Outline

• How Does Testosterone Influence The Metabolic Syndrome?
• Low Testosterone Is Common In Diabetes
• Low Testosterone: Symptoms and Complaints
• Endocrine Guidelines for Treating Low Testosterone
• References

I. How Does Testosterone Influence The Metabolic Syndrome?

Hypogonadism is likely a fundamental component of metabolic syndrome.

Testosterone is not only a sexual hormone. It also affects body tissues by modifying fat metabolism and insulin sensitivity. Testosterone (T) levels decline about 100 ng/dl for each decade of life. This relative decline caused by normal aging may not significantly affect glucose or insulin metabolism, but it plays a central role in diabetes and obesity and in all liklihood, the metabolic syndrome.

About 98 percent of the testosterone in the body is bound to sex hormone binding globulin, abbreviated as SHBG and albumin. It is the small portion of unbound testosterone in the blood (about 2 percent of the total T or TT), known as free testosterone, (FT) which largely determines the quantity actually available to the tissues. Circulating or free testosterone is the main indicator of sexual drive for both men and women and is affected by their weight. This level, as determined by equilibrium dialysis, was previously considered the “gold standard” for the diagnosis of testosterone deficiency. A drop in FT usually occurs somewhere in mid-life or in the early fifties and can be explained by the general decline of certain hormones during the aging process plus increases in weight. Increasing weight lowers TT levels and FT levels much more than natural aging.

Both men and women experience a drop in testosterone after menopause and the male equivalent, andropause. In both sexes, this can result in anemia and fatigue. About ten years ago, Vermulen, a well known Belgian endocrinologist found that in obese men, T, FT, and SHBG levels were significantly lower than those in the nonobese men and inversely correlated with BMI. We know that BMI increases with age but the age dependent decrease in T levels persisted despite correction for BMI. What that means is that the decrease in testosterone is related more to weight than age.

Tibblin and his group in Sweden offered compelling evidence that obesity alone can influence the levels of circulating androgens, particularly in their test group of men aged 67 years. Those with impaired glucose tolerance had increased BMI and waist size in addition to lower total and free testosterone and SHBG. These three hormones were useful predictors for developing diabetes and subsequent heart attacks and stroke. Testosterone deficiency was often followed by insulin resistance but was correctable with testosterone replacement.

In 2005, Vermulen published a second study in which he stated “to date there is no evidence-based documentation of clinical benefits of androgen administration to elderly men with normal or moderately low serum testosterone in terms of diminished morbidity or of improved survival or quality of life.” The key words here are “normal or moderately low serum testosterone”. There is no advantage to treating men who do not have T levels below the normal range for their age group. But what are these normal ranges? In order to diagnose hypogonadism we must use specific and sensitive testing when it is not clear whether a T deficiency exists. All physicians ought to be familiar with the link between erectile dysfunction and low free testosterone (FT) levels in diabetic patients.

The FT levels are particularly important, as hypogonadism had not been recognized as a complication of type 2 diabetes in the past. In a British study, at a hospital diabetes clinic involving over 3600 diabetics, 86 percent of non-insulin dependent diabetics were obese. Obesity is not only a strong risk factor for type 2 diabetes, but it also progresses in combination with low testosterone or hypogonadism. While SHBG, testosterone, DHT and estrogen levels increase in male type 1 diabetic patients, levels of FT are lower. During improvement of blood sugar control with insulin, levels of FT and its bioprecursors and metabolites rise.

Diabetes affects almost 21 million Americans and more than 15,000 of those individuals are residents of the Monterey Peninsula. Approximately five percent of persons ages 20 to 79 years have diabetes, according to data from the International Diabetes Federation. This includes 48 million Europeans and 43 million residents of the Western Pacific. Diabetes rates are highest in the United States and Europe . With population aging, as well as unhealthful diets, sedentary lifestyles, and/or associated obesity, the number of people with DM has increased from 30 million in 1985 to more than 150 million in 2000. The number is projected to escalate to nearly 333 million by the year 2025.

Nearly 70 percent of recently diagnosed diabetics say they were NOT aware of any symptoms, when their diabetes was detected. By simply measuring patient's waist size, we have a screening test for obesity, a common precursor of diabetes. From referenced studies it also appears that abdominal obesity is a more important predictor of diabetes than overall obesity. So where you carry your fat is most important. How can a man tell if his testosterone level is subnormal?

The hormone parameters, including FT and SHBG or sex hormone binding globulin, in addition to the form known as bioavailable T (BT), provide an overall picture of testosterone's action. Testosterone availability makes a significant difference in a diabetic's capacity to regulate their blood sugar. In men with well-controlled type 1 diabetes, lower free testosterone levels in the presence of higher SHBG levels, reflect a tendency to hypogonadism even if the TT are within the normal range.

In this deficiency state, the pituitary fails to recognize that a hormonal deficiency exists and does not respond with increased LH as is expected ( hypogonadotropic hypogonadism). It is interesting to note that in type 2 diabetics, SHBG tends to be lower than normal. One would assume then that free testosterone should be plentiful, since the binding hormone is lacking. But SHBG has been found to be more complex than simply an off-on switch for hormones. Low levels of T and SHBG play a major role in the development of insulin resistance. Over one third of type 2 diabetics develop hypogonadotropic hypogonadism. The good news is that although a testosterone deficiency is followed by insulin resistance, it can be corrected by testosterone replacement.

All diabetics benefit from some form of testosterone replacement. For this reason FT and SHBG are important hormones for glucose stabilization and should be measured in all diabetics. A Finnish study offers more evidence that obesity also influences the levels of the sex-steroid hormones in women, especially after menopause. Circulating IGF-I, androgens and SHBG, appear to be closely related to each other in post-menopausal women and men after age 55. It is interesting to note that the testosterone decline caused by normal aging in men and women, does not significantly affect other aspects of testosterone action, such as body composition and lipid metabolism. Then why does it seem to play such an important role in diabetes?

“Multiple interventional studies have shown that exogenous testosterone has a favorable impact on body mass, insulin secretion and sensitivity, lipid profile and blood pressure, which are the parameters most often disturbed in metabolic syndrome. Hypogonadism is likely a fundamental component of metabolic syndrome. Testosterone therapy may not only treat hypogonadism, but may also have tremendous potential to slow or halt the progression from metabolic syndrome to overt diabetes or cardiovascular disease via beneficial effects on insulin regulation, lipid profile and blood pressure. Furthermore, the use of testosterone to treat metabolic syndrome may also lead to the prevention of urological complications commonly associated with these chronic disease states, such as neurogenic bladder and erectile dysfunction.” (Metabolic Syndrome Called Into Question, Family Practice News, Sept. 2005).

Physicians should evaluate all men diagnosed with metabolic syndrome for hypogonadism. On the other hand, also consider the metabolic syndrome in all men diagnosed with hypogonadism as hypogonadotropic hypogonadism, occurs frequently in type 2 diabetes. Future research in the form of randomized clinical trials should focus on defining the function of testosterone in diabetes and the metabolic syndrome. Guay A, Influence of testosterone on the metabolic syndrome. But for now, we know enough to influence this epidemic that endangers the health of every American.

II. Low Testosterone Is Common In Diabetes

Low testosterone is associated with diabetes and hyptertension more often than we used to think.

About one third of men with type 2 diabetes who are obese and have poor controlled sugar have hypogonadism or low FT. A total of 58 percent of massively obese individuals with diabetes and a BMI of more than 40 had hypogonadism According to the authors, FT should be measured before designating any diabetic patient as hypogonadal. Using only a low T (<300 ng/dl) to define hypogonadism resulted in 36 percent false positives and 12 percent false negatives compared with low FT.

A single measurement of testosterone is not sufficient to diagnose hypogonadism,” according to Dr. Adrian Dobbs, a respected endocrinologist and andrologist at Johns Hopkins. For some men the optimal testosterone level is below average; for others it is above. The gray zones blend into normal ranges and nobody knows what levels is best for everyone. In medical school, doctors are taught the importance of treating hormone deficiencies as vigorously as any disease. That means a diagnosis must be made and the best therapy selected.

Silence creates a difficulty in diagnosis for both doctors and their patients. Most men don't know they are hormonally deficient until they get tested and the majority doesn't want to discuss it. Doctors depend on patients to tell them what is wrong yet they seldom ask about their sexual performance. Men are not alone in keeping their sexual problems secret. Most women are more candid with their hairdressers more than they are with their gynecologists. I find that women try to discuss sexual problems with other women but seldom with their husbands and rarely with a physician.

When a regular guy visits a doctor to be checked for ED or low T levels, he has to accept a decision based on a single sample of blood. This is grossly unfair to our patients. Viagra is often recommended as a temporary solution for men with erectile dysfunction as if restoring erectile function is a solution to the problem. ” Testosterone levels are influenced by conditions that are partly controlled or initiated by the hormone itself, but by circumstances beyond hormonal or individual control. Different kinds of behaviour are not only subject to influence by the environment, but androgens can also reinforce the particular kind of conduct and the behavioural impact can wield negative or positive feedback on testosterone secretion. Therefore, both generalisation and individualisation of study results will lead to doubtful conclusions and prejudices. Results of such studies must be viewed with caution, and over-simplification as well as over-interpretation should be avoided..”

What do you think happens when your hormone levels start to drop and your hormonal balance goes awry? What does that feel like? Mid-life crises affect over 40 million people in the US. In spite of what you may think, sexual dysfunction is not an automatic consequence of aging. A normal human being should be able to enjoy an active sex life over the entire span of his or her life. What stops it? Low testosterone is a factor more often than we used to think. Low testosterone leads to a bulging waist (a potbelly), plus a lack of motivation to get things done. Combine that with low energy and the absence of any sex drive and you have the makings of a disaster.

One of my patients, a 45-year-old carpenter from Iowa, considered dyeing his gray hair and wanted me to check his testosterone levels. His wife said he was just going through a mid-life crisis but he felt that it was more than that. He had lost his desire to lift weights and he needed to use Viagra in order to get a firm erection. When his personal physician refused to check his testosterone, he flew to California to see me and sure enough, his total testosterone was around 164 ng/dl.

One out of ten men over 40 years of age has hypogonadism, or below normal testosterone levels. Yet medical records show that it is rarely the diagnosis. The interpretation of testosterone levels is so complex that the condition is often overlooked and certainly not treated adequately. Plenty of men and women in their eighties have high normal testosterone—people who are still enjoying sex and looking 10 to 20 years younger than their contemporaries. Most people accept lack of motivation, a diminished enthusiasm for hobbies, business ventures or sexual pleasure and think they are just getting old and that there is nothing that can be done to correct the problem. They couldn't be more mistaken. Just because a doctor tells you that your testosterone levels are normal doesn't mean that you have to put up with undiagnosed hormone-induced sexual problems. A man can still maintain sexual function even though tests still show low levels of testosterone. Only when the circulating testosterone (FT) falls below 50 pg/ml will erections disappear. At that point hormone supplementation is no longer an option.

The drop in free testosterone usually occurs somewhere in mid-life or in the early fifties and can be explained by the general decline of certain hormones during the aging process. Circulating or free testosterone is the form of testosterone you need to remember, as this is the main indicator of sexual ability in both men and women. When a man has problems with sexual functioning, his wife is far more likely to bring concerns about sexual dysfunction to the doctor than he is. Since this is the role women are taking with their men, they should understand what their husband or partner is going through. This is a common story from men who visit me.

David, a rancher from Montana, hates discussing his sexual drive, but after encouragement from his wife decided to write to me. “My sexual drive seems normal,” he wrote, “not that I know what normal is. I don't have problems getting erect, maintaining and so forth. I wake up at least once a day with 'morning wood.' I never really paid that much attention to it because I probably only have sex once a week due to my wife's low desire. She suggested I write to you. I usually masturbate two to four times a week. I have felt a decline in sexual desire since my peak, but isn't that normal at age 46?” Again, it was his wife that encouraged him to communicate.

Dale masturbates more frequently than he has sex with his wife. He blames his wife's lack of sex drive for his declining sexual desire and accepts the idea that familiarity has resulted in boredom in the marriage. Imagine his surprise when he learned that his free testosterone was that of an 80-year-old man. No wonder he was feeling old! You might expect men past middle age to have some sexual problems but what about younger men?

Another patient who I saw with erectile dysfunction was an amateur bodybuilder complaining of unusual symptoms. He was not yet 40 when he began suffering from problems maintaining an erection. Fortunately in his case a simple test led to a correct diagnosis and testosterone replacement therapy. It's important to realize that not every patient with these symptoms suffers from low testosterone. But it is important for doctors to suspect that hormone deficiency may be the cause in patients with symptoms of hypogonadism before recommending any course of treatment.

Men with controlled type 1 diabetes treated with subcutaneous insulin have a lower free testosterone levels in the presence of similar total testosterone levels and higher SHBG levels. A low calorie diet in combination with metformin leads to reduced FT levels in obese nondiabetic men and to reduced TT levels in obese men with type 2 diabetes. Increased SHBG levels may account for the decrease in FT levels.

A lower level of testosterone, must be detected and treated early on to restore normal sexual function. The diagnosis of hypogonadism requires an early morning blood test to check the FT level before starting any hormone therapy in men under 40. For the most accurate results in younger men, samples should be collected between 6 to 10 a.m. and TT, FT and SHBG should be ordered for all men over the age of 40.

III. Low Testosterone: Symptoms and Complaints

Just as levels of testosterone vary greatly among both men and women, the symptoms vary even more.

Fatigue is a common symptom in many medical conditions. Yet it consistenly accompanies low levels of testosterone. Whereas some men might not be able to get an erection with completely normal T levels, others are still having sex with a strong drive at levels far below the normal range. For this reason I have found that the following symptoms are most consistent when further testing is required. Above normal levels of estradiol and low dihydrotestosterone seem to correlate more closely with the following complaints among my patients.

• Lowered sexual drive as compared to previous interest in sexual partners.
• Loss of early morning erections from previous levels.
• Erectile dysfunction including premature ejaculation with decreased firmness of erections.
• Central obesity with a potbelly or an increase of more than 2-inches in waist size,
• Affected mood and cognition, including loss of motivation, desire to exercise or interest in sports.
• Moodiness and anger outbursts with feelings of aggression when frustrated.
• Irritable male syndrome or grumpiness and total lack of interest in touching or kissing women.
• Fatigue that peaks in the afternoon and makes men feel like they could fall asleep easily.
• Loss of muscle tone and weakness manifest by joint aches and pains unrelated to level of activity.

Clinically known as hypogonadism, low T leads to a bulging waistline plus a lack of motivation to get things done. Combine that with low energy and the absence of a sex drive and you have the makings of a disaster. That disaster often manifests as a “couch potato” with irritable male syndrome. The signs of hypogonadism range from the obvious to the surprising, yet several patterns emerge in men who are suffering with this condition. These findings can be measured and documented in the patients medical record.

• Decreased bone density by dexa scan and loss in height of more than 1 inch.
• H igh blood pressure and heart enlargement with associated chest pain
• Increase in abdominal girth with 40” as maximum for men and waist size of in excess of 34 inches in women
• Low Free Testosterone, occasionally low total testosterone, and low normal bioavailable testosterone
• Loss of penile reflexes (cremasteric and bulbocavernosus) and decreased penis sensitivity
• Insulin resistance, high blood glucose and progression to diabetes
• Below normal HDL and sex hormone binding globulin

Contrary to what many men think, hypogonadism is not caused by a defect in their testicles. Instead, it is due to improper functioning of the pituitary gland (which controls production of testosterone) or in the hypothalamus (the region of the brain that controls the pituitary). Previous studies have linked erectile dysfunction and low testosterone levels in diabetic patients to lower levels of pituitary hormones. The small portion of unbound testosterone in the blood, known as FT or free testosterone, largely determines the amount of testosterone that is functional. The concentration of pituitary hormones in the blood directly correlates with free testosterone levels.

The diagnosis is confirmed when total testosterone (TT), currently considered the “gold standard” for the identification of testosterone deficiency, is below 300 ng/dl. These findings are particularly important, as hypogonadism has not previously been recognized as a complication of diabetes. The 30 percent incidence in the research paper referenced below was most certainly unexpected. The analysis, which involved over 3000 men with diabetes, researchers aimed to further investigate the testosterone-related concern in male diabetics. None of the subjects tested had been previously diagnosed with low testosterone levels, yet nearly one-third of the men analyzed had hypogonadism.

One of my patients, a 45-year-old lawyer from Kansas, wanted me to check his testosterone levels. His wife said he was just going through a mid-life crisis when he considered dyeing his gray hair, but he felt that it was more than that. He had lost his desire to lift weights and he needed to use Viagra in order to get a firm erection. When his private physician refused to check his testosterone, he flew to Monterey to see me and sure enough, his total testosterone was around 164 ng/dl. “What's the problem, Doc?” he asked me. “I don't use drugs, I eat healthy, I go to the gym, why is my testosterone so low?” This is what I told him.

One out of ten men over 40 years of age has hypogonadism, or testosterone levels which are below normal. One third of the men with type 2 diabetes have hypogonadism. Yet medical records show that this is rarely the diagnosis. The interpretation of testosterone levels is so complex that the condition is often overlooked and certainly not treated adequately. Plenty of men and women in their eighties can have high normal testosterone—for example, people who are still enjoying sex and looking 10 to 20 years younger than their contemporaries. Ufortunately, this is not the point most people reach. Aging is too often association with crippling deterioration and disease.

Even in mid-life many people complain of a lack of motivation that dampens their enthusiasm for hobbies, business ventures and sexual pleasure. Many men think they are just getting old and that there is nothing that can be done to correct the problem of losing their erections. They couldn't be more mistaken. Just because a doctor tells a patient that his testosterone levels aren't abnormal doesn't mean he should put up with hormone-induced sexual problems. A man can have good sexual function even though tests reveal low levels of testosterone. Only when the circulating testosterone falls below minimal levels will erections disappear. At that point hormone supplementation is no longer optional but rather becomes essential.

The drop in free testosterone usually occurs somewhere in mid-life or in the early fifties and can be explained by the general decline of certain hormones during the aging process and increases in weight. Circulating or free testosterone is the form of testosterone your doctor needs to check, as this is the main indicator of sexual potential in both sexes.

When a man has problems with sexual functioning, his wife is far more likely to bring concerns about sexual dysfunction to the doctor than he is. Since this is the role women are taking with their men, they usually suffer with whatever their husband or partner is going through. This is a common story from women who visit me. For this reason, I wrote “A Woman's Guide To Men's Health”.

IV. Endocrine Guidelines for Treating Low Testosterone

Further testing is indicated for patients with symptoms of low testosterone whose test results indicate normal levels.

Guidelines are just that. They do not always recommend the unique tests a doctor should perform when a man's testosterone is in the normal range but deficiency symptoms are present. Many doctors are unaware of these newer procedures and continue measuring total T instead of free T; telling their patients they are “normal” when they are suffering an obvious hormonal deficiency. Consequently, millions are not being properly diagnosed or treated. Currently it is estimated that over 13 million men suffer with hypogonadism but less than one million receive a prescription for testosterone replacement. “ Low total testosterone and SHBG levels independently predict development of the metabolic syndrome and diabetes in middle-aged men. Thus, hypoandrogenism (can be considered) an early marker for disturbances in insulin and glucose metabolism that may progress to the metabolic syndrome or frank diabetes and may contribute to their pathogenesis.”

Younger and younger patients with testosterone deficiency appear in my office every day, many of whom I refer to endocrinologists or urologists for consultation. These primary hormone specialists usually follow a course of action recommended by the American Academy of Clinical Endocrinologists (AACE) for the treatment of hypogonadism. While these guidelines give clear information about hormone replacement for any man suffering from testosterone deficiency, most family practice doctors do not follow them or even know that they exist.

In simple English the guidelines state that all men with symptoms of a testosterone deficiency should be “treated with hormone replacement therapy.” These guiding principles are written for any medical doctor but are usually adhered to only by endocrinologists treating hypogonadism. If you are having trouble finding an endocrinologist, you can find a list by state from the AACE. These are available at: http://www.aace.com/resources/memsearch.php . The first AACE standards for testosterone prescribing, published in 2003, can be found at: http://www.aace.com/pub/pdf/guidelines/hypogonadism.pdf .

The AACE androgen guidelines do not attempt to explain why we are seeing more cases of testosterone deficiency in the world's industrialized countries. They merely provide diagnostic, monitoring and treatment recommendations for men with hypogonadism. They have modified the diagnosis of hypogonadism several times as new research determines the different levels of testosterone associated with aging. Total testoterone levels below 300 ng/dl are considered an essential component of this condition. The 2006 testosterone prescribing guidelines , Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline are available for purchase online at : http://www.endo-society.org/quickcontent/clinicalpractice/clinical-guidelines/CG_Androgen.cfm . Table 1,2 and 3 plus their recommendations (in bold below) are from the new guidelines, reproduced with permission of the endo-society.

TABLE 1. Symptoms and signs suggestive of androgen deficiency in men

• Incomplete sexual development, eunuchoidism, aspermia
• Reduced sexual desire (libido) and activity
• Decreased spontaneous erections
• Breast discomfort, gynecomastia
• Loss of body (axillary and pubic) hair, reduced shaving
• Very small or shrinking testes (especially < 5 mL)
• Inability to father children, low or zero sperm counts
• Height loss, low-trauma fracture, low bone mineral density
• Reduced muscle bulk and strength
• Hot flushes, sweats

We recommend measurement of serum LH and FSH levels to distinguish between primary (testicular) and secondary (pituitaryhypothalamic) hypogonadism. We recommend testosterone therapy for symptomatic men with classical androgen deficiency syndromes aimed at inducing and maintaining secondary sex characteristics and at improving their sexual function, sense of well being, and bone mineral density .

TABLE 2. Conditions associated with alterations in SHBG concentrations

Conditions associated with decreased SHBG concentrations

• Moderate obesity*
• Nephrotic syndrome*
• Hypothyroidism
• Use of glucocorticoids, progestins, and androgenic steroids*

Conditions associated with increased SHBG concentrations

• Aging*
• Hepatic cirrhosis*
• Hyperthyroidism
• Use of anticonvulsants*
• Use of estrogens
• HIV infection

*Particularly common conditions associated with alterations in SHBG concentrations.

In men with secondary hypogonadism, we suggest further evaluation on an individualized basis to identify the etiology of hypothalamic and/or pituitary dysfunction. This evaluation may include measurements of serum prolactin and iron saturation, pituitary function testing,and magnetic resonance imaging (MRI) scanning. We suggest that when clinicians prescribe testosterone therapy, the therapeutic target should be to raise serum testosterone levels into a range that is mid-normal for healthy, young men.

Nevertheless, unless a man has symptoms compatable with the condition, treatment is not recommended for older men. Obviously certain patients with low testosterone, especially if affected by wasting or catabolic diseases such as cancer and HIV or sexual dysfunction unresponsive to erection enhancers, could probably benefit from testosterone administration. With adequate replacement the beneficial effects on men's nutritional status, insulin sensitivity, sexual drive and ultimately their business motivation, are beyond belief. Additional testing is indicated for patients with symptoms of low testosterone whose test results indicate apparently normal or low normal levels. These patients should be retested to determine free testosterone, pituitary hormones and sex hormone-binding globulin levels. However hormone supplementation in hypogonadal older men cannot be expected to influence nutritional status and body composition to the same extent that it does other well known targets of testosterone action, such as sexual activity and muscular strength. All men notice a huge improvement in quality of life when they have adequate testosterone levels.

TABLE 3. Conditions in which there is a high prevalence of low testosterone levels and in which we suggest measurement of serum testosterone

Levels (author's comments in brackets)

• Sellar mass, radiation to the sellar region, or other diseases of the sellar region (in the area of the pituitary)
• Treatment with medications that affect testosterone production or metabolism, such as glucocorticoids, ketoconazole, and opioids (or narcotics)
• HIV-associated weight loss (AIDS wasting syndrome or AWS)
• End-stage renal disease and maintenance hemodialysis (kidney failure and dialysis)
• Moderate to severe chronic obstructive lung disease (also called emphysema)
• Infertility
• Osteoporosis or low trauma fracture, especially in a young man

• Type 2 diabetes mellitus

A high prevalence of low testosterone levels has been reported in men with several chronic disorders. This list is not exhaustive. Most surveys of men with chronic illness included relatively small, convenience samples. The information about the benefits and risks of testosterone therapy in these conditions is either limited or not available.

Unfortunately, low testosterone is only one of many undiagnosed conditions that both men and women face. Generally women have problems with obesity more often than men. Women suffer with depression more often than testosterone deficiency. Both low testosterone and low SHBG levels have been linked to diabetes. But that doesn't make any of these health risks less important. Women also respond positively to testosterone supplementation. Many physicians do not realize that women with sexual dysfunction after menopause may be testosterone deficient. It was not until April of 2005, that testosterone guidelines, which change with age and menopause, were determined for women by Susan Davis in Australia. However, there is a cautionary note here, in that women who use both estrogen and testosterone seem to have an increased risk of invasive breast cancer.

Testosterone supplementation is critical for some men, particularly diabetics and obese men. Their T levels are low and they are prone to multiple conditions related to their excess weight. Delivery systems for testosterone are safe and uncomplicated. A new scrotal TRT system using Testocreme® is extremely effective in raising testosterone numbers into the normal range and is available by prescription. Although it is proving very useful, the use of testosterone in treating diabetes and obesity is not considered standard of care at this point in time. In the meantime, diet seems to be the most common therapy for weight loss and diabetes management.

V. References

Ferrucci L, et al. LOW TESTOSTERONE LEVELS AND THE RISK OF ANEMIA IN OLDER MEN AND WOMEN. Arch Intern Med. 2006;166:1380-1388. Clinical Research Branch, Longitudinal Studies Section, National Institute on Aging, Baltimore, MD 21225, USA.

Anemia is a frequent feature of male hypogonadism and anti-androgenic treatment. We hypothesized that the presence of low testosterone levels in older persons is a risk factor for anemia.

Testosterone and hemoglobin levels were measured in a representative sample of 905 persons 65 years or older without cancer, renal insufficiency, or anti-androgenic treatments. Hemoglobin levels were reassessed after 3 years. …Among nonanemic participants and independent of confounders, men and women with low vs normal total and bioavailable testosterone levels had a significantly higher risk of developing anemia at 3-year follow-up. Conclusion Older men and women with low testosterone levels have a higher risk of anemia.

Vermeulen A , Kaufman JM , Giagulli VA . Influence of some biological indexes on sex hormone-binding globulin and androgen levels in aging or obese males. J Clin Endocrinol Metab. 1996 May;81(5):1821-6. BMI increased with age, but although BMI was negatively correlated with T, FT, and SHBG, respectively, the age-dependent decrease in T levels persisted after correction for BMI. Data not corrected for BMI may, nevertheless, overestimate the age-associated decrease in T levels. The albumin concentration decreased with age, and if FT is the feedback regulator of plasma T levels, albumin concentration might be a codeterminant (although, evidently, less important than SHBG) of T levels and contribute to the age-associated decrease in T levels. In any case, albumin concentration is a codeterminant of DHEAS concentration. T, DHEA, and DHEAS levels were significantly correlated, but this correlation disappeared after controlling for age; hence, there is no evidence for an adrenal-gonadal interaction in men. In obese men, T, FT, and SHBG levels were significantly lower than those in the nonobese men and inversely correlated with BMI; DHEAS levels were slightly lower than those in the nonobese controls, but no significant correlation between DHEA or DHEAS, and insulin levels was observed.

Tibblin G , Adlerberth A , Lindstedt G , Bjorntorp P . The pituitary-gonadal axis and health in elderly men: a study of men born in 1913. Diabetes. 1996 Nov;45(11):1605-9. It was concluded that low testosterone and SHBG concentrations in elderly men are associated with established risk factors for diabetes and in established diabetes. Moreover, low testosterone levels independently predict the risk of developing diabetes. In different degrees of expression, the diabetic state predicts strongly (and gradually mortality from) myocardial infarction and stroke. It has been suggested that a relative hypogonadism might be a primary event, because other studies have shown that testosterone deficiency is followed by insulin resistance, which is ameliorated by testosterone substitution. The data suggest that the relative hypogonadism involved might be of both central and peripheral origin.

Kaufman JM , Vermeulen A . The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev. 2005 Oct;26(6):833-76. Epub 2005 May 18. jean.kaufman@ugent.be

Aging in men is accompanied by a progressive, but individually variable decline of serum testosterone production, more than 20% of healthy men over 60 yr of age presenting with serum levels below the range for young men. Albeit the clinical picture of aging in men is reminiscent of that of hypogonadism in young men and decreased testosterone production appears to play a role in part of these clinical changes in at least some elderly men, the clinical relevancy of the age-related decline in sex steroid levels in men has not been unequivocally established. In fact, minimal androgen requirements for elderly men remain poorly defined and are likely to vary between individuals. Consequently, borderline androgen deficiency cannot be reliably diagnosed in the elderly, and strict differentiation between "substitutive" and "pharmacological" androgen administration is not possible. To date, only a few hundred elderly men have received androgen therapy in the setting of a randomized, controlled study, and many of these men were not androgen deficient. Most consistent effects of treatment have been on body composition, but to date there is no evidence-based documentation of clinical benefits of androgen administration to elderly men with normal or moderately low serum testosterone in terms of diminished morbidity or of improved survival or quality of life. Until the long-term risk-benefit ratio for androgen administration to elderly is established in adequately powered trials of longer duration, androgen administration to elderly men should be reserved for the minority of elderly men who have both clear clinical symptoms of hypogonadism and frankly low serum testosterone levels.

Dhindsa S , Prabhakar S , Sethi M , Bandyopadhyay A , Chaudhuri A , Dandona P . Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. . J Clin Endocrinol Metab. 2004 Nov;89(11):5462-8.

Daousi C, et al. Prevalence of obesity in type 2 diabetes in secondary care: association with cardiovascular risk factors. Postgrad Med J. 2006 Apr;82(966):280-4. Obesity is the rule among patients attending this hospital diabetes clinic, with 86% of those with type 2 diabetes overweight or obese. Obesity is associated with significantly worse cardiovascular risk factors in this patient group, suggesting that more active interventions to control weight gain would be appropriate.

Christensen L , et al. Elevated levels of sex hormones and sex hormone binding globulin in male patients with insulin dependent diabetes mellitus. Effect of improved blood glucose regulation. Dan Med Bull. 1997 Nov;44(5):547-50.

International Diabetes Federation. Diabetes prevalence. Available at http://www.idf.org/home/index.cfm?node=264. Accessed January 28, 2005.

Wang Y , Rimm EB , Stampfer MJ , Willett WC , Hu FB . Comparison of abdominal adiposity and overall obesity in predicting risk of type 2 diabetes among men. Am J Clin Nutr. 2005 Mar;81(3):555-63. youfwang@uic.edu Adult men with fairly controlled type 1 diabetes without complications who are treated with subcutaneous insulin have a tendency to hypogonadism, as reflected by lower free testosterone levels in the presence of similar total testosterone levels and higher SHBG levels.

Stellato RK , Feldman HA , Hamdy O , Horton ES , McKinlay JB . Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care. 2000 Apr;23(4):490-4.

Dhindsa S , et al . Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. . J Clin Endocrinol Metab. 2004 Nov;89(11):5462-8.

Type 2 diabetes is associated with lower total testosterone (T) levels in cross-sectional studies. However, it is not known whether the defect is primary or secondary. We investigated the prevalence of hypogonadism in type 2 diabetes by measuring serum total T, free T (FT), SHBG, LH, FSH, and prolactin (PRL) in 103 type 2 diabetes patients. FT was measured by equilibrium dialysis. FT was also calculated by using T and SHBG (cFT). Hypogonadism was defined as low FT or cFT. The mean age was 54.7 +/- 1.1 yr, mean body mass index (BMI) was 33.4 +/- 0.8 kg/m(2), and mean HbA1c was 8.4 +/- 0.2%. The mean T was 12.19 +/- 0.50 nmol/liter SHBG was 27.89 +/- 1.65 nmol/liter, and FT was 0.250 +/- 0.014 nmol/liter. Thirty-three percent of patients were hypogonadal. LH and FSH levels were significantly lower in the hypogonadal group compared with patients with normal FT levels for LH and 4.25 +/- 0.45 vs. 5.53 +/- 0.40 mIU/ml for FSH; P < 0.05). There was a significant inverse correlation of BMI with FT (r = -0.382; P < 0.01) and T. SHBG correlated inversely with BMI (r = -0.267; P < 0.05) but positively with age and T. FT correlated strongly with cFT but not with SHBG. LH levels correlated positively with FT. We conclude that hypogonadotropic hypogonadism occurs commonly in type 2 diabetes.

Dhindsa S, et al. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab 2004; 89: 5462-5468.

M Zitzmann and E Nieschlag. Testosterone levels in healthy men and the relation to behavioural and physical characteristics: facts and constructs. European Journal of Endocrinology, Vol 144, Issue 3, 183-197

This review summarises the correlations between testosterone levels and male physical appearance and behaviour. Methodological shortcomings concerning the measurement of testosterone could limit the value of these findings. In addition, testosterone measured in body fluids represents only one step in the cascade of action from production to biological effect, and could therefore provide only a limited view of the complexity of physiological events. Testosterone levels are influenced by conditions that are partly controlled or initiated by the hormone itself, but also by circumstances beyond hormonal or individual control. Different kinds of behaviour are not only subject to influence by environment, but also androgens can reinforce the particular kind of conduct and the behavioural impact can wield negative or positive feedback on testosterone secretion. Therefore, both generalisation and individualisation of study results will lead to doubtful conclusions and prejudices. Results of such studies must be viewed with caution, and over-simplification as well as over-interpretation should be avoided.

van Dam EW , et al. Steroids in adult men with type 1 diabetes: a tendency to hypogonadism. Diabetes Care. 2003 Jun;26(6):1812-8.   ew.vandam@vumc.nl . To compare steroids and their associations in men with type 1 diabetes and healthy control subjects. We studied 52 adult men with type 1 diabetes without microvascular complications, compared with 53 control subjects matched for age and BMI. Steroids and their binding globulins were assessed in a single venous blood sample and a 24-h urine sample. RESULTS: In adult men with type 1 diabetes, total testosterone did not differ from healthy control subjects, but sex hormone-binding globulin (SHBG) (42 [14-83] vs. 26 [9-117] nmol/l, P < 0.001), cortisol-binding globulin (CBG; 0.87 +/- 0.17 vs. 0.73 +/- 0.10 nmol/l, P < 0.001), and cortisol levels (0.46 +/- 0.16 vs. 0.39 +/- 0.14 nmol/l, P < 0.01) were higher. The free testosterone index was lower (60 [17-139] vs. 82 [24-200], P < 0.001), and the calculated free testosterone was slightly lower (497 [115] vs. 542 [130], P < 0.064), but the pituitary-gonadal axis was not obviously affected in type 1 diabetes. The calculated free serum cortisol was not different, and 24-h urinary free cortisol excretion was lower in type 1 diabetes (121 [42-365] vs. 161 [55-284] nmol/24 h, P < 0.009). Testosterone was mainly associated with SHBG. Estimated portal insulin was a contributor to SHBG in control subjects but not in type 1 diabetes. Cortisol was associated with CBG. HbA(1c) contributed to CBG in men with diabetes but not in control subjects, whereas estimated portal insulin did not contribute. CONCLUSIONS: Adult men with fairly controlled type 1 diabetes without complications who are treated with subcutaneous insulin have a tendency to hypogonadism, as reflected by lower free testosterone levels in the presence of similar total testosterone levels and higher SHBG levels.

Ozata M, et al. The effects of metformin and diet on plasma testosterone and leptin levels in obese men. Obes Res. 2001 Nov;9(11):662-7. mozata@obs.gata.edu.tr . The aim of this study was to investigate the effects of combined hypocaloric diet and metformin on circulating testosterone and leptin levels in obese men with or without type 2 diabetes.Twenty obese men with type 2 diabetes (mean body mass index [BMI]: 35.5 +/- 1.1 kg/m(2)) and 20 nondiabetic obese men were enrolled in the study. We measured serum follicle-stimulating hormone, luteinizing hormone (LH), total testosterone (TT), free testosterone (FT), sex-hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), and plasma leptin levels before and 3 months after metformin treatment. Both groups were placed on a hypocaloric diet and 850 mg of metformin taken orally twice daily for 3 months. Metformin and hypocaloric diets led to decreases in BMI and waist and hip circumferences in both groups. A significant decrease in TT levels in the diabetic group and FT levels in the control group was found, whereas follicle-stimulating hormone, LH, and DHEAS levels were not changed significantly. A significant increase in SHBG levels was observed in the control group but not in the patient group. Leptin levels also decreased after treatment in both groups. Decreased testosterone levels were not correlated to changes in waist and hip circumference, waist-to-hip ratio, BMI, and levels of fasting blood glucose, leptin, SHBG, or DHEAS in the diabetic group. However, a decrease in FT was correlated to changes in the levels of SHBG (r = -0.71, p = 0.001) and LH (r = 0.80, p = 0.001) but not to other parameters. DISCUSSION: We conclude that metformin treatment combined with a hypocaloric diet leads to reduced FT levels in obese nondiabetic men and to reduced TT levels in obese men with type 2 diabetes. Increased SHBG levels may account for the decrease in FT levels in the former group.

van Dam Ew, et al. Steroids in adult men with type 1 diabetes: a tendency to hypogonadism. Diabetes Care. 2003 Jun;26(6):1812-8. To compare steroids and their associations in men with type 1 diabetes and healthy control subjects. RESEARCH DESIGN AND METHODS: We studied 52 adult men with type 1 diabetes without microvascular complications, compared with 53 control subjects matched for age and BMI. Steroids and their binding globulins were assessed in a single venous blood sample and a 24-h urine sample. RESULTS: In adult men with type 1 diabetes, total testosterone did not differ from healthy control subjects, but sex hormone-binding globulin (SHBG) (42 [14-83] vs. 26 [9-117] nmol/l, P < 0.001), cortisol-binding globulin (CBG; 0.87 +/- 0.17 vs. 0.73 +/- 0.10 nmol/l, P < 0.001), and cortisol levels (0.46 +/- 0.16 vs. 0.39 +/- 0.14 nmol/l, P < 0.01) were higher. The free testosterone index was lower (60 [17-139] vs. 82 [24-200], P < 0.001), and the calculated free testosterone was slightly lower (497 [115] vs. 542 [130], P < 0.064), but the pituitary-gonadal axis was not obviously affected in type 1 diabetes. The calculated free serum cortisol was not different, and 24-h urinary free cortisol excretion was lower in type 1 diabetes (121 [42-365] vs. 161 [55-284] nmol/24 h, P < 0.009). Testosterone was mainly associated with SHBG. Estimated portal insulin was a contributor to SHBG in control subjects but not in type 1 diabetes. Cortisol was associated with CBG. HbA(1c) contributed to CBG in men with diabetes but not in control subjects, whereas estimated portal insulin did not contribute. CONCLUSIONS: Adult men with fairly controlled type 1 diabetes without complications who are treated with subcutaneous insulin have a tendency to hypogonadism, as reflected by lower free testosterone levels in the presence of similar total testosterone levels and higher SHBG levels.

Kryger AH. A Woman's Guide To Men's Health, RDR Books 2006. http://www.sexloveandhormones.com

Laaksonen DE , et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care. 2004 May;27(5):1036-41. In men, hypoandrogenism is associated with features of the metabolic syndrome, but the role of sex hormones in the pathogenesis of the metabolic syndrome and diabetes is not well understood. We assessed the association of low levels of testosterone and sex hormone-binding globulin (SHBG) with the development of the metabolic syndrome and diabetes in men. RESEARCH DESIGN AND Concentrations of SHBG and total and calculated free testosterone and factors related to insulin resistance were determined at baseline in 702 middle-aged Finnish men participating in a population-based cohort study. These men had neither diabetes nor the metabolic syndrome. After 11 years of follow-up, 147 men had developed the metabolic syndrome (National Cholesterol Education Program criteria) and 57 men diabetes. Men with total testosterone, calculated free testosterone, and SHBG levels in the lower fourth had a severalfold increased risk of developing the metabolic syndrome and diabetes after adjustment for age. Adjustment for potential confounders such as cardiovascular disease, smoking, alcohol intake, and socioeconomic status did not alter the associations. Factors related to insulin resistance attenuated the associations, but they remained significant, except for free testosterone. Low total testosterone and SHBG levels independently predict development of the metabolic syndrome and diabetes in middle-aged men. Thus, hypoandrogenism is an early marker for disturbances in insulin and glucose metabolism that may progress to the metabolic syndrome or frank diabetes and may contribute to their pathogenesis.

Laaksonen DE , et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care. 2004 May;27(5):1036-41.

In men, hypoandrogenism is associated with features of the metabolic syndrome, but the role of sex hormones in the pathogenesis of the metabolic syndrome and diabetes is not well understood. We assessed the association of low levels of testosterone and sex hormone-binding globulin (SHBG) with the development of the metabolic syndrome and diabetes in men. Concentrations of SHBG and total and calculated free testosterone and factors related to insulin resistance were determined at baseline in 702 middle-aged Finnish men participating in a population-based cohort study. These men had neither diabetes nor the metabolic syndrome. After 11 years of follow-up, 147 men had developed the metabolic syndrome (National Cholesterol Education Program criteria) and 57 men diabetes. Men with total testosterone, calculated free testosterone, and SHBG levels in the lower fourth had a severalfold increased risk of developing the metabolic syndrome and after adjustment for age. Adjustment for potential confounders such as cardiovascular disease, smoking, alcohol intake, and socioeconomic status did not alter the associations. Factors related to insulin resistance attenuated the associations, but they remained significant, except for free testosterone. CONCLUSIONS: Low total testosterone and SHBG levels independently predict development of the metabolic syndrome and diabetes in middle-aged men. Thus, hypoandrogenism is an early marker for disturbances in insulin and glucose metabolism that may progress to the metabolic syndrome or frank diabetes and may contribute to their pathogenesis.

Davison SL , Bell R , Donath S , Montalto JG , Davis SR . Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab. 2005 Jul;90(7):3847-53. Epub 2005 Apr 12. This cross-sectional study of 1423 randomly recruited community based women aged 18 to 75 years, explores the effects of age, natural and surgical menopause on androgen levels in healthy women. “We report that serum androgen levels decline steeply in the early reproductive years; do not vary as a consequence of actual menopause and that the postmenopausal ovary appears to be an ongoing site of testosterone production.” (quote from Dr. Susan Davis).

Tamimi RM, et al. COMBINED ESTROGEN AND TESTOSTERONE USE AND RISK OF BREAST CANCER IN POSTMENOPAUSAL WOMEN. Arch Intern Med. 2006;166:1483-1489.

Background The role of androgens in breast cancer etiology has been unclear. Epidemiologic studies suggest that endogenous testosterone levels are positively associated with breast cancer risk in postmenopausal women. Given the increasing trend in the use of hormone therapies containing androgens, we evaluated the relation between the use of estrogen and testosterone therapies and breast cancer.

Methods We conducted a prospective cohort study in the Nurses' Health Study from 1978 to 2002 to assess the risk of breast cancer associated with different types of postmenopausal hormone (PMH) formulations containing testosterone. During 24 years of follow-up (1 359 323 person-years), 4610 incident cases of invasive breast cancer were identified among postmenopausal women. Information on menopausal status, PMH use, and breast cancer diagnosis was updated every 2 years through questionnaires. Results Among women with a natural menopause, the risk of breast cancer was nearly 2.5-fold greater among current users of estrogen plus testosterone therapies (multivariate relative risk, 2.48; 95% confidence interval, 1.53-4.04) than among never users of PMHs. This analysis showed that risk of breast cancer associated with current use of estrogen and testosterone therapy was significantly greater compared with estrogen-only therapy (P for heterogeneity, .007) and marginally greater than estrogen and progesterone therapy (P for heterogeneity, .11). Women receiving PMHs with testosterone had a 17.2% (95% confidence interval, 6.7%-28.7%) increased risk of breast cancer per year of use. Conclusion Consistent with the elevation in risk for endogenous testosterone levels, women using estrogen and testosterone therapies have a significantly increased risk of invasive breast cancer.