Outline

• Introduction
• Testosterone and the Metabolic Syndrome
• Hypogonadism and Its Effects
• Symptoms of Hypogonadism
• Guidelines for Treating Low Testosterone
• References

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I. Introduction

Testosterone is not only a sexual hormone. It also affects body composition, lipid metabolism and insulin sensitivity. Testosterone levels decline about 100 ng/dl each decade. The androgen decline caused by normal aging does not significantly affect glucose or insulin metabolism, but it does play a central role in diabetes and obesity.

About 98 percent of the testosterone in the body is bound to sex hormone binding globulin or SHBG and albumin. It is the small portion of unbound testosterone in the blood (about 2 percent of the total T), known as free testosterone, (FT) which largely determines the amount actually available to the tissues. This level, as determined by equilibrium dialysis, is now considered the “gold standard” for the diagnosis of testosterone deficiency. (RIA is used for T analysis by most labs).

The 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. Circulating or free testosterone is the main indicator of sexual drive for both men and women and is affected by their weight.

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 and lower total and free testosterone (T, FT) and SHBG. These three hormones were predictors for developing diabetes and subsequently MI and stroke. Testosterone deficiency was followed by insulin resistance and then corrected by testosterone replacement. (1)

Both men and women experience a drop in testosterone after menopause and the male equivalent, andropause. 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. (2) We know that BMI increases with age but the age dependent decrease in T levels persisted despite correction for BMI.

In 2005, Vermulen published another 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.” (3)

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 adequate and sensitive testing when it is not clear whether a T deficiency exists. We ought to be familiar with the link between erectile dysfunction and low free testosterone (FT) levels in diabetic patients.

These FT levels are particularly important, as hypogonadism has not previously been recognized as a complication of type 2 diabetes. In the British study at a hospital diabetes clinic involving over 3600 diabetics, 86 percent of non-insulin dependent diabetics were obese. (4) Obesity is a strong risk factor for type 2 diabetes.

Diabetes affects almost 21 million Americans and more than 15,000 of those individuals are residents of the Monterey Peninsula. 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. (5)

The hormone parameters, including FT and SHBG in addition to the form known as bioavailable T (BT), provide an overall picture of testosterone activity. These make a significant difference in a diabetic’s ability to regulate their blood glucose. In men with well-controlled type 1 diabetes, lower free testosterone levels in the presence of higher SHBG levels reflect a tendency to hypogonadism. It is interesting to note that in type 2 diabetes, SHBG tend to be lower than normal. (6)

All diabetics benefit from some form of testosterone replacement. Low levels of T and SHBG play a significant role in the development of insulin resistance and over one third of type 2 diabetics develop hypogonadotropic hypogonadism. (7) In this condition the pituitary fails to recognize that a hormonal deficiency exists and does not respond with increased LH. It becomes clear that FT and SHBG are important hormones in glucose regulation and should be measured in all diabetics.

II. Testosterone and the Metabolic Syndrome

Metabolic syndrome, characterized by central obesity, insulin resistance, dyslipidemia and hypertension, is highly prevalent in the United States. When left untreated, it significantlyincreases the risk of diabetes mellitus and cardiovascular disease. It has been suggested that hypogonadism may be an additional component of metabolic syndrome. This has potential implications for the treatment of metabolic syndrome with testosterone. Hypoandrogenism is not only an early marker for disturbances in insulin and glucose metabolism that may progress to the metabolic syndrome or even frank diabetes but it may actually contribute to their pathogenesis. (8)

“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, ICD9 code 277.7, Family Practice News, Sept. 2005).

III. Hypogonadism and Its Effects

Contrary to what many think, hypogonadism is not generally caused by a defect in the testes except in HIV. Instead, it is due to improper functioning of the pituitary gland (LH which controls the production of testosterone) or an imbalance in the hypothalamic regulation by gonadotropin releasing hormone, GnRH.

Low testosterone is also associated with diabetes more often than we once thought. Low testosterone, known clinically as hypogonadism, leads to a lot more than a bulging waistline or a lack of motivation to get things done. Combine low energy with the absence of a sex drive and sexual dysfunction and you have the makings of a relationship disaster.

One out of ten men over 40 years of age has 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. It is not inevitable as plenty of men and women in their seventies can have normal testosterone—for example, people who are still enjoying sex and looking 10 to 20 years younger than their contemporaries. Unfortunately, this is not the peak most people reach. Aging is too often association with crippling deterioration and impotence.

Even in mid-life certain people complain of a lack of motivation that dampens their enthusiasm for hobbies, business ventures and sexual pleasure. Countless 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 possible hormone-induced sexual problems.

A man can have totally normal sexual function even though his tests reveal low levels of testosterone. Only when the circulating or free testosterone falls below the minimum will erections disappear. At that point there is not enough free T to convert to dihydrotestosterone or DHT, which regulates libido in both sexes.

“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.” When a man visits a doctor to be checked for low T levels, he usually has to accept a decision based on a single sample of blood and often FT is not even measured. This is grossly unfair to your patients and inaccurate.

IV. Symptoms of Hypogonadism

When a man has problems with sexual functioning, his wife is far more likely to bring concerns about sexual dysfunction to the doctor. Since health monitor is the role women play with their men, they typically suffer with whatever condition their partner has.

Silence regarding sexual concerns creates a difficulty in diagnosis for both doctors and their patients. Doctors depend on patients to tell them what is wrong yet they seldom ask about their sexual performance. Less than 12 percent of men with premature ejaculation are asked about their problem when they visit their physician, yet this condition occurs in almost one third of our male patients.

Men are not alone in keeping their sexual problems secret. Most women are more candid with their hairdressers than their gynecologists. I find that women try to discuss sexual problems with other women but seldom with their husbands and rarely with a physician.

• Lowered sexual drive as compared to previous level of interest in sexual partners.
• Erectile dysfunction including premature ejaculation and decreased firmness of erections.
• Loss of muscle tone manifest by joint aches and pains unrelated to level of activity.
• Increase in abdominal fat or more than a 2-inch-increase in waist size with 40” as maximum for men.
• Loss of bone density by dexa scans and a decrease in height of more than 1 inch.
• Affected mood and cognition including loss of motivation, desire to exercise or interest in sports.

V. Guidelines for Treating Low Testosterone

Hypogonadism jeopardizes not only sexual and reproductive health of our patients, but also threatens their cardiovascular system, memory and their emotional well-being. More than one-third of diabetics have hypogonadism. (9) What can we do to improve this situation, and how can we help those who have been diagnosed get better?

Younger and younger patients with testosterone deficiency appear in my office every day, some of whom I refer to endocrinologists or urologists for consultation to confirm the diagnosis. Endocrinologists 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. But it’s not only men who are affected.

Problems of testosterone measurement are further complicated by the fact that the available assays were designed for men, in whom normal testosterone levels range from 350 to 1100 ng/dl, whereas a range of 3 to 115 ng/dl is normal for women. This is a non-specific range and new age-specific levels have been determined for both men and women. (10, 11)

Guidelines recommend the various 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 new procedures and continue measuring only 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. It is estimated that over 13 million men suffer with hypogonadism and less than one million receive a prescription for testosterone replacement.

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 often only adhered to by endocrinologists treating hypogonadism. If you are having trouble finding an endocrinologist for referral, you can find a list by state from the AACE. Available at: http://www.aace.com/memsearch.php. The complete AACE standards for testosterone prescribing, published in 2003, can be found at: www.aace.com/clin/guidelines/sexdysguid.pdf.

Further testing is indicated for patients with symptoms of low testosterone whose test results indicate normal levels. These patients should be retested for free testosterone, pituitary hormones and SHBG. Any laboratory can perform these tests, but endocrine specialty labs such as ARUP in Utah and Nichols and Esoterix Labs in California, specialize in these tests and are better able to provide consistent, accurate and reproducible results.

The AACE guidelines do not attempt to explain why we are seeing more cases of testosterone deficiency in the world’s industrialized countries. Though numerous environmental factors have been discussed in my book, Listen To Your Hormones, more research is needed in order to understand how these factors give rise to such widespread testosterone deficiency in our population.

As physicians, we must be alert to evaluate hypogonadism in all men diagnosed with metabolic syndrome as well as metabolic syndrome in all men diagnosed with hypogonadism. Future research in the form of randomized clinical trials should focus on further defining the role of testosterone for metabolic syndrome.

We cannot rule out the observation that a selected subsets of patients with low androgens, especially those affected by catabolic diseases, diabetes and sexual dysfunction, benefit from the effects of testosterone administration on their physical status, insulin sensitivity, sexual drive and ultimately their motivation to get the most out of life.

VI. References:

1. 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.

The results of recent studies suggest that a relative hypogonadism in men is associated with several established risk factors for prevalent diseases. Therefore, we determined total and free testosterone, luteinizing hormone (LH), and sex-hormone binding globulin (SHBG) in a cohort of randomly selected men (n = 659) at 67 years of age. These data were analyzed cross-sectionally in relation to blood glucose and serum insulin, which were measured while fasting and after an oral glucose tolerance test, in addition to plasma lipids and blood pressure. The data were also analyzed in relation to impaired glucose tolerance (IGT) and diabetes, which were discovered at examination or earlier diagnosis. Risk factors for the development of diabetes up to 80 years of age were analyzed with univariate and multivariate statistics. Total and free testosterone and SHBG concentrations correlated negatively with glucose and insulin values; total testosterone and SHBG, with triglycerides; and SHBG, with blood pressure (from P < 0.05 to P < 0.01). Men with IGT or newly diagnosed diabetes had higher BMI values (26.2 +/- 0.31 and 27.0 +/- 0.59 [mean +/- SE], respectively) and waist circumference (99.0 +/- 1.03 and 100.5 +/- 1.57) than nondiabetic men (BMI, 25.1 +/- 0.14; waist circumference, 95.4 +/- 0.47; P < 0.05), indicating abdominal obesity. Such men and men with previously diagnosed diabetes had, in general, lower total and free testosterone and SHBG levels, while those for LH were not different. In multivariate analyses that included BMI, waist-to-hip ratio, total and free testosterone, and SHBG, the remaining independent predictors for the development of diabetes were low total testosterone (P = 0.015) and, on the borderline, low SHBG (P = 0.053). In relation to nondiabetic men, the risk ratio for mortality, myocardial infarction, and stroke increased gradually and significantly from 1.18 to 1.68, from 1.51 to 1.78, and from 1.72 to 2.46 in men with IGT, newly diagnosed diabetes, and previously known diabetes, respectively. 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.

2. 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.

Several aspects of the regulation of androgen secretion and plasma levels in males remain controversial. Among these, we cite the problem of whether the age-related decrease in testosterone (T) levels is an intrinsic aging phenomenon or is a sequel of previous illness, the mechanisms underlying the increase in sex hormone-binding globulin (SHBG)-binding capacity in aging men and the supranormal capacity observed immediately after a weight-reducing diet, and the role of insulin in the age-associated decrease in dehydroepiandrosterone (sulfate) [DHEA (DHEAS)] levels. To gain further insight into these issues, we investigated the influence of age, smoking, body mass index (BMI), serum albumin, insulin, GH, and insulin-like growth factor I (IGF-I) levels, respectively, on androgen levels and SHBG-binding capacity in a nonobese healthy population (n = 250) as well as in an obese population (n = 50) before and after weight loss. The influence of GH supplementation on SHBG, DHEAS, DHEA, and insulin levels was studied in a small group of men (n = 8) with isolated GH deficiency. In nonobese healthy men, age was inversely correlated with serum levels of all androgens studied (although total T levels stayed relatively stable until age 55 yr) as well as with albumin, GH, and IGF-I levels and positively correlated with BMI, insulin levels, and SHBG-binding capacity. Nevertheless, SHBG levels were significantly negatively correlated with insulin levels (P < 0.001) as well as with mean 24-h GH and IGF-I levels. Among possible confounding factors affecting (free) T [(FT)] levels in healthy men, smoking appeared to be accompanied by higher (F)T levels than those in nonsmokers. 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. After a weight-reducing, protein-rich diet, resulting in a mean weight loss of +/- 15 kg, SHBG-binding capacity increased to normal values notwithstanding the fact that the subjects were still obese and that the insulin levels remained higher than those in the nonobese controls. Considering that after weight loss, GH and IGF-I levels remained lower than those in the nonobese controls, that adult men with isolated GH deficiency presented with higher SHBG levels than normal controls, which decreased to normal levels during GH substitution, and that elderly men have elevated SHBG levels notwithstanding high insulin levels, we suggest that the low GH and/or IGF-I levels might play a role in the elevated SHBG levels observed in both elderly males and obese men after a weight-reducing diet. As weight loss did not influence DHEAS levels notwithstanding an important decrease in insulin levels, our data do not support a role of insulin in the regulation of plasma DHEAS levels.

3. 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.

4. 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.

AIMS: To determine the prevalence of overweight and obesity among patients with type 1 and type 2 diabetes mellitus attending a secondary care diabetes clinic in the United Kingdom, and to assess the impact of overweight and obesity on glycaemic control and cardiovascular risk factors in patients with type 2 diabetes. METHODS: 3637 patients with diabetes were identified from the hospital electronic diabetes register, 916 with type 1 diabetes (mean (SD) age 40.4 (15.1) years, 496 male) and 2721 with type 2 diabetes (mean (SD) age 62.5 (11.8) years, 1436 male). Data on body mass index (BMI), glycaemic control, lipid profiles, and blood pressure were extracted. RESULTS: Of patients with type 1 diabetes, 55.3% were overweight (BMI >or=25 kg/m(2)), 16.6% were obese (BMI >or=30 kg/m(2)), and 0.4% had morbid obesity (BMI >or=40 kg/m(2)). In contrast, 86% of patients with type 2 diabetes were overweight or obese, 52% were obese, and 8.1% had morbid obesity. Obese patients with type 2 diabetes were younger, had poorer glycaemic control, higher blood pressures, worse lipid profiles, and were more likely to be receiving antihypertensive and lipid lowering drugs compared with patients with BMI <30 kg/m(2). CONCLUSIONS: 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.

5. 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

BACKGROUND: Obesity is a strong risk factor for type 2 diabetes. However, few studies have compared the predictive power of overall obesity with that of central obesity. The cutoffs for waist circumference (WC) and waist-to-hip ratio (WHR) as measures of abdominal adiposity remain controversial. OBJECTIVE: The objective was to compare body mass index (BMI), WC, and WHR in predicting type 2 diabetes. DESIGN: A prospective cohort study (Health Professionals Follow-Up Study) of 27 270 men was conducted. WC, WHR, and BMI were assessed at baseline. Covariates and potential confounders were assessed repeatedly during the follow-up. RESULTS: During 13 y of follow-up, we documented 884 incident type 2 diabetes cases. Age-adjusted relative risks (RRs) across quintiles of WC were 1.0, 2.0, 2.7, 5.0, and 12.0; those of WHR were 1.0, 2.1, 2.7, 3.6, and 6.9; and those of BMI were 1.0, 1.1, 1.8, 2.9, and 7.9 (P for trend < 0.0001 for all). Multivariate adjustment for diabetes risk factors only slightly attenuated these RRs. Adjustment for BMI substantially attenuated RRs for both WC and WHR. The receiver operator characteristic curve analysis indicated that WC and BMI were similar and were better than WHR in predicting type 2 diabetes. The cumulative proportions of type 2 diabetes cases identified according to medians of BMI (>/=24.8), WC (>/=94 cm), and WHR (>/=0.94) were 82.5%, 83.6%, and 74.1%, respectively. The corresponding proportions were 78.9%, 50.5%, and 65.7% according to the recommended cutoffs. CONCLUSIONS: Both overall and abdominal adiposity strongly and independently predict risk of type 2 diabetes. WC is a better predictor than is WHR. The currently recommended cutoff for WC of 102 cm for men may need to be reevaluated; a lower cutoff may be more appropriate.

6. 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.

OBJECTIVE: 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.

7. 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.

OBJECTIVE: The objective was to examine prospectively the association between low testosterone and sex hormone-binding globulin (SHBG) levels and the subsequent development of type 2 diabetes in men. RESEARCH DESIGN AND METHODS: Analyses were conducted on the cohort of the Massachusetts Male Aging Study, a population-based random sample of men aged 40-70. Of the 1,709 men enrolled in 1987-1989 (T1), 1,156 were followed up 7-10 years later (T2). Testosterone and SHBG levels at T1 were used to predict new cases of diabetes between T1 and T2. RESULTS: After controlling for potential confounders, diabetes at follow-up was predicted jointly and independently by lower baseline levels of free testosterone and SHBG. The odds ratio for future diabetes was 1.58 for a decrease of 1SD in free testosterone (4 ng/dl) and 1.89 for a 1SD decrease in SHBG (16 nmol/l), both significant at P < 0.02. CONCLUSIONS: Our prospective findings are consistent with previous, mainly cross-sectional reports, suggesting that low levels of testosterone and SHBG play some role in the development of insulin resistance and subsequent type 2 diabetes.

8. 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.

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 (351.7 +/- 14.4 ng/dl), 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 (3.15 +/- 0.26 vs. 3.91 +/- 0.24 mIU/ml 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 (r = -0.327; P < 0.01). SHBG correlated inversely with BMI (r = -0.267; P < 0.05) but positively with age (r = 0.538; P < 0.001) and T (r = 0.574; P < 0.001). FT correlated strongly with cFT (r = 0.919; P < 0.001) but not with SHBG. LH levels correlated positively with FT (r = 0.287; P < 0.05). We conclude that hypogonadotropic hypogonadism occurs commonly in type 2 diabetes.

10. 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.

OBJECTIVE: 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 METHODS: 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. RESULTS: 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 (odds ratio [OR] 2.3, 95% CI 1.5-3.4; 1.7, 1.2-2.5; and 2.8, 1.9-4.1, respectively) and diabetes (2.3, 1.3-4.1; 1.7, 0.9-3.0; and 4.3, 2.4-7.7, respectively) 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.

11. 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).

12. Mohr B, Guay AT, O'Donnell AB, McKinley JB, Morley JE, et al. Normal, bound and nonbound testosterone levels in normally ageing men: results from the Massachusetts Male Ageing Study. Clinical Endocrinology (2005) 62, 64-73. Updated testosterone ranges for men and women are found in my new book, A Woman’s Guide To Men’s Health. (RDR Books, July 2006).

Reference Labs for Testing Hormones

Esoterix, Inc. (Now with Lab Corp) ARUP Labs Nichols Labs (Now Quest)
4301 Lost Hills Road 500 Chipeta Way 1311 Calle Batido
Calabasas Hills, CA 91301 Salt Lake City, Utah 84108 San Clemente, CA 92673
www.esoterix.com www.arup.com www.nicholsdiag.com
800-444-9111 415-957-9445 (SF) 949-940-7200

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© 2007 A. H. Kryger, MD, DMD Monterey Preventive Medical Clinic 1084 Cass Street

Email: DrK@WellnessMD.com www.WellnessMD.com