Friday, September 24, 2010

Low Testosterone Associated With Fracture Risk in Older Men

Jennifer Reid Holman, MA, Medscape Medical News.ASBMR 28th Annual Meeting: Abstract 1020.
Older men who have lower levels of testosterone tend to be at significantly higher risk for bone fracture, according to a study presented here at the 28th annual meeting of the American Society for Bone and Mineral Research.

Like other recent research, this study suggests that age-related declines in sex steroid hormones - which affect both men and women - may have some association with age-related decline in bone health.

"One third of all osteoporotic fractures occur in men," noted lead researcher Christian Meier, MD, from the University of Basel in Switzerland. "This is one of the largest prospective studies looking at whether testosterone may have some correlation."

The study by Dr. Meier and colleagues included 609 men older than 60 years (mean age, 72.6 ± 5.7 years) who took part in the Dubbo Osteoporosis Epidemiology Study, an Australian population-based study. At baseline, the men were assessed for weight, calcium intake, smoking habits, spinal bone mineral density (BMD), and serum levels of total testosterone and sex hormone binding globulins (SHBG). In addition, free testosterone was calculated based on total testosterone and SHBG levels. Symptomatic low-trauma fractures, from incidents like minor falls, were recorded during prospective follow-up.

During the median 6-year follow-up period, 113 men (18.6%) sustained at least 1 low-trauma fracture. At baseline and compared with the no fracturing control subjects, these patients tended to be older (typically older than 70 years) and to have lower weight, height, BMD, calcium intake, and serum levels of both total and free testosterone. In addition, they had higher SHBG levels than control subjects.

In multivariate analysis, total and free testosterone levels were found to be significant and independent predictors of osteoporotic fracture. The risk for any fracture increased by 40% and the risk for no vertebral fracture increased by 50% for each SD decrease in testosterone levels.

According to the National Osteoporosis Foundation, fractures - especially those of the hip - can be particularly catastrophic in older men because they are more likely to die or be chronically disabled afterward than women.

The role that testosterone may play in the bone health of aging men is still unclear. Some studies show that testosterone levels are not associated with BMD in older men, noted Jane Cauley, DrPH, researcher and professor of epidemiology at the University of Pittsburgh in Pennsylvania. "But low testosterone could still explain some of the fracture risk in older men even if it has nothing to do with [BMD]," Dr. Cauley told Medscape.

For instance, lower testosterone level may be related to reduced muscle strength and instability, which can make men more vulnerable to falls and fractures, Dr. Cauley pointed out. And because testosterone is converted to estradiol in the body, low testosterone levels, in turn, could lead to lower estradiol levels, she added.

The Impact of Sleep Deprivation on Hormones and Metabolism

Medscape Neurology & Neurosurgery.2005;7(1)©
Eve Van Cauter, PhD; Kristen Knutson, PhD; Rachel Leproult, PhD; Karine Spiegel, PhD

Sleep loss can occur as a result of habitual behavior or due to the presence of a pathological condition that is associated with reduced total sleep time. This column focuses on the impact of behavioral sleep curtailment, an endemic condition in modern society, and provides evidence against the old notion that "sleep is for the mind, and not for the rest of the body."

Prevalence of Sleep Curtailment in Modern Society
Changes in self-reported sleep duration over the past 50 years:
In 1960, a survey of over 1 million people found a modal sleep duration of 8.0-8.9 hours In 2000, 2001, and 2002, polls conducted by the National Sleep Foundation indicated that the average duration of sleep for Americans had fallen to 6.9-7.0 hours. Overall, sleep duration thus appears to have decreased by 1.5-2 hours during the second half of the 20th century. Today, many people are in bed only 5-6 hours per night on a regular basis.

The release of hormones by the pituitary - the "master" endocrine organ that controls the secretion of other hormones from the peripheral endocrine glands - is markedly influenced by sleep. Modulation of pituitary-dependent hormonal release is partly mediated by the modulation of the activity of hypothalamic-releasing and/or hypothalamic-inhibiting factors controlling pituitary function. During sleep, these hypothalamic factors may be activated - as in the case of growth hormone (GH)-releasing hormone - or inhibited, as is the case for corticotropin-releasing hormone.
The other pathway by which sleep affects peripheral endocrine regulation is via the modulation of autonomic nervous system activity. During deep sleep, sympathetic nervous system activity is generally decreased and parasympathetic nervous system activity is increased. Sleep loss is associated with an elevation of sympathovagal balance, with higher sympathetic but lower parasympathetic tone. Most endocrine organs are sensitive to changes in sympathovagal balance. Well-documented examples are pancreatic insulin secretion and release by the fat cells of leptin, an appetite-suppressing hormone.
A profound and generalized impact of sleep loss on the endocrine system should therefore be expected. 

Alterations of Pituitary-Dependent Hormones During Sleep Loss

The first effect of partial sleep loss on circulating levels of pituitary-dependent hormones to be documented under various study conditions is an increase in the early evening levels of the stress hormone cortisol. Normally at that time of day, cortisol concentrations are rapidly decreasing to attain minimal levels shortly before habitual bedtime. The rate of decrease of cortisol concentrations in the early evening was approximately 6-fold slower in subjects who had undergone 6 days of sleep restriction than in subjects who were fully rested. Elevations of evening cortisol levels in chronic sleep loss are likely to promote the development of insulin resistance, a risk factor for obesity and diabetes. 

The impact of sleep restriction on the thyroid axis: 

After 6 days of 4-hour sleep time, the normal nocturnal thyroid-stimulating hormone (TSH) rise was strikingly decreased, and the overall mean TSH levels were reduced by more than 30%. A normal pattern of TSH release reappeared when the subjects had fully recovered. Thyroid axis function was thus markedly altered by partial recurrent sleep restriction.
chart The temporal organization of GH secretion is also altered by chronic partial sleep loss. The normal single GH pulse occurring shortly after sleep onset splits into 2 smaller pulses, 1 before sleep and 1 after sleep; as a result, the peripheraltissues are exposed to high GH levels for an extended period of time, which, because GH has anti-insulin-like effects, could also have an adverse impact on glucose tolerance.
The temporal organization of GH secretion is also altered by chronic partial sleep loss. The normal single GH pulse occurring shortly after sleep onset splits into 2 smaller pulses, 1 before sleep and 1 after sleep; as a result, the peripheral tissues are exposed to high GH levels for an extended period of time, which, because GH has anti-insulin-like effects, could also have an adverse impact on glucose tolerance. 

Impact of Sleep Loss on Hormones Controlling Appetite

Sleeping and feeding are intricately related. Animals faced with food shortage or starvation sleep less; conversely, animals subjected to total sleep deprivation for prolonged periods of time increase their food intake markedly. Recent studies in humans have shown that the levels of hormones that regulate appetite are profoundly influenced by sleep duration. Sleep loss is associated with an increase in appetite that is excessive in relation to the caloric demands of extended wakefulness.
The regulation of leptin, a hormone released by the fat cells that signals satiety to the brain and thus suppresses appetite, is markedly dependent on sleep duration. After 6 days of bedtime restriction to 4 hours per night, the plasma concentration of leptin was markedly decreased, particularly during the nighttime. The magnitude of this decrease was comparable to that occurring after 3 days of restricting caloric intake by approximately 900 kcal/day. But the subjects in the sleep-restriction condition received identical amounts of caloric intake and had similar levels of physical activity as when they were fully rested. Thus, leptin levels were signaling a state of famine in the midst of plenty.
In a later study, the levels of ghrelin, a peptide that is secreted by the stomach and stimulates appetite, were measured with the levels of leptin after 2 days of sleep restriction (4 hours of sleep) or sleep extension (10 hours of bedtime). The subjects also assessed their levels of hunger and appetite at regular intervals. Sleep restriction was associated with reductions in leptin (the appetite suppressant) and elevations in ghrelin (the appetite stimulant) and increased hunger and appetite, especially an appetite for foods with high-carbohydrate contents. Similar findings were obtained simultaneously in a large epidemiologic study in which sleep duration and morning levels of leptin and ghrelin were measured in over 1,000 subjects. The summarizes the remarkable concordance between the results of the 2 studies. Despite the differences in study design, both studies found a decrease in the satiety hormone leptin and an increase in appetite-stimulating ghrelin with short sleep.
Sleep loss therefore seems to alter the ability of leptin and ghrelin to accurately signal caloric need and could lead to excessive caloric intake when food is freely available. The findings also suggest that compliance with a weight-loss diet involving caloric restriction may be adversely affected by sleep restriction.
During the second half of the 20th century, the incidence of obesity has nearly doubled, and this trend is a mirror image of the decrease in self-reported sleep duration illustrated in Figure 1. The discovery of a profound alteration in the neuroendocrine control of appetite in conditions of sleep loss is consistent with the conclusions of several epidemiologic studies that revealed a negative association between self-reported sleep duration and body mass index. Taken together, the current evidence suggests a possible role for chronic sleep loss in the current epidemic of obesity. 

Metabolic Implications of Recurrent Sleep Curtailment

Recent work also indicates that sleep loss may adversely affect glucose tolerance and involve an increased risk of type 2 diabetes.
In young, healthy subjects who were studied after 6 days of sleep restriction (4 hours in bed) and after full sleep recovery, the levels of blood glucose after breakfast were higher in the state of sleep debt despite normal or even slightly elevated insulin responses. The difference in peak glucose levels in response to breakfast averaged ±15 mg/dL, a difference large enough to suggest a clinically significant impairment of glucose tolerance
These findings were confirmed by the results of intravenous glucose tolerance testing. Indeed, the rate of disappearance of glucose post injection - a quantitative measure of glucose tolerance - was nearly 40% slower in the sleep-debt condition than after recovery, and the acute insulin response to glucose was reduced by 30%. Glucose tolerance measured at the end of the recovery period was similar to that reported in an independent study in young, healthy men, but glucose tolerance in the state of sleep debt was comparable to that reported for older adults with impaired glucose tolerance. Thus, less than 1 week of sleep restriction can result in a pre-diabetic state in young, healthy subjects. Of note, the adverse impact of sleep deprivation on glucose tolerance demonstrated in laboratory studies is consistent with the finding of an increased risk of symptomatic diabetes with short sleep in a cohort study of women.
Multiple mechanisms are likely to mediate the adverse effects of sleep curtailment on parameters of glucose tolerance, including decreased cerebral glucose utilization, increases in sympathetic nervous system activity, and abnormalities in the pattern of release of the counter regulatory hormones cortisol and GH.

Chronic Insomnia: Just maybe it's a hormone imbalance

Bonnie has always been able to enjoy good sleep in the past. No matter how stressed she might be, she could count on laying her head on her pillow, falling fast asleep and waking up the next morning refreshed and rejuvenated. However, when she reached her mid 40's, her periods started changing and she began experiencing sleep problems. First, she would just have insomnia the night before starting her period. As her periods became more irregular, she started waking up in the middle of the night around 2 or 3 am and would find herself wide awake and unable to go back to sleep. With so little sleep, she would be exhausted the next morning.
Over-the-counter sleep aids would make her feel sluggish the following day. By the afternoon and early evening, she would be crashing. She came to see me on maximal doses of prescription sleep medicine and still was sleeping poorly
Bonnie suffered from a very common sleep disorder that occurs with declining levels of estrogen and/or progesterone that accompany perimenopause and/or menopause. It is characterized by wakefulness in the middle of the night and can be very debilitating when it continues long-term. The typical patient with this type of insomnia often becomes addicted to prescription sleeping pills. Bonnie's insomnia totally resolved after her estrogen and progesterone levels were normalized.
While menopause occurs in all women, insomnia does not uniformly affect all women and therefore, women may not recognize that this is a low estrogen symptom. Furthermore, if the insomnia has gone on for many years, other secondary conditions such as depression, anxiety, chronic fatigue, fibromyalgia, sleep apnea and obesity may develop.
It's important to emphasize that insomnia can result from endocrine problems in both men and women. Disorders of thyroid hormone, testosterone, cortisol, and growth hormone can all cause sleep disorders.
People can also develop insomnia from poor lifestyle choices. Overzealous Americans intent on squeezing more work, more fun, more family time and more sheer activity into their lives often short-change their sleep. What are ways to promote a good night's sleep? Try going to bed at the same time each night and getting up at the same time. The body likes a regular schedule. Sleep in a cool, dark room - use nightshades, white noise or a sleep mask if necessary. Avoid spicy food or caffeine-containing foods in the evening. Finish eating at least 3 hours before bedtime. Many individuals find that heavy intake of sugar or alcohol at dinner leads to restless sleep. Start winding down in the evening. Do not engage in heavy exercise late at night. Don't watch the 10 o'clock news or read grisly books which cause mental over-stimulation. Individuals who can't function without a large dose of coffee in the morning are usually sleep-deprived.
Just how much sleep is enough sleep? Individuals who consistently get less than seven or eight hours of sleep per night are often sleep-deprived. Interestingly, people who need MORE than eight hours of sleep may also have a sleep disorder. They need more than eight hours of sleep because the sleep they are getting is poor quality sleep. People do not have less need for sleep with aging. It's just that sleep disorders are so common in older people. Most sleeping pills will knock you out but do not tend to promote normal sleep architecture. There are now new sleep agents that promote the deep sleep, which tends to be more restorative.

Wilson's Syndrome- Reverse T3 Dominance

The thyroid is a small, butterfly-shaped gland located just below the Adam's apple. This gland plays a very important role in controlling your body's metabolism, that is, the rate at which your body uses energy. It does this by producing thyroid hormones (primarily thyroxine, or T4, and triiodothyronine, or T3). These thyroid hormones tell the cells in your body how fast to use energy and create proteins. The thyroid gland also makes calcitonin, a hormone that helps to regulate calcium levels in the blood by inhibiting the breakdown (reabsorption) of bone and increasing calcium excretion from the kidneys.

In a healthy patient a normal thyroid gland secretes all of the circulating T4 (about 90 to 100mcg daily) and about 20% of the circulating T3. The T4 made by the thyroid gland circulates throughout the body and is converted into roughly equal amounts of T3 and reverse T3. Most of the biological activity of thyroid hormones is due to T3. It has a higher affinity for thyroid receptors and is approximately 4 times more potent than T4. Because 80% of serum T3 is derived from T4 in tissues such as the liver and kidney, T4 is considered a pro-hormone. No receptors have ever been identified for T4.

Reverse T3 (rT3) is virtually inactive having only 1% the activity of T3 and being a T3 antagonist binds to T3 receptors blocking the action of T3. Normal metabolism of T4 requires the production of the appropriate ratio, or balance, of T3 to rT3. If the proportion of rT3 dominates then it will antagonize T3 thus producing hypothyroid symptoms despite sufficient circulating levels of T4 and T3. Reverse T3 has the same molecular structure as T3 however its three dimensional arrangement (stereochemistry) of atoms is a mirror image of T3 and thus fits into the receptor upside down without causing a thyroid response and thus preventing or antagonizing the active T3 from binding to the receptor acting as a metabolic break.

Reverse T3 dominance, also known as Wilson's Syndrome, is a condition that exhibits most hypothyroid symptoms although circulating levels of T3 and T4 are within normal test limits. The metabolism of T4 into rT3 is in excess when compared to T3 therefore it is a T4 metabolism malfunction rather than a straight forward thyroid deficiency. Periods of prolonged stress, may cause an increase in cortisol levels as the adrenal glands respond to the stress. The high cortisol levels inhibit the conversion of T4 into T3 thus reducing active T3 levels. The conversion of T4 is then shunted towards the production of the inactive reverse T3. This reverse T3 dominance may persist even after the stress passes and cortisol levels have returned to normal as the reverse T3 itself may also inhibit the conversion of T4 to T3 thus perpetuating the production of the inactive reverse T3 isomer. Also conversion of T4 into T3 is decreased in the following cases that need to be rules out, such as hypoglycemia (low blood sugar-possibly due to low carb diets), adrenal exhaustion, nutritional deficiencies (such as Vit B6, B12, Zinc, Vit E and iodine) and/or low sex hormone (such as testosterone).

Therefore, besides testing for TSH, Free T4, Free T3, rT3, is also tested, and a ratio of T3/rT3 is obtained. If reverse T3 dominance is present appropriate therapy is needed to safely treat the patient, and relieve all symptoms that brought them into the physician's office in the first place.

Exercise Reduces Risk for Premature Death from Cancer

A study from Finland has shown that men who exercised for at least 30 minutes a day at moderate to high intensity halved their risk of dying prematurely from cancer, mainly gastrointestinal and lung cancer. The results were published online July 28, 2009 in the British Journal of Sports Medicine. Physical inactivity over a person's lifespan might be a "key factor in the initiation of cancer development," the authors note.
"We found a 50% reduction in the risk of dying prematurely from cancer," Dr. Kurl pointed out. Exercise also improves well being and confidence, and leads to better sleep and weight control, he added.
The study was carried out in men, but Dr. Kurl said he expects to see similar results in women.
Intensity of Physical Activity Was Important
The reduction in the risk for premature death from cancer was seen in men who exercised for more than 30 minutes every day, and with an intensity that was moderate to high, Dr. Kurl noted. The activities they performed included jogging, swimming, cycling to work, and gardening or yard work, he said
Exercise intensity was measured in metabolic equivalents of oxygen consumption (METs). The average intensity of jogging was 10.1 MET, of skiing was 9.6 MET, of ball games was 6.7 MET, of swimming was 5.4 MET, of rowing was 5.4 MET, of cycling was 5.1 MET, of gardening/farming/yard work was 4.3 MET, and of walking was 4.2 MET.
"Anything above an average of 4 MET can be considered [to be] moderate-intensity exercise," Dr. Kurl told Medscape Oncology.
"The intensity of leisure-time physical activity should be at least moderate so that the beneficial effect of physical activity for reducing overall cancer mortality can be achieved," the authors write.
The results show that at least moderate-intensity physical activity is more beneficial than low-intensity physical activity in the prevention of cancer, the authors note. This finding is consistent with American consensus statements suggesting that at least moderate-intensity physical activity is needed to prevent chronic diseases caused mainly by cardiovascular disease, they add.
Several Mechanisms Involved
"Our results indicate that those with an active lifestyle have a decreased risk of gastrointestinal cancers," the researchers note. This finding may be due to changes in energy balance, which includes body mass, which is particularly important for colon cancer, they note. In addition, the increased gut motility with exercise training decreases gastrointestinal transit time, thereby reducing the contact time between fecal carcinogens and the colonic mucosa, as well as allowing less opportunity for the initiation of carcinogenesis and colonic cell division and proliferation. There may also be an affect on insulin and fat metabolism, they add.
Medscape Medical News, July 27, 2009.