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Review |
From the Center for Sexual Function/Endocrinology, Lahey Clinic, Peabody, Massachusetts, and Harvard Medical School, Boston, Massachusetts.
| Correspondence to: Dr André Guay, Lahey Clinic Northshore, One Essex Center Dr, Peabody, MA 01960 (e-mail: andre.t.guay{at}lahey.org). |
| Received for publication June 13, 2008; accepted for publication August 29, 2008. |
The metabolic syndrome (MS) is comprised of various medical conditions that
confer increased risk of diabetes and cardiovascular disease. The
pathophysiologic components of MS include glucose abnormality, obesity or
increased waist circumference, increased blood pressure, and hyperlipidemia.
There is an increased risk of hypogonadism in men with MS and its individual
components, including insulin resistance, considered by some to be at the core
of MS. Hypogonadism may even predict MS. These factors are interwoven and
impact overall health, including sexual dysfunction. One interesting and
important question is whether treating hypogonadism with testosterone
replacement will ameliorate the pathological components of MS.
Key words: Low testosterone, insulin resistance, cardiovascular risk, obesity
MS takes on more meaning because it is widespread, and more common than once thought. In North America, the prevalence of MS has been estimated to be about 25% in Caucasians and 30% in Hispanics (Meigs et al, 2003). The prevalence increases with age, and the prevalence in women closely mirrors that in men (Ford et al, 2002). This has been related, in part, to the worldwide epidemic of obesity, of which a number of components, if not all, are related to MS, either directly or indirectly (Cameron et al, 2004).
An early definition was made by the World Health Organization, but the most commonly used definition in North America is that of the National Cholesterol Education Program (NCEP) (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 2001), although the definition by the International Diabetes Federation (IDF) is gaining popularity (Balkau and Charles, 1999). The debate among the proponents and detractors of each definition is beyond the scope of this review, and is still ongoing, but the concept of MS by whatever definition is related to cardiovascular risk and is favored by a majority of investigators.
The risk factors of MS are concerned with abnormal glucose metabolism, insulin resistance, increased waist circumference and abdominal fat, increased blood pressure, and abnormalities of triglyceride and high-density lipoprotein (HDL) cholesterol metabolism. Table 1 compares the NCEP Adult Treatment Panel III (ATP III) with the IDF criteria; the former defines 3 of 5 criteria as consistent with MS, whereas the IDF insists on increased waist circumference plus 2 of the other 4 criteria as their definition.
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Hypogonadism and MS
The definition of hypogonadism is at best arbitrary and imprecise. There
are many opinions, such as, should we use total testosterone (T) or free T,
and which type of assay should we use in these categories? There are many
techniques for each type, which vary considerably between themselves and
between the laboratories that perform them. To elucidate all of the variations
would be impossible and beyond the scope of a brief review. We have the
solace, in many studies, that levels are compared in a case-controlled fashion
so that significant differences between groups can be appreciated. In the
United States, the standard definition of hypogonadism by the Food and Drug
Administration and the Endocrine Society is a total T value <300 ng/dL
(<10.4 nmol/L). Although less than ideal, this is the commonly used
definition in the literature.
Recently, the close association between hypogonadism and MS has received more attention. This is because the prevalence of hypogonadism has been shown to be higher than previously thought, both in epidemiological studies (Morley et al, 1997; Araujo et al, 2004) and in a survey of clinical practice (Mulligan et al, 2006). The epidemiological studies show a prevalence of hypogonadism of 10%–12% (Morley et al, 1997; Araujo et al, 2004), which has been found to be only slightly lower, at 6%, when men with symptomatic androgen deficiency are counted (Araujo et al, 2007). Data from physicians' clinical practices, however, show a higher prevalence of hypogonadism, in the range of 36%–39% (Mulligan et al, 2006; Guay and Seftel, unpublished data). This is because of the association of high prevalence of hypogonadism with chronic illnesses. Clearly, prior estimates of hypogonadism were underestimated.
Although age, geography, ethnicity, and lifestyle issues like obesity are related to MS, hypogonadism also has been shown to have a strong relationship with MS. Kupelian et al (2006) showed that low total T and low sex hormone–binding globulin (SHBG) levels were risk factors for MS, even when they restricted the association to men who were asymptomatic from their androgen deficiency. They confirmed a previous study by Muller et al (2005) showing a high prevalence of low endogenous sex hormones with MS. Blouin et al (2005) showed that men with fewer than 3 components of MS had higher T levels, and that men with 3 or more components of MS had lower levels of T. This is in keeping with the findings of Kaplan et al (2006), who found a definite inverse relationship between the number of components of MS and total T levels, even in nondiabetic men. These findings suggest that the more medical problems a man has, and thus the more stress on his body, the lower his T will be. Stress of acute illness does lower T, and 1 study did look at this relationship. Woolf et al (1985) studied men with head trauma and found that there was an inverse relationship between the level of noradrenaline and the level of T, showing that, at least in acute medical stress, the more adrenalin, the more the hypothalamic-pituitary suppression. Longitudinal studies, from the Massachusetts Male Aging Study (Kupelian et al, 2006) and from the Baltimore Longitudinal Aging Study (Rodriguez et al, 2007), have confirmed that the prevalence of MS increases with aging and that it is related to hypogonadism. The relationship of hypogonadism to MS remains even when using different definitions of MS, and when following patients prospectively for over 10 years (Laaksonen et al, 2005).
T Levels, Hypogonadism, and Components of MS
The components of MS, and correlates of these components, have been related
to sex hormone levels and hypogonadism. Abnormal glucose metabolism, often
with insulin resistance and glucose intolerance and resultant diabetes, is a
key component of MS. In a meta-analysis, Ding et al
(2006) found approximately 20
studies that showed a high prevalence of hypogonadism in diabetic men. The
relationship was so strong in 4 of these studies that it was stated that low T
levels predicted future diabetes.
Increased weight and obesity is a core element of MS. Visceral obesity is especially strongly related to MS and insulin resistance, and has been negatively associated with T levels (Seidell et al, 1990). Common thinking in the past indicated that obesity increased cardiac risk by aggravating other cardiac risks, such as hypertension and hyperlipidemia, but Rogers et al (2007) showed, in a meta-analysis of more than 300,000 persons, that obesity was an independent risk factor for MS. In a clinical study (Mulligan et al, 2006), and in a long-term longitudinal study (Travison et al, 2007), obesity has also been shown to be negatively related to T levels.
Central or abdominal obesity, as measured by waist circumference, is a classical feature of MS, and is the central feature of the IDF definition of MS. It has independently been associated with reduced T levels (Pasquali et al, 1991; Osuna et al, 2006). Svartberg et al (2004) not only found this association in a large number of community-dwelling men, but also found that increasing waist circumference predicted low T levels (Svartberg et al, 2003). It has been suggested that waist circumference is better at predicting T levels than is body mass index (BMI) (Svartberg et al, 2004). However, the inverse relationship of BMI with low T levels is very significant (Pasquali et al, 1991; Laaksonen et al, 2003). The mechanisms by which T production is decreased as BMI increases are not fully understood, but several facts are known that might be pertinent. Obesity is associated with decreased SHBG production, which increases total T but decreases free T; this would seem contradictory, but other factors are at play. Obesity is associated with increased inflammatory cytokine production, as well as increased aromatization of T to estradiol in peripheral fat tissue. Both of these factors then decrease the pituitary production of gonadotropins, which, in turn, decrease testicular production of T (Laaksonen et al, 2003; Kalyani and Dobs, 2007). It has also been hypothesized that elevated leptin levels in obese individuals interfere with luteinizing hormone/human chorionic gonadotropin stimulation of androgen production, thereby decreasing androgen levels (Isidori et al, 1999). Insulin resistance is an integral part of MS, because it has a high prevalence in obesity and type 2 diabetes. A definite inverse relationship has been found between T and insulin resistance, and persists whether total, free, or bioavailable T measurements are used (Tsai et al, 2004).
Hypertension has also been associated with hypogonadism, as well as long being known to have an affiliation with cardiovascular risk. Mulligan et al (2006) have shown that more men with hypertension have low T levels than have normal T levels. The incidence of hypogonadism was found to be 30.8% in men with erectile dysfunction (Guay and Seftel, unpublished data), whereas the prevalence of hypertension in men with erectile dysfunction was found to be 44.0%, similar to that seen in primary care practices. Svartberg et al (2004) also found that individuals presenting with hypertension will have lower total T values than those who do not have hypertension, independent of age. Smith et al (2006) showed that androgen deprivation in men with prostate cancer could also induce hypertension and arterial stiffness, even after only several months.
Lipid abnormalities are also part of MS, in the form of elevated triglycerides and decreased HDL cholesterol. Dobs et al (2001) found that in hypogonadal men, before therapy, the BMI had strong negative correlations with both HDL cholesterol and T concentrations, whereas T had slight and nearly significant correlation with HDL concentrations. T suppression in men with prostate cancer resulted in elevated total and low-density lipoprotein cholesterol levels over baseline values after only 3 months of therapy (Dockery et al, 2003); these same authors also showed an increase in insulin resistance with T depletion. Smith et al (2006) showed abnormalities in both cholesterol and triglycerides after both short- and long-term androgen deprivation therapy. Similar abnormalities in cholesterol and triglyceride metabolism have been demonstrated in diabetic men undergoing androgen deprivation as T levels declined (Haider et al, 2007).
Hypogonadism, MS, and Sexual Dysfunction
MS and erectile dysfunction are related, because the same risk factors are
seen in both conditions (Walczak et al,
2002; Traish et al,
2009a). Thompson et al
(2007) studied over 9000 men
for over 5 years and found that the hazard ratio of men with new erectile
dysfunction for cardiovascular events was 1.45. Corona et al
(2006) consecutively evaluated
over 800 men seen for sexual dysfunction, and found MS in 29.4%; further,
96.5% of the men with MS had erectile dysfunction. Using strict criteria for
hypogonadism, a total T <8 nmol/L (<230 ng/dL), the incidence of
hypogonadism in the men with MS was 11.9%, vs 3.8% in the rest of the sample.
Low T in men with MS was also related to other sexual symptoms, such as
hypoactive sexual desire and decreased frequency of sexual intercourse, and
was also related to depressive symptoms, although it was not certain whether
these were primary or reactive to the sexual issues. The authors also showed
an inverse relationship between total T levels and the number of MS
components; low T levels were strongly related to fasting glucose levels and
to elevated waist circumference measurements. Of interest also was the inverse
relationship between penile blood flow and erectile function, which also is
significantly related to the number of MS components. As opposed to T and MS
components, the strongest factors relating to penile blood flow were elevated
blood pressure and elevated fasting blood glucose. The relationship of
erectile physiology to MS and hypogonadism is not surprising, because a recent
review of the literature proved that T is related to many facets of erectile
physiology and penile blood flow mechanics
(Traish and Guay, 2006).
Esposito et al (2004) have shown that the prevalence of ED among men with MS increases with the number of MS components. With increasing components, the prevalence increases from 20% to 35%. Heidler et al (2007) have further shown that MS is an independent risk factor for erectile dysfunction. Bansal et al (2005) reviewed 154 men with organic erectile dysfunction, and found that 43% had MS by the NCEP ATP III criteria, vs 24% in a similar population of Caucasian men. Of further interest, 79.2% of the men had insulin resistance, vs 25% in the general population. Insulin resistance is thought to be at the core of MS, and 90.9% of the men with MS in this population had insulin resistance. A further analysis showed that the more severe the erectile dysfunction, the higher the incidence of MS and of insulin resistance (Table 2). Guay and Jacobson (2007) made a further analysis of this population in which they examined the relationship between hypogonadism and insulin resistance. In men with hypogonadism, 92.3% had insulin resistance, and in the men without hypogonadism, 25.2% had insulin resistance. This highlights the strong relationship between low T and insulin resistance. Clearly, erectile dysfunction represents a warning signal regarding the presence of MS and insulin resistance, all being clear risk factors for cardiovascular disease, and reinforcing the relationship shown in the Figure.
|
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In a recent study by Zhody et al
(2007), the relationship
between erectile dysfunction, androgen deficiency, and MS was solidified by
another means: the measurement of BMI. With increasing BMI, the incidence of
erectile dysfunction and hypogonadism increased in a strong positive
correlation. Using the corpus duplex ultrasound, the authors found that if BMI
was <25, approximately 23.1% of the men had vasculogenic erectile
dysfunction, as compared to 59.3% of the men whose BMI was 
25. It follows
that if circulation is decreased, then oxygen saturation to the penis would be
decreased. Padmanahbhan and McCullough
(2007) found that men with
erectile dysfunction had lower penile corporeal oxygen saturation than did men
without erectile dysfunction. Recently, a good review of the literature found
a strong link between male infertility and MS, with good discussions of the
contributions of the various components of MS
(Kasturi et al, 2008).
Could Treatment of Hypogonadism Help to Correct Components of MS?
It is well known that T therapy in men with androgen deficiency improves
energy, body composition, and a number of other abnormalities. It is
intriguing to speculate that correcting the hypogonadism associated with
insulin resistance and MS might correct some or all its components. The data
available in this area is preliminary but promising. Pitteloud et al
(2005a,b)
showed that acutely lowering human Leydig cell production of T rapidly caused
insulin resistance (Pitteloud et al,
2005a), and later showed that T replacement rapidly increased
insulin sensitivity within a few days, eliminating implicating changes in BMI
or fat mass (Pitteloud et al,
2005b). This also highlights the possible bidirectionality of low
T with medical conditions. Here we have a very close and rapid relationship
between low T and insulin resistance, with very rapid reversal, suggesting
bidirectionality of cause and effect. There is much more to be studied
here.
In another clinical situation, Kapoor et al (2007) studied men with type 2 diabetes. The authors found that a significant percentage of the men had symptomatic low T levels and that the T levels were negatively correlated with BMI and waist circumference. The authors treated hypogonadism in these diabetic men and found that there was improvement in a number of metabolic parameters related to MS, including fasting glucose, fasting insulin, HbA1C, and weight (Kapoor et al, 2006). Muller et al (2005) actually found that for every standard deviation that T is raised in aging men (approximately 152 ng/dL per SD) the risk of MS is reduced by 57%.
Saad et al (2008) compared the results of T treatment in elderly men with late onset hypogonadism with either a T gel or a long-acting injection. Both treatment parameters aided sexual symptoms and also improved waist circumference and several lipid parameters, with a trend toward lowering blood pressure. Allen et al (2008) showed that T replacement therapy for a year selectively lessened visceral fat accumulation, the fraction that best correlates with cardiovascular risk. Heufelder et al (unpublished) showed that lifestyle modifications, when used with T supplementations in hypogonadal men with type 2 diabetes, may have a synergistic effect on waist circumference.
Although these studies are promising, the numbers of patients studied are small, and the treatment courses are short term. Larger, prospective studies are needed in hypogonadal men with MS, which will determine whether T therapy indeed correct multiple components of MS and decrease the risk of cardiovascular disease.
Footnotes
This paper is based on a presentation at a Special Symposium on April 12, 2008, "Therapeutic Strategies for Male Sexual and Hormonal Health," associated with the American Society of Andrology Annual Meeting, for which the presenting author received an honorarium.
Dr Guay has consulting and/or financial relationships with Indevus Pharmaceuticals Inc; Auxilium Pharmaceuticals, Inc; Solvay Pharmaceuticals; Pfizer; Eli Lilly and Co; Bayer AG; GlaxoSmithKline; and Schering-Plough.
References
Allen CA, Strauss BJG, Burger HG, Forbes EA, McLachlan RI.
Testosterone therapy prevents visceral adipose tissue and loss of skeletal
muscle in non-obese aging men. J Clin Endocrinol
Metab. 2008;93: 139
–146.
Araujo AB, O'Donnell AB, Brambilla DJ, Simpson WB, Longcope C,
Matsumoto AM, McKinlay JB. Prevalence and incidence of androgen deficiency in
middle-aged and older men: estimates from the Massachusetts Male Aging Study.
J Clin Endocrinol Metab. 2004; 89: 5920
–5926.
Araujo AB, Gretchen R, Esche MS, Kupelian V, O'Donnell AB, Travison
TG, Williams RE, Clark RV, McKinlay JB. Prevalence of symptomatic androgen
deficiency in men. J Clin Endocrinol Metab. 2007; 92: 4241
–4247.
Balkau B, Charles MA. Comment on the provisional report from the WHO consultation: European Group for the Study of Insulin Resistance (EGIR). Diabetes Med. 1999; 16: 442 –443.[CrossRef][Medline]
Bansal TC, Guay AT, Jacobson J, Woods BO, Nesto RW. Incidence of metabolic syndrome and insulin resistance in a population with organic erectile dysfunction. J Sex Med. 2005; 2: 96 –103.[Medline]
Blouin K, Despres JP, Couillard C, Tremblay A, Prud'homme D, Bouchard C, Tchernof A. Contribution of age and declining androgen levels to features of the metabolic syndrome in men. Metabolism. 2005; 54: 1034 –1040.[CrossRef][Medline]
Cameron AJ, Shaw JE, Zimmet PZ. The metabolic syndrome: prevalence in worldwide populations. Endocrinol Metab Clin N Am. 2004; 33: 351 –355.[CrossRef][Medline]
Corona G, Mannucci E, Schulman C, Petrone L, Mansani R, Cilotti A, Balercia G, Chiarini V, Forti G, Maggi M. Psychobiologic correlates of the metabolic syndrome and associated sexual dysfunction. Eur Urol. 2006;50: 595 –604.[CrossRef][Medline]
Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex
hormones and risk of type 2 diabetes: a systematic review and meta-analysis.
JAMA. 2006;295: 1288
–1299.
Dobs AS, Bachorik PS, Arver S, Meikle AW, Sanders SW, Caramelli KE,
Mazer NA. Interrelationships among lipoprotein levels, sex hormones,
anthropometric parameters, and age in hypogonadal men treated for 1 year with
a permeation-enhanced testosterone transdermal system. J Clin
Endocrinol Metab. 2001;86: 1026
–1033.
Dockery F, Bulpitt CJ, Agarwal S, Donaldson M, Rajkumar C. Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinemia. Clin Sci. 2003; 104: 195 –201.[CrossRef][Medline]
Esposito K, Giugliano F, Martedi E, Feola G, Marfella R, D'Armiento M, Giugliano D. High proportions of erectile dysfunction in men with metabolic syndrome. Diabetes Care. 2004; 28: 1201 –1203.[CrossRef]
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. Executive summary of the third report of the National
Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation,
and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
JAMA. 2001;285: 2486
–97.
Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome
among US adults: findings from the Third National Health and Nutritional
Examination Survey. JAMA. 2002; 287: 356
–359.
Guay AT, Jacobson J. The relationship between testosterone levels, the metabolic syndrome (by two criteria) and insulin resistance in a population of men with organic erectile dysfunction. J Sex Med. 2007;4: 1046 –1055.[CrossRef][Medline]
Haider A, Yassin A, Saad F, Shabsigh R. Effects of androgen deprivation on glycemic control and on cardiovascular biochemical risk factors in men with advanced prostate cancer with diabetes. Aging Male. 2007;10: 189 –196.[CrossRef][Medline]
Heidler S, Temml C, Broessner C, Mock K, Rauchenwald M, Madersbacher S, Ponholzer A. Is the metabolic syndrome an independent risk factor for erectile dysfunction? J Urol. 2007; 177: 651 –654.[CrossRef][Medline]
Isidori AM, Caprio M, Strollo F, Moretti C, Frajese G, Isidori A,
Fabbri A. Leptin and androgens in male obesity: evidence for leptin
contribution to reduced androgen levels. J Clin Endocrinol
Metab. 1999;84: 3673
–3680.
Kalyani RR, Dobs AS. Androgen deficiency, diabetes, and the metabolic syndrome in men. Curr Opin Endocrinol Diabetes Obesity. 2007;14: 226 –234.
Kaplan SA, Meehan AG, Shah A. The age related decrease in testosterone is significantly exacerbated in obese men with the metabolic syndrome. What are the implications for the relatively high incidence of erectile dysfunction observed in these men? J Urol. 2006; 176: 1524 –1528.[CrossRef][Medline]
Kapoor D, Aldred H, Clark S, Channer KS, Jones TH. Clinical and
biochemical assessment of the hypogonadism in men with type 2 diabetes.
Correlations with bioavailable and visceral adiposity. Diabetes
Care. 2007;30: 911
–917.
Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement
therapy improves insulin resistance, glycaemic control, visceral adiposity and
hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur
J Endocrinol. 2006;154: 899
–906.
Kasturi SS, Tannir J, Brannigan RE. The metabolic syndrome and male
infertility. J Androl. 2008; 29: 251
–259.
Kupelian V, Page ST, Araujo AB, Travison TG, Bremner WJ, McKinlay
JB. Low sex hormone-binding globulin, total testosterone, and symptomatic
androgen deficiency are associated with development of the metabolic syndrome
in nonobese men. J Clin Endocrinol Metab. 2006; 91: 843
–850.
Laaksonen DE, Niskanen L, Punnonen K, Nyyssonen K, Tuomainen TP, Salonen R, Rauramaa R, Salonen JT. Sex hormones, inflammation and the metabolic syndrome: a population-based study. Eur J Endocrinol. 2003;149: 601 –608.[Abstract]
Laaksonen DE, Niskanen L, Punnonen K, Nyyssonen K, Tuomainen TP,
Valkonen VP, Salonen JT. The metabolic syndrome and smoking in relation to
hypogonadism in middle-aged men: a prospective cohort study. J Clin
Endocrinol Metab. 2005;90: 712
–719.
Meigs JB, Wilson PWF, Nathan DM, D'Agostino RB, Williams K, Haffner
SM. Prevalence and characteristics of the metabolic syndrome in the San
Antonio Heart and Framingham Offspring Studies.
Diabetes. 2003;52: 2160
–7.
Morley JE, Kaiser FE, Perry 3rd HM, Patrick P, Morley PMK, Stauber PM, Vellas B, Baumgartner RN, Garry PJ. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism. 1997; 46: 410 –413.[CrossRef][Medline]
Muller M, Grobbee DE, den Tonkelaar I, Lamberts SW, van der Schouw
YT. Endogenous sex hormones and metabolic syndrome in aging men. J
Clin Endocrinol Metab. 2005; 90: 2618
–2623.
Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006; 60: 762 –769.[CrossRef][Medline]
Osuna JA, Gomez-Perez R, Arata-Bellabarba G, Villaroel V. Relationship between BMI, total testosterone, sex hormone-binding globulin, leptin, insulin and insulin resistance in obese men. Arch Androl. 2006;52: 355 –361.[CrossRef][Medline]
Padmanahbhan P, McCullough AR. Penile oxygen saturation in the
flaccid and erect penis in men with and without erectile dysfunction.
J Androl. 2007;28: 223
–228.
Pasquali R, Casimirri F, Cantobelli S, Melchionda N, Morselli Labata AM, Fabbri R, Capelli M, Bortoluzzi L. Effect of obesity and body fat distribution on sex hormones and insulin in men. Metabolism. 1991; 40: 101 –104.[CrossRef][Medline]
Pitteloud N, Hardin M, Dwyer AA, Valassi E, Yialamis M, Elahi D,
Hayes FJ. Increasing insulin resistance is associated with a decrease in
Leydig cell testosterone secretion in men. J Clin Endocrinol
Metab. 2005a;90: 2636
–2641.
Pitteloud N, Mootha VK, Dwyer AA, Hardin M, Lee H, Eriksson KF,
Tripathy D, Yialamas M, Groop L, Elahi D, Hayes FJ. Relationship between
testosterone levels, insulin sensitivity, and mitochondrial function in men.
Diabetes Care. 2005b; 28: 1636
–1642.
Rodriguez A, Muller DC, Metter EJ, Maggio M, Harman SM, Blackman
MR, Andres R. Aging, androgens, and the metabolic syndrome in a longitudinal
study of aging. J Clin Endocrinol Metab. 2007; 92: 3568
–3572.
Rogers RP, Bemelmans WJ, Hoogenveen RT, Boshuizen HC, Woodward M,
Knekt P, van Dam RM, Hu FB. BMI-CHD Collaboration Investigators. Association
of overweight with increased risk of coronary heart disease partly independent
of blood pressure and cholesterol levels: a meta-analysis of 21 cohort studies
including more than 300,000 persons. Arch Intern Med. 2007; 167: 1720
–1728.
Saad F, Gooren LJ, Haider A, Yassin A. A dose-response study of
testosterone on sexual dysfunction and features of the metabolic syndrome
using testosterone gel and parenteral testosterone undecanoate. J
Androl. 2008;29: 102
–105.
Seidell JC, Bjomtorp P, Sjostrom L, Kvist H, Sannerstedet R. Visceral fat accumulation in men is positively associated with insulin, glucose and C-peptide levels, but negatively with testosterone levels. Metabolism. 1990; 39: 897 –901.[CrossRef][Medline]
Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined
androgen blockade for prostate cancer. J Clin Endocrinol
Metab. 2006;91: 1305
–1308.
Svartberg J, Jorde R, Sundsfjord J, Bonaa KH, Barrett-Connor E. Seasonal variation of testosterone and waist to hip ratio in men: the Tromso study. J Clin Endocrinol Metab. 2003; 83: 3099 –3104.
Svartberg J, von Muhlen D, Sundsfjord J, Jorde R. Waist circumference and testosterone levels in community dwelling men. The Tromso Study. Eur J Epidemiol. 2004; 19: 657 –663.[CrossRef][Medline]
Thompson IM, Tangen CM, Goodman PJ, Probstfield JL, Moinpour CM, Coltman CA. Erectile dysfunction and subsequent cardiovascular disease. JAMA. 2007;294: 2996 –3002.[CrossRef]
Traish AM, Guay AT. Are androgens critical for penile erections in humans? Examining the clinical and preclinical evidence. J Sex Med. 2006;3: 382 –407.[Medline]
Traish AM, Guay A, Feeley R, Saad F. The dark side of testosterone
deficiency: I. Metabolic syndrome and erectile dysfunction. J
Androl. 2009a; 30(1): 10
–22,.
Traish AM, Saad F, Guay A. The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance. J Androl. 2009b;302: 23 –32.
Travison TG, Araujo AB, Kupelian V, O'Donnell AB, McKinlay JB. The
relative contribution of aging, health, and lifestyle factors to serum
testosterone decline in men. J Clin Endocrinol Metab. 2007; 92: 549
–555.
Tsai EC, Matsumoto AM, Fujimoto WY, Boyho E. Association of
bioavailable, free, and total testosterone with insulin resistance: influence
of sex hormone-binding globulin and body fat. Diabetes
Care. 2004;27: 861
–868.
Walczak MK, Lokhandwala N, Hodge MB, Guay AT. Prevalence of cardiovascular risk factors in erectile dysfunction. J Gender-Specific Med. 2002;5: 19 –24.
Woolf PD, Hamill RW, McDonald JV, Lee LA, Kelly M. Transient
hypogonadotropic hypogonadism caused by critical illness. J Clin
Endocrinol Metab. 1985;60: 444
–450.
Zhody W, Kamal EE, Ibrahim Y. Androgen deficiency and hormonal duplex parameters in obese men with erectile dysfunction. J Sex Med.2007;4: 797 –808.[CrossRef][Medline]
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