased.

One further study reviewed the effects of testosterone therapy on the lumbar spine and hip mineral density in elderly men.  The study took place in Mexico and the aim of the study was to analyze the effect of testosterone therapy on bone mineral density in healthy elderly men who had low levels of total testosterone.

In this case, 48 men over 60 years old with decreased testosterone levels, that is levels less than or equal to 320 ng/dL comprised the study.  25 of the 48 received intramuscular injections of Testosterone Enanthate every three weeks for a period of 12 months straight.  The remaining 23 participants formed a control group.  All participants had measurements of bone mineral density of both the lumbar spine and hip before and at the end of the study as well as testosterone and estradiol levels.

The conclusion was that testosterone therapy elicited a positive effect in lumbar BMD in elderly men who otherwise had diminished testosterone serums levels.

One further study made note of the therapeutic role of androgens in the treatment of osteoporosis in men.  The source of the study was the Harvard Medical School, Massachusetts General Hospital, Boston, USA.  The study recognized the interest in the relationship between androgens and bone mineralization in men.  The study recognized that increases in serum androgens during puberty allow for skeletal maturation and the attainment of peak bone mass, and the persistence of normal testosterone secretion during adulthood was important for the maintenance of bone density.

It was stated that testosterone deficiency was associated with heightened bone turnover and was a major risk factor for osteoporosis in men.  The administration of testosterone in androgen-deficient men led to increases in BMD and a reduction in markers of bone turnover suggesting that the androgens did have a dampening effect on bone remodeling.

For more information, please visit us at the Southwest Age Intervention Institute blog.

Hormonal Decline and Osteoporosis in Men and Women - Part 1

Hormonal Therapy

Osteoporosis is a common post-menopausal disease that has a substantial impact on the quality of life in women and is associated with significant morbidity and mortality.  Estrogen therapy (in hysterectomized women) and estrogen/progestin therapy (in non-hysterectomized women) are the most effective treatments available for the relief of vasomotor and urogenital symptoms in post-menopausal women and provide significant protection against osteoporotic fractures or loss of bone mineral density (BMD).

Every medical study has confirmed that estrogens are the most effective way of increasing bone mineral density to prevent osteoporotic fractures even in low-risk women.  This treatment has been found to be safe when started in women under the age of 60.  It is more effective and beneficial than biphosphonates that are frequently used by physicians as first choice or by general practitioners unsure about the safety of estrogen therapy.

Hormonal therapy should be considered as a first-line therapy in preventing bone loss and fractures.  Certain selective estrogen receptor modulators are known to reduce bone loss and help prevent vertebral fractures without endometrial or breast stimulation.  Future therapies are likely to include selective estrogen receptor modulators and the appropriate hormonal therapies.  Interestingly, biphosphonates and other non-hormonal treatments for low bone mineral density do not have the same beneficial effect upon intervertebral disc structure. 

Some believe that these non-hormonal drugs with their considerable long-term complications should have no immediate place in maintaining bone mineral density in women under the age of 60.  Women receiving estrogen therapy for climacteric symptoms such as flushes, sweats, or vaginal dryness, experience a considerable increase in BMD, up to 15% in 10 years, to the extent that osteoporotic fractures 20 years later are much less likely to occur.

One significant benefit is that hormone replacement therapy also is known to protect intervertebral discs.  Several studies have conclusively shown that estrogen could prevent collagen being lost from intervertebral discs, thus maintaining their strength and function.  As discs make up one-quarter of the length of the spinal column and act as cushions preventing crush injuries of the vertebral bodies, the maintenance of these structures is paramount.  Compression fractures lead to loss of vertebral height and lordosis of the thoracic spine (Dowager's hump) can occur.  This is an important benefit to the use of estrogen and testosterone. 

It has been found that women with low bone density, even without typical menopausal symptoms, should use estrogen as a first-choice therapy.  For those younger women with severe osteopenia or osteoporosis due to premature menopause, early hysterectomy and oophorectomy or anorexia with amenorrhea, estrogens are an essential long-term treatment. 

In one particular study the effects of hormonal therapy on bone mineral density was evaluated.  Participants in this study who participated in the placebo group lost an average of 1.8% of spine BMD and 1.7% of hip BMD by the 36-month visit, while those assigned to active hormonal supplementation gained BMD at both sites ranging from 3.5% to 5%. 

Of all the women, women with low initial BMD, and those with no previous hormonal use, gain significantly more bone than younger women, women with higher BMD, and those who had used hormones previously.

In conclusion, postmenopausal women assigned to the placebo demonstrated decreased BMD at the spine and hip, whereas women assigned to estrogen therapy increased BMD during the following 36-month period.

For more information or to read Part 2 of the series, please visit us at the Southwest Age Intervention Institute blog.