Low Testosterone

Posted on Aug 17, 2010 in Expired CME | 2 comments

Testosterone Deficiency and Men’s Health: A Cruicial Connection

 

 

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CME Information

Learning Objectives

After participating in this educational activity, clinicians should be better able to
1. Identify symptoms of male hypogonadism
2. Identify comorbid conditions associated with low levels of testosterone

Introduction

Testosterone levels in men are known to decrease with age; the prevalence of symptomatic testosterone deficiency (TD) increases with age and comorbidities.[1] In recent years, however, epidemiologic evidence has been accumulating to suggest that serum free testosterone and total testosterone levels decrease as men age, even in the absence of advanced illness.[1-3] Total testosterone levels fall at a rate of about 0.4% per year, while free testosterone decreases about 1.2% per year with a corresponding increase in sex hormone binding globulin (SHBG). Increases in SHBG cause the higher rate of decrease for free and bioavailable testosterone.[3]

Not surprisingly, a phenomenon such as decreased testosterone levels does not exist in isolation but interacts with multiple physiologic systems—with widespread ramifications. Recently, links between low testosterone level and osteoporosis, frailty, obesity, metabolic syndrome, and diabetes have come to light in clinical and epidemiologic studies.[1,4,5] A possible mechanism by which some of these factors are linked is shown in the accompanying illustration.

This article reviews the recent literature about these findings, explores a case study, and discusses contemporary treatment and management options.

Case Presentation

Phil, whom we will revisit throughout this article, is a 63-year-old white male who received a diagnosis of type 2 diabetes mellitus 10 months ago, at which time he had a body mass index (BMI) of 40.3 kg/m2 (height 5’ 8”, weight 265 lb). He consulted with a dietician, was placed on a reduced-calorie diet, and began walking for 15 minutes a day. He currently weighs 250 lb (BMI, 38 kg/m2), and his waist circumference is 40 inches. He is currently taking metformin, 1000 mg BID. Recent determinations of his fasting blood sugar level have ranged from 144 to 178 mg/dL. Postprandial glucose levels have been in the 155 to 210 mm/dL range. His A1C level is currently 8.1. Phil’s blood pressure is 140/75 mm Hg, and he takes the angiotensin II receptor antagonist irbesartan, 300 mg daily. He also takes atorvastatin, 40 mg daily, and his lipid profiles are within the American Diabetes Association goals (LDL cholesterol <100 mg/dL). The results of his most recent comprehensive medical panel are normal; however, he remains obese.

Phil has made good progress since his diabetes diagnosis, having lost 15 lb and sticking to a routine of walking every day, if only for 15 minutes. It’s likely that additional diabetes medication will be required to bring his A1C level down, and his clinician makes note of this.

Today at his visit, Phil brings some complaints that he says “don’t have anything to do with the sugar problem.” Specifically, he says he’s feeling “low” and is tired all the time. He mentions that he had to do some work in his backyard that he does every spring to maintain his above-ground swimming pool and says that he felt “weak” and barely finished the chores. The next day, he felt even more fatigued and “spent” than usual. Finally, he reports that his wife is unhappy with their infrequent sexual activity, a marked departure from what it was several years ago, he says. Phil admits that his libido is low. “All-round, I’m not the guy I was,” he says.

The Possibility of Testosterone Deficiency

Phil has additional ongoing issues stemming from his diagnosis of type 2 diabetes. He needs to lose more weight, exercise more, and take additional steps to get better A1C control. But he has signs and symptoms that raise the possibility of additional metabolic problems. Hypogonadism, or TD, may be one of these. In The New England Journal of Medicine in 2004, Rhoden and Morgentaler defined hypogonadism as “a clinical condition characterized by low serum testosterone levels occurring in association with specific signs and symptoms, including diminished libido and sense of vitality, erectile dysfunction (ED), reduced muscle mass and bone density.”[6]

Multiple terms have been used to describe findings that include hypogonadism. The term andropause has been used to describe hypogonadism in older men, but androgen deficiency in aging men or other terms that emphasize the deficiency of androgens are preferred.[6] One way of defining late-onset hypogonadism is by the presence of at least 3 sexual symptoms associated with a total testosterone level of less than 11 nmol/L (3.2 ng/mL) and a free testosterone level of less than 220 pmol/L (64 pg/mL).[7] Many men find that this condition diminishes their daily quality of life. Further, many organ systems may be affected by late-onset hypogonadism.[8]

The known clinical manifestations of hypogonadism are summarized in the accompanying table and can be categorized as physical, psychological, and sexual.

Medical manifestations include decreased bone mineral density, decreased muscle mass and strength, increased body fat or BMI, gynecomastia, anemia, frailty, and fatigue. Psychological manifestations include depression, diminished energy, loss of vitality or sense of well-being, and impaired cognition and memory. Sexual symptoms associated with hypogonadism include diminished libido, ED or difficulty achieving an orgasm, and decreased sexual performance.[9,10] When discussing changes in patients’ sexual lives, it may be helpful to ask about reduced sexual activity or loss of interest in sex, fewer or absent sexual fantasies, and a worsening of sexual performance.

Considering Phil’s history and his current complaints, it may be prudent to consider the possibility of hypogonadism as his workup proceeds. Some of the symptoms he complains of, including diminished vigor/physical strength and diminished sexual desire, are common among men with hypogonadism. Then again, they might also be the result of his diabetes or another illness. Depression is a possibility, as he has not explained what he means by feeling “low.”

The Prevalence of Hypogonadism

Is hypogonadism prevalent enough to consider early in Phil’s workup? Many epidemiologic studies have shown that the prevalence of hypogonadism increases with age and diabetes. This relationship between age and the prevalence of hypogonadism is particularly strong when free testosterone or bioavailable testosterone is measured. For example, a longitudinal epidemiologic study, the Baltimore Aging Study, determined the percentage of men at different ages who had bioavailable testosterone (a measure of both free testosterone and testosterone loosely bound to albumin) in the hypogonadal range, defined as a total testosterone less than 11.3 nmol/L (325 ng/dL).[2] As shown in Figure 2, the percentage of men with testosterone values in the hypogonadal range varied from 12% in the 50- to 59-year-old age group to 49% in the 80+ year age group.[2]

In the Hypogonadism in Males (HIM) study, the prevalence of hypogonadism, defined as total testosterone level less than 300 ng/dL, was determined in men older than 45 years visiting mainly primary care practices in the United States for any reason.[11] The investigators obtained morning blood samples. Total testosterone, free testosterone, and bioavailable testosterone levels were determined in each sample. Participants were questioned about common symptoms of hypogonadism and whether conditions that are commonly comorbid with hypogonadism were present. They also answered questions about demographics and the reason for the current visit. In this group of patients, the crude hypogonadism prevalence rate was 38.7%, and findings were similar for levels of free testosterone and bioavailable testosterone. Of the 836 hypogonadal men, only 80 were receiving testosterone therapy.[11] This is an especially important study as it reflects patients seen every day in clinical practice, and shows how prevalent hypogonadism is in a medical office.

It is important to understand that unlike women, who all eventually undergo menopause and a relatively abrupt decrease in circulating estrogen levels, men do not universally experience “andropause” or a rapid loss of testosterone as they age. In fact, according to the findings of the Baltimore Aging Study, more than half of men older than 80 years remain eugonadal.[2] 

Based on these data, we might expect about 20% of men who are about Phil’s age (60-69 years) to have TD. The combination of this information and his symptoms suggest that hypogonadism is, in fact, worth considering as his workup continues. With Phil’s medical conditions, the HIM study would lead us to expect a 39% chance of hypogonadism.

Hypogonadism and the Risk of Comorbid Illness and Mortality

The HIM investigators also determined the odds ratios for having hypogonadism among men who had chronic medical conditions. The relative risk of hypogonadism for hypertension was 1.84, hyperlipidemia 1.47, diabetes 2.09, obesity 2.38, prostate disease 1.29, and asthma or chronic obstructive pulmonary disease 1.40.[11] The 4 most common conditions—hypertension, hyperlipidemia, diabetes, and obesity—are known to increase the risk of cardiovascular disease (CVD) [Figure 3].

Data from a large longitudinal epidemiologic study, the Rancho Bernardo study, have linked TD to increased death from all causes in relatively healthy men. The Rancho Bernardo study included nearly 800 men ages 50 to 91 who were followed for an average of 11.8 years. At the start of the study, 27% of subjects had suboptimal testosterone levels (less than the lower limit of 246 ng/dL for the reference range of young men for this assay). Compared to men with higher testosterone levels, those with levels in the lowest quartile were 40% more likely to die during follow-up. The difference in mortality between men in the low and high testosterone groups was not explained by age, BMI, lipid levels, estradiol levels, glycemia, diabetes mellitus, metabolic syndrome, or CVD. The relationship between low testosterone and mortality was independent of existing diseases including diabetes, metabolic syndrome, and CVD, but was attenuated by levels of the inflammatory cytokines C-reactive protein and interleukin-6; these substances are known to increase atherosclerotic vascular disease and its consequences. Although low testosterone levels were associated with a higher risk of death, higher levels of testosterone were not associated with a decreased risk of death.[12]

A study more recently completed in veterans also highlights the relationship between testosterone levels and mortality. Two testosterone levels were assessed twice over a 5-year period. As shown in the accompanying graphic, men in whom both determinations were normal had the highest survival rate. Those in whom both testosterone determinations were low had the lowest survival. Survival was intermediate in those with 1 normal testosterone and 1 low testosterone determination (Figure 4).[13]

The issue of bone loss and hormonal factors has been brought to light by a recent review. New imaging techniques reveal that in men, significant ongoing trabecular bone loss begins in young adulthood. Even in young men, testosterone levels are positively correlated with bone size.[14] Hypogonadism in men is a risk factor for hip fracture.[15] Serum estradiol levels predict male fracture risk, and a threshold effect exists.[16] In addition, a surprising 39% of osteoporotic fractures occur in men.[17] Because men have a higher peak bone mass than women, they are somewhat protected from fractures compared to women until they are quite old.[18] It is probable that a significant component of testosterone’s effect on fracture risk is mediated by nonskeletal effects, such as those on muscle mass, balance, or risk of falls. Low free testosterone may also contribute to fracture risk, related to the rising levels of SHBG with aging. Further studies directly addressing this issue are needed.

As we continue to think about Phil’s case, it is significant that he has diabetes, hypertension, hyperlipidemia, and is overweight—conditions which were more common among men with hypogonadism than in those who were eugonadal in the HIM study. Given what we have learned about Phil’s medical history, especially his recently diagnosed diabetes, and current symptoms, as well as what is known about the relationships among testosterone level, mortality, and the prevalence of CVD risk factors, including the metabolic syndrome, the next step with Phil might be to determine whether he does, in fact, have TD.

Hypogonadism and the Metabolic Syndrome

In the HIM study, the prevalence of obesity, hypertension, hyperlipidemia, and diabetes is increased among men with untreated hypogonadism.[11] As seen in the accompanying illustration, these same factors comprise the metabolic syndrome, which is typically defined as the presence of at least 3 of these 5 conditions:

• Obesity
• Hypertension
• Dyslipidemia
• Hyperglycemia
• Insulin resistance

In a study of 803 patients with sexual dysfunction (ED, 96.5%; hypoactive sexual desire, 39.6%; premature ejaculation, 22.7%; and delayed ejaculation, 4.8%), 236 patients (29.4%) were diagnosed as having metabolic syndrome according to National Cholesterol Education Program criteria. The prevalence of hypogonadism was 11.9% in patients with metabolic syndrome, but only 3.8% in patients without metabolic syndrome. Patients with hypogonadism reported various symptoms, notably hypoactive sexual desire, low frequency of sexual intercourse (both as rated on the Structured Interview on Erectile Dysfunction, or SIEDY, instrument) and depressive symptoms. In men in whom metabolic syndrome had been diagnosed, the diagnosis was most accurately predicted by 2 factors: waist circumference and hyperglycemia. In men who were hypogonadal and who had metabolic syndrome, gonadotropin levels were higher and free testosterone levels were lower. According to the investigators, this set of findings was evidence of primary hypogonadism.[19] In another study of the prevalence of hypogonadism in about 1000 men with ED, it was determined that several chronic conditions, including hypertension, tobacco abuse, sleep apnea, and work stress, were associated with hypogonadism.[20] There is also strong evidence linking low testosterone levels to high insulin levels, which are indicative of insulin resistance.[21]

The ultimate question about the relationship between hypogonadism and chronic illness—especially those that are linked to CVD—is whether testosterone treatment reverses the cofactors of metabolic syndrome and reduces CVD risk. No data support the possibility that testosterone treatment reduces CVD risk, but data are beginning to emerge that suggest that testosterone treatment may improve the cofactors of metabolic syndrome. The population-based Rotterdam Study examined possible links between levels of dehydroepiandrosterone sulfate (DHEAS), total testosterone, and bioavailable testosterone with aortic atherosclerosis among 1032 male and female nonsmokers aged 55 years and older. Compared to men whose total and bioavailable testosterone levels were determined to be in the lowest tertile, men whose total and bioavailable testosterone levels were in the highest tertile had age-adjusted relative risks of 0.4 [95% confidence interval (CI), 0.2–0.9] and 0.2 (CI, 0.1–0.7), respectively, for severe aortic atherosclerosis; however, the authors did not identify a statistically significant association between DHEAS levels and aortic atherosclerosis.[22]

Hypogonadism: Strategies for Management

From Phil’s physical examination, it is determined that his testes are 18 cc in size (range is typically 12 to 30 cc), with normal external genitalia. His prostate gland size is within normal limits. This is a summary of his laboratory work:

• Serum glutamic oxaloacetic transaminase: 73 IU/L (11-40)
• Serum glutamic pyruvic transaminase: 116 IU/L (7-40)
• Alkaline phosphatase: 75 IU/L (30-115)
• Total testosterone: 400 ng/dL (300-1000)
• Repeat total testosterone: 410 ng/dL
• Luteinizing hormone (LH): 5 IU/L (2-9)
• Follicle-stimulating hormone (FSH): 7 IU/L (1-15)
• Prolactin: 4 ng/mL (2-15)
• Prostate specific antigen (PSA): 0.6 ng/mL (<3.5) 
• Thyroid-stimulating hormone: 2.9 mIU/L (0.4-4.2)

Guidelines recently published by the Endocrine Society note that most symptoms of TD are more likely to occur below the lower limit of the normal range in healthy young men, or 280 to 300 ng/dL total testosterone, depending on the laboratory used, with variability among symptoms, target organs, and individual men. The lower limit of the normal range of serum free testosterone for healthy young men ranges from 5 to 9 pg/mL, again varying by laboratory.[10]

The level of total testosterone considered diagnostic by the International Society of Andrology, International Society for the Study of the Aging Male, European Association of Urology, European Academy of Andrology, and American Society of Andrology is less than 230 ng/dL; at that point, initiation of testosterone replacement therapy (TRT) is definitely warranted.[8] According to this international consensus, if the testosterone level is above 350 ng/dL, treatment is probably not necessary. For patients with levels between 230 and 350 ng/dL, consider performing a free testosterone level. If that measurement does not clarify the situation and the patient has symptoms of androgen deficiency, a 3- to 4-month trial of TRT may be appropriate.[8] The decision to treat is based on a combination of laboratory findings, symptomatology, and clinical judgment.

As discussed in the case of Phil, the first step in the recognition of low testosterone is the suspicion of the disease. The signs and symptoms of hypogonadism may be present or need to be elicited by a careful history. Many times a medical visit is occasioned by another complaint, as it has been in Phil’s case. If the patient’s age or concurrent medical condition warrants a suspicion of the diagnosis of low testosterone, the first step in pursuing a diagnosis is to obtain a morning serum testosterone level. The finding of a normal testosterone level, of course, steers the clinical investigation in other directions. If the serum testosterone level is low, however, it is appropriate to verify the abnormal level by obtaining a second morning serum testosterone level. If a low testosterone level has been established and it has been determined that both the PSA and digital rectal examination (DRE) findings are normal, it may be appropriate to begin TRT. If the PSA and/or the DRE are abnormal, however, consultation with a urologist for prostate evaluation is essential; further evaluation, as by transrectal ultrasound-guided biopsy of the prostate, may be required.[8] A diagnosis and treatment algorithm is presented in Figure 6.

If a condition other than hypogonadism is suspected based on clinical or laboratory findings, further laboratory testing is required. (Other assessments may be required when a condition such as depression is suspected.) Determination of LH and FSH levels is usually sufficient to differentiate whether hypogonadism is primary or secondary. Serum prolactin may be measured to rule out the presence of a pituitary tumor. If these hormone levels are abnormal, a different diagnosis should be considered. Further evaluation by an endocrinologist is indicated.[8]

Additional laboratory findings for Phil are now available and are as follows:

• Serum glutamic oxaloacetic transaminase: 73 IU/L (11-40)
• Serum glutamic pyruvic transaminase: 116 IU/L (7-40)
• Alkaline phosphatase: 75 IU/L (30-115)
• Total testosterone: 400 ng/dL (300-1000)
• Repeat total testosterone: 410 ng/dL
• Calculated free testosterone: 133 pmol/L (135-900)
• SHBG: 91 nmol/L (13-71)

In Phil’s case the first total testosterone was normal, and so was the second. Because he had many symptoms of hypogonadism, however, it was decided to do a free testosterone, which provided additional helpful information. Either equilibrium dialysis or mass spectrometry may be used to assess free testosterone. Most guidelines recommend a morning draw (before 11 am) for any testosterone measurement.

In light of these findings, his clinician decided that Phil had TD. TRT with testosterone gel was initiated.

Goals and Potential Benefits of Testosterone Replacement Therapy

TRT is used to treat the signs and symptoms of hypogonadism as well as to achieve and maintain eugonadal serum testosterone levels. Therapy should be individualized for specific patient needs. In addition to restoring libido and erectile function, maintaining eugonadal serum testosterone levels can increase energy and improve mood and body composition by reducing fat mass, increasing lean body mass, and possibly increasing muscle strength. TRT has been shown to stabilize or increase bone mineral density, which may reduce the risk for fractures.[9,23,24]

Currently approved TRT options in the United States include

• Intramuscular injection
  • Testosterone propionate, enanthate (Delatestryl®), cypionate (Depo-Testosterone®)
• Buccal administration
  • Striant®
• Transdermal patch
  • Androderm®
• Transdermal gel
  • AndroGel®, Testim®
• Subcutaneous pellets
  • Testopel®

Testosterone propionate, administered at a dosage of 10 to 25 mg two or three times a week, and testosterone enanthate and testosterone cypionate, both given at a dosage of 200 mg every 2 to 4 weeks, are intramuscular options. The intramuscular preparations are cost effective and raise serum testosterone levels to the normal range, but they must be administered frequently and have variable pharmacokinetics.

Each dose of testosterone for buccal administration, with the proprietary name Striant®, contains 30 mg. Each tablet is applied to the gum above the incisor twice daily and raises testosterone levels to within the physiological range. Compared to other testosterone formulations, it is expensive and may cause irritation of the mouth and gums.

The testosterone patch, known by the trade name Androderm®, is applied to the back, abdomen, thigh, or upper arm at night. Each patch contains 2.5 or 5 mg of testosterone to meet the needs of the patient. The delivered testosterone mimics circadian levels of testosterone with daily administration. Skin irritation has been reported, and the patch is generally more expensive than other formulations.

Testosterone gel formulations, with the marketed names AndroGel® and Testim®, both 1% concentration, are available in 5- and 10-g packets or tubes. The gel is applied to the upper arm, shoulder, or abdomen each morning and the absorbed dose of testosterone mimics the circadian range seen in healthy young men. Testosterone gel is generally well tolerated, with skin irritation being the most common complaint.[25] This information is summarized in Table 2.

A cylindrical, 8- to 9-mm subcutaneous testosterone pellet is marketed as Testopel®. Each pellet contains 75 mg of testosterone, and these are typically inserted at the upper hip. The number of pellets inserted varies according to an individual’s requirements. Pellets slowly dissolve over the course of 3 to 6 months.

Risks Associated With Testosterone Replacement Therapy

The most common dermatologic reactions associated with TRT are erythema and induration, which are most often associated with use of the testosterone patch. Other potential skin problems include increased oiliness, acne, and skin reactions.[26] A recent community-based study of men aged 65 years and older who had difficulties with mobility and total serum testosterone levels in the range of 100 to 350 ng/dL or free testosterone levels of less than 50 pg/mL compared testosterone gel with placebo as a means of building muscle strength and muscle mass. The study was discontinued early when it became clear that men receiving testosterone gel had an excess of cardiovascular adverse events. The authors noted the caveat that the study population was small (a total of 209 men in both treatment groups) and consisted of a “unique population.”[27]

Breast enlargement or tenderness, usually seen when the testosterone level is low, is occasionally seen after treatment, but is transient and abates with continued treatment. Patients can be reassured that breast enlargement is uncommon at standard dosing levels.[26] Although there are no reports of older men developing sleep apnea while on TRT, experts generally do not prescribe TRT for men who have chronic obstructive pulmonary disease and are also overweight or heavy smokers.[26]

Clinically significant polycythemia is an uncommon development of treatment, but the risk factors for polycythemia include age, chronic obstructive pulmonary disease, and a history of smoking. The biggest risk appears to be in older men using intramuscular products.[25] The injectable testosterone esters and transdermal formulations are only rarely associated with liver function abnormalities or the development of liver tumors.[26]

Edema of the lower extremities is possible during the first few months of therapy, but it is usually modest and transient. When prescribing TRT, carefully consider how fluid retention might affect a chronically ill or frail man with early stage congestive heart failure.[26]

The possible development of symptomatic benign prostatic hypertrophy and prostate cancer have been a concern with TRT. Reported increases in prostate volume have been modest and inconsistent, and not associated with any increase in clinical symptoms of benign prostatic hyperplasia (BPH). Nonobstructive BPH is not a contraindication to treatment.[26] A broader discussion of malignancy follows in a later section of this article.

Monitoring of Men Receiving Testosterone Replacement Therapy

Current guidelines recommend that TRT be monitored through physical examinations and laboratory tests as follows:

• The baseline evaluation should determine voiding symptoms via patient history or International Prostate Symptom Score and any history of sleep apnea. A DRE should be performed, and testosterone levels, PSA, hematocrit, and hemoglobin should be determined.
• Assess treatment efficacy at 1 to 2 months after initiation of therapy and adjust the dosage if there is a suboptimal response.
• The patient should be evaluated at 3 months and annually thereafter to assess symptom response and any adverse events.
• Recheck hematocrit and hemoglobin at 3 months; if the hematocrit exceeds 54%, therapy should be stopped until it decreases to a safe level, and a lower dose of testosterone considered. The patient should be evaluated for hypoxia and sleep apnea. 
• Perform a DRE and recheck the PSA at 3 months, then in accordance with guidelines for prostate cancer screening depending on the age and race of the patient.
• Measure bone mineral density of the lumbar spine and/or femoral neck after 1 to 2 years of treatment in patients with osteoporosis or low trauma fracture in accordance with the regional standard of care.
• Evaluate formulation-specific adverse events at each visit; for example, oral irritation from buccal testosterone tablets, skin irritation from testosterone patches, or changes in mood or libido with intramuscular testosterone.[10]

Managing Diabetes With Lifestyle Plus Testosterone

In a patient like Phil, who has recent-onset diabetes, the question of whether lifestyle factors alone might be able to reverse his diabetes is worth investigating. A recent 52-week randomized trial focused on managing diabetes with lifestyle and TRT. A total of 32 men with newly diagnosed type 2 diabetes who were aged 35 to 70 years were enrolled. The average waist circumference was 41.7 inches (106.8 cm) at entry. All participants had subnormal plasma testosterone levels. Each participant followed a supervised diet and exercise program; half of the group was randomized to receive treatment with a testosterone gel, 50 mg/d.[4] All participants were contacted at least twice weekly (by phone, e-mail, or text message) to encourage adherence.

After 52 weeks of follow-up, improvements were reported in these areas, regardless of whether subjects were treated with testosterone or not:

• Serum testosterone
• A1C and fasting plasma glucose
• HDL-C
• Triglyceride concentration
• Waist circumference[4]

Patients who used TRT had better results, however. The findings are shown in Figure 7. Testosterone therapy had a large impact when added to the diet and exercise component of the intervention. After 52 weeks, just 40% of participants in the diet and exercise group attained an A1C goal of less than 7.0%, and none attained a level of 6.5%. In the TRT group, however, 100% attained the less than 7.0% goal, and nearly 88% attained the less than 6.5% target. In addition, metabolic syndrome was reversed in more participants who received TRT in addition to diet and exercise than in those who performed only the diet and exercise strategy.[4] It’s also important to note that testosterone therapy was not associated with any differences between the treatment groups with regard to serum SHBG or circulating PSA levels. Although the results are promising, this is a small study, lacking an actively treated placebo group, although investigators were blinded as to which participants were using testosterone therapy. Compliance with the diet and exercise modification program was higher than that typically achieved in practice, possibly as a result of the frequent follow-up contact with participants.[4]

More recently, results from the TIMES2 Study were reported. TIMES2 is a European, multicenter, prospective, randomized, double-blind, placebo-controlled trial of TRT in men with metabolic syndrome or type 2 diabetes. The findings included associations between TRT and improved insulin resistance, as well as reductions in body fat, waist circumference, and cholesterol and lipoprotein(a) levels.[5]

What Is Known About High Testosterone in Men With Prostate Cancer?

At a follow-up visit 3 months after the initiation of TRT, Phil’s metabolic profile is much improved. He has lost another 10 lb, his waist circumference is now 39 inches (down from 40 inches), and his A1C level is 7.6%, down from 8.1%. His total testosterone level is 600 ng/dL, up from 400 ng/dL (normal range, 300-1000). Phil’s blood pressure and lipid profile are both at goal. His clinician decides that Phil needs additional therapy to help him attain a conventional A1C goal of 7%, and he is started on a  once-daily insulin regimen, starting with a 20-U injection of basal insulin glargine or detemir every evening. The metformin is continued. While discussing these treatment changes, Phil expresses concern about continuing with TRT. A friend has told him that TRT causes prostate cancer, and Phil asks his provider about stopping therapy.  

The relationship between high testosterone levels in men with prostate cancer was explored in a pooled study of 18 worldwide longitudinal studies that included nearly 4000 men with prostate cancer and more than 6400 control subjects. No association was found between prostate cancer and serum androgens. The investigators concluded that a high testosterone level seems unassociated with prostate cancer risk.[28]

Shabsigh and colleagues undertook a systematic review of studies of TRT and prostate cancer risk. They found 44 studies that met their inclusion criteria. Of these, 11 were placebo-controlled, randomized studies; 29 were nonplacebo-controlled studies of men with no prostate cancer history; and 4 studies used a population of hypogonadal men with history of prostate cancer. Upon completion of their systematic review of TRT and the risk of prostate cancer in hypogonadal men, the authors concluded that there was no evidence that TRT increased the risk of prostate cancer in hypogonadal men. Further, TRT did not increase the risk that high-grade prostatic intraepithelial neoplasia would progress to prostate cancer, and TRT did not have a consistent effect on PSA levels.[29]

Knowing that TRT often causes patients to worry about an increased risk of prostate cancer, Phil’s clinician spent more time than usual with him and helped him understand that no relationship between TRT and prostate cancer has been shown. The clinician also took time to review the information with Phil about the beneficial effect that continued TRT is likely to have on Phil’s sexual function, sense of well-being, and diabetes (in conjunction with standard diabetes therapy). Phil was directed to some reputable, noncommercial Web sites such as WebMD or MayoClinic.com for more information about TRT as well as diabetes.  

Conclusion

Our review of Phil’s case and of the contemporary literature on the relationship among low testosterone levels, metabolic syndrome/diabetes, and hypertension show that

• In patients with low testosterone levels, look for other chronic illnesses that are frequent comorbidities, especially those known to elevate cardiac risk, such as insulin resistance/ diabetes, hypertension, or other components of the metabolic syndrome.
• In patients with chronic conditions associated with cardiovascular risk (eg, diabetes, hypertension, hyperlipidemia, or obesity), look for low testosterone levels.
• After initiating TRT in men who require it, periodically check testosterone levels both to monitor for therapeutic adequacy and to reinforce the importance of remaining on therapy.

 

 

André T. Guay, MD, and Martin Miner, MD
Published on August 17, 2010

 
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