Low Testosterone Associated with Increased Mortality
by Jeffrey Dach MD
Forty Per Cent More Likely to Die
Two reports published in the recent medical literature showed that low testosterone is associated with increased mortality.(1)(2)(3) Upper Left Image: Chemical structure of human, bio-identiical testosterone courtesy of wikimedia commons.
In the first study from 2006, low testosterone was found to be associated with increased mortality among veterans. (1) . A low testosterone level was a total testosterone level of less than 250 ng/dL and 858 men were followed for 8 years. Those with low testosterone levels had an increased mortality rate (hazard ratio, 1.88). (1)
Left chart from Arch Int Med 2006 Molly Shores (1) Low Testosterone group (Green Line) had highest mortality rate.
In the second study published in 2008 tracked nearly 800 men, 50 to 91 years old, living in California. Their testosterone level was measured at the beginning of the study, and their health was then tracked over the next 20 years. Low testosterone symptoms reported by these men included decreased libido, erectile dysfunction, fatigue, loss of strength, decrease in bone density and decreased muscle mass. Also, these men tended to be overweight or obese, and at higher risk for cardiovascular disease and diabetes. Men with the lowest testosterone, below 241 total serum level, were 40% more likely to die.(2)
A third study published by Dr Malkin in Heart 2010 showed that men with known coronary artery disease commonly had low testosterone levels which was associated with double the mortality rate compared with men with normal levels. (6) Dr Malkin says: “Excess mortality was noted in the androgen-deficient group compared with normal (41 (21%) vs 88 (12%)”
Reduced Mortality in Testosterone Treated Compared to Untreated
Left image shows mortality rate In Diabetic Males with Normal or Low testosterone. Note the increased mortality in Low Testosterone untreated group. Mortality rate of androgen deficient group returns to Normal after testosterone treatment.(13)
Above Left image courtesy of Muraleedharan, Vakkat, et al. “Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes.” European Journal of Endocrinology 169.6 (2013): 725-733.
A second observational study by Dr Molly Shores in 1031 male veterans over 4-5 years showed that men with low testosterone had 20% mortality while in those who were treated with testosterone, mortality decreased in half to only 10%.(14)
More recently, in the past few years a flurry of articles and studies have come to light by Drs Traish and Morgentaler debunking the two unfounded fears regarding testosterone therapy in andogen deficient males.(7-13)
The first unfounded fear is the false medical myth that testosterone therapy somehow causes prostate cancer. This has been shown to be false.(7,8)
The second unfounded fear is that testosterone somehow increases cardiovascular disease. Not only is this false, the exact opposite is true. Testosterone therapy in androgen deficient males decreases cardiovascular mortality in numerous studies.(7,8) Indeed, Dr Traish makes the plea to the medical community to treat more androgen deficient men.(7,8) He says” “There is an urgent need among the medical community for greater awareness of the impact of TD on general health in men with TD.” (7,8)
Conclusion: The fears regarding testosterone supplementation in androgen deficient males have been debunked. The great tragedy is that androgen deficient males are either ignored or denied treatment by the conventional medical system. Hopefully this state will soon be rectified. Low testosterone in males is associated with , loss of libido, depression. metabolic syndrome ,increased coronary artery disease and increased mortality. (4,5,7-13) Testosterone supplementation in androgen deficient males is beneficial in reducing mortality, improving metabolic syndrome, and improving quality of life.
Low Testosterone – Diagnosis and Treatment
Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Florida 33314
Links and References
Low Serum Testosterone and Mortality in Male Veterans Arch Intern Med. 2006;166:1660-1665 Molly M. Shores, MD; Alvin M. Matsumoto, MD; Kevin L. Sloan, MD; Daniel R. Kivlahan, PhD .Conclusions Low testosterone levels were associated with increased mortality in male veterans.
The Journal of Clinical Endocrinology & Metabolism 2008 Jan;93(1):68-75.
Low Serum Testosterone and Mortality in Older Men. Gail A. Laughlin, Eliza beth Barrett-Connor and Jaclyn Bergstrom. Department of Family and Preventive Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093
Results: During an average 11.8-yr follow-up, 538 deaths occurred. Men whose total testosterone levels were in the lowest quartile (<241 ng/dl) were 40% [hazards ratio (HR) 1.40; 95% confidence interval (CI) 1.14–1.71] more likely to die than those with higher levels, independent of age, adiposity, and lifestyle. Additional adjustment for health status markers, lipids, lipoproteins, blood pressure, glycemia, adipocytokines, and estradiol levels had minimal effect on results. The low testosterone-mortality association was also independent of the metabolic syndrome, diabetes, and prevalent cardiovascular disease but was attenuated by adjustment for IL-6 and C-reactive protein. In cause-specific analyses, low testosterone predicted increased risk of cardiovascular (HR 1.38; 95% CI 1.02–1.85) and respiratory disease (HR 2.29; 95% CI 1.25–4.20) mortality but was not significantly related to cancer death (HR 1.34; 95% CI 0.89–2.00). Results were similar for bioavailable testosterone.
Conclusions: Testosterone insufficiency in older men is associated with increased risk of death over the following 20 yr, independent of multiple risk factors and several preexisting health conditions.
Low Testosterone Could Kill You. Low Levels of Male Hormone May be More Dangerous Than Previously Thought By SUPINDA BUNYAVANICH, M.D. ABC News Medical Unit June 6, 2007
Low testosterone may lead to a greater risk of death, according to a study presented Tuesday at the annual meeting of the Endocrine Society in Toronto.
Men with low testosterone had a 33 percent greater death risk over their next 18 years of life compared with men who had higher testosterone, according to the study conducted by Dr. Elizabeth Barrett-Connor and colleagues at the University of California at San Diego. “It’s very exciting and potentially a groundbreaking study,” said Barrett-Connor. “But it needs to be confirmed.” The study tracked nearly 800 men, 50 to 91 years old, living in California. Their testosterone level was measured at the beginning of the study, and their health was then tracked over the next 20 years.
Testosterone Replacement For Men With Low Testosterone Improves Liver Function, Metabolic Syndrome. Testosterone deficiency, which becomes more common with age, is linked not only to decreased libido but also to a number of medical problems. These include the metabolic syndrome a cluster of metabolic risk factors that increase the chances of developing heart disease, stroke and type 2 diabetes.
Low testosterone levels linked to depression in older men March 2008
Older men with lower free testosterone levels in their blood appear to have higher prevalence of depression, according to a report in the March issue of Archives of General Psychiatry.
6) Malkin, Chris J., et al. “Low serum testosterone and increased mortality in men with coronary heart disease.” Heart 96.22 (2010): 1821-1825. low-serum-testosterone-and-increased-mortality-in-men-with-coronary-heart-disease-malkin-chris-heart-2010 Background To examine the effect of serum testosterone levels on survival in a consecutive series of men with confirmed coronary disease and calculate the prevalence of testosterone deficiency.
Design Longitudinal follow-up study. Setting Tertiary referral cardiothoracic centre. Patients 930 consecutive men with coronary disease referred for diagnostic angiography recruited between June 2000 and June 2002 and followed up for a mean of 6.9±2.1 years.
Outcome All-cause mortality and vascular mortality. Prevalence of testosterone deficiency.
Results The overall prevalence of biochemical testosterone deficiency in the coronary disease cohort using bio-available testosterone (bio-T) <2.6 nmol/l was 20.9%, using total testosterone <8.1 nmol/l was 16.9% and using either was 24%. Excess mortality was noted in the androgen-deficient group compared with normal (41 (21%) vs 88 (12%), p=0.002). The only parameters found to influence time to all-cause and vascular mortality (HR ± 95% CI) in multivariate analyses were the presence of left ventricular dysfunction (3.85; 1.72 to 8.33), aspirin therapy (0.63; 0.38 to 1.0), β-blocker therapy (0.45; 0.31 to 0.67) and low serum bio-T (2.27; 1.45 to 3.6).
Conclusions In patients with coronary disease testosterone deficiency is common and impacts significantly negatively on survival. Prospective trials of testosterone replacement are needed to assess the effect of treatment on survival.
7) Traish, Abdulmaged. “Testosterone therapy in men with testosterone deficiency: Are we beyond the point of no return?.” Investigative and Clinical Urology 57.6 (2016): 384-400.
Although testosterone therapy in men with testosterone deficiency was introduced in the early 1940s, utilization of this effective treatment approach in hypogonadal men is met with considerable skepticism and resistance. Indeed, for decades, the fear that testosterone may cause prostate cancer has hampered clinical progress in this field. Nevertheless, even after considerable knowledge was acquired that this fear is unsubstantiated, many in the medical community remain hesitant to utilize this therapeutic approach to treat men with hypogonadism. As the fears concerning prostate cancer have subsided, a new controversy regarding use of testosterone therapy and increase in cardiovascular disease was introduced. Although the new controversy was based on one ill-fated clinical trial, one meta-analysis with studies that utilized unapproved formulation in men with liver cirrhosis, and two retrospective studies with suspect or nonvalidated statistical methodologies and database contaminations, the flames of such controversy were fanned by the lay press and academics alike. In this review we discuss the adverse effect of testosterone deficiency and highlight the numerous proven benefits of testosterone therapy on men’s health and debunk the myth that testosterone therapy increases cardiovascular risk. Ultimately, we believe that there is considerable scientific and clinical evidence to suggest that testosterone therapy is safe and effective with restoration of physiological levels in men with testosterone deficiency, irrespective of its etiology.
TD is associated with increased incidence of metabolic syndrome, obesity, sexual dysfunction, impaired fertility, reduced motivation, increased fatigue, depressed mood, loss of bone and muscle mass, anemia, decreased energy and vigour, insulin resistance, diabetes, inflammation, dyslipidemia, sarcopenia and frailty, reduced quality of life (QoL) and increased mortality [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 40, 41, 42, 43, 44]. A substantial body of evidence indicates that coronary artery disease incidence and severity, carotid intima-media thickness, atherosclerosis is inversely correlated with serum T concentrations . There is an urgent need among the medical community for greater awareness of the impact of TD on general health in men with TD.
8) Traish, Abdulmaged M. “Testosterone therapy in men with testosterone deficiency: are the benefits and cardiovascular risks real or imagined?.” American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. Vol. 311. No. 3. American Physiological Society, 2016.
In the adult male, testosterone (T) deficiency (TD) also known as male hypogonadism, is a well-established medical condition, which has been recognized for more than a century. T therapy in men with TD was introduced as early as 1940s and was reported to improve overall health with no concomitant serious adverse effects. A wealth of recent studies demonstrated that T therapy in men with TD is associated with increased lean body mass, reduced fat mass and waist circumference, improvement in glycemic control, and reduced obesity. T therapy is also associated with improvements in lipid profiles, amelioration of metabolic syndrome (Met S) components, reduced inflammatory biomarkers, reduced systolic and diastolic blood pressure, and improvements in sexual function. More importantly, T therapy is associated with amelioration of diabetes and reduced mortality. However, few studies, marred with serious methodological and analytical flaws reported between 2010 and 2014, suggested that T therapy is associated with increased cardiovascular (CV) risk. As summarized in this review, a thorough and critical analysis of these studies showed that the risks purported are unsubstantiated and such studies lacked credible scientific and clinical evidence. Moreover, recent observational, registry studies, clinical trials, and meta-analyses, all revealed no increase in CV risks in men receiving T therapy. In this review, the benefits of T therapy in adult men with TD and the lack of credible evidence suggesting that T therapy is linked to increased CV risks are discussed. It should be noted that the literature is replete with studies demonstrating beneficial effects of T therapy on CV and overall health.
Of importance, the study by Snyder et al.  and the resolutions of the consensus panel on T  debunked the notion that age-related hypogonadism is not a clinical condition and should remain untreated. As reported in the study , T therapy in older men has several benefits and age-related hypogonadism is a clinical condition worthy of treatment. We hope that the findings of this large and well executed study  and the summary provided by the consensus panel  will serve as a reminder to those who are beating the drums of fear and hysteria on the dangerous use of T in the treatment of men with TD and reassure men suffering from TD and their physicians that such fears and hysteria are unfounded.
9) free pdf Anderson Jeffrey testosterone replacement myocardial infarction low testosterone 2016 Anderson, Jeffrey L., et al. “Impact of testosterone replacement therapy on myocardial infarction, stroke, and death in men with low testosterone concentrations in an integrated health care system.” The American journal of cardiology 117.5 (2016): 794-799.
The aim of this study was to assess the effect of testosterone replacement therapy (TRT) on cardiovascular outcomes. Men (January 1, 1996, to December 31, 2011) with a low initial total testosterone concentration, a subsequent testosterone level, and >3 years of follow-up were studied. Levels were correlated with testosterone supplement use. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of death, nonfatal myocardial infarction, and stroke at 3 years. Multivariate adjusted hazard ratios (HRs) comparing groups of persistent low (<212 ng/dl, n = 801), normal (212 to 742 ng/dl, n = 2,241), and high (>742 ng/dl, n = 1,694) achieved testosterone were calculated by Cox hazard regression. A total of 4,736 men were studied. Three-year rates of MACE and death were 6.6% and 4.3%, respectively. Subjects supplemented to normal testosterone had reduced 3-year MACE (HR 0.74; 95% confidence interval [CI] 0.56 to 0.98, p = 0.04) compared to persistently low testosterone, driven primarily by death (HR 0.65, 95% CI 0.47 to 0.90). HRs for MI and stroke were 0.73 (95% CI 0.40 to 1.34), p = 0.32, and 1.11 (95% CI 0.54 to 2.28), p = 0.78, respectively. MACE was noninferior but not superior for high achieved testosterone with no benefit on MI and a trend to greater stroke risk. In conclusion, in a large general health care population, TRT to normal levels was associated with reduced MACE and death over 3 years but a stroke signal with high achieved levels suggests a conservative approach to TRT.
10) Saad, Farid, et al. “Testosterone Deficiency and Testosterone Treatment in Older Men.” Gerontology (2016).
Gerontology Testosterone Deficiency and Testosterone Treatment in Older Men Saad F.a, b · Röhrig G.c, d · von Haehling S.e · Traish A.f, g
aGlobal Medical Affairs Andrology, Bayer AG, Berlin, Germany;
Frailty is a clinical condition related to changes in metabolism, to sarcopenia, and to decline in muscle mass and strength, bone mineral density, and physical function with aging. The pathophysiology of frailty is multifactorial and associated with comorbidities. Testosterone is implicated in regulating metabolic functions, maintenance of muscle and bone, and inhibition of adipogenesis. In older individuals, reduced testosterone is thought to contribute to an altered state of metabolism, loss of muscle and bone, and increased fat, leading to sarcopenia, sarcopenic obesity, and frailty. While no direct relationship between testosterone deficiency (commonly known as hypogonadism) and frailty has been established (due to the multifactorial nature of frailty), clinical evidence suggests that testosterone deficiency is associated with increased sarcopenia and obesity. Testosterone treatment in frail older men with limited mobility and with testosterone deficiency improved insulin resistance, glucose metabolism, and body composition. These changes contribute to better physical function and improved quality of life. Because frailty increases disability, comorbidities, and the risk of hospitalization, institutionalization, and mortality in older men, it is warranted to explore the potential usefulness of testosterone treatment in frail men with hypogonadism in order to attenuate the progression of sarcopenia and frailty. In this paper, we will discuss the impact of testosterone deficiency on frailty and the potential role of testosterone treatment in ameliorating and reducing the progression of frailty. Such an approach may reduce disability and the risk of hospitalization and increase functional independence and quality of life.
11) free pdf Morgentaler Abraham Testosterone therapy and cardiovascular risk Mayo Clinic 2015
Morgentaler, Abraham, et al. “Testosterone therapy and cardiovascular risk: advances and controversies.” Mayo Clinic Proceedings. Vol. 90. No. 2. Elsevier, 2015.
a modest number of randomized controlled
trials (RCTs), indicate that low serum T concentrations
are associated with increased CV
risk and mortality and that T therapy may
have clinically relevant CV benefits
Established benefits of T therapy in hypogonadal
men include improved sexual desire
and function,12-15 improved energy, mood,
and vitality,15-19 increased lean mass,14,19-22
decreased waist circumference,23-27 reduced
total body fat mass,19-22 and increased bone
mineral density.28-31 Promising new data
reveal that T therapy improves insulin sensitivity32-
34 and reduces blood glucose23,25,35
and hemoglobin A1c (HbA1c)23,25,27,35 levels
in men with type 2 diabetes or obesity.
In summary, we find no scientific basis for
the suggestion that T therapy increases CV
risk. In fact, as of this date, we are unaware
of any compelling evidence that T therapy is
associated with increased CV risk. On the contrary,
the weight of evidence accumulated by
researchers around the world over several decades
clearly indicates that higher levels of T
are associated with amelioration of CV risk
factors and reduced risk of mortality.
12) Sharma, Rishi, et al. “Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men.” European Heart Journal (2015): ehv346.
Aims There is a significant uncertainty regarding the effect of testosterone replacement therapy (TRT) on cardiovascular (CV) outcomes including myocardial infarction (MI) and stroke. The aim of this study was to examine the relationship between normalization of total testosterone (TT) after TRT and CV events as well as all-cause mortality in patients without previous history of MI and stroke.
Methods and results We retrospectively examined 83 010 male veterans with documented low TT levels. The subjects were categorized into (Gp1: TRT with resulting normalization of TT levels), (Gp2: TRT without normalization of TT levels) and (Gp3: Did not receive TRT). By utilizing propensity score-weighted Cox proportional hazard models, the association of TRT with all-cause mortality, MI, stroke, and a composite endpoint was compared between these groups. The all-cause mortality [hazard ratio (HR): 0.44, confidence interval (CI) 0.42–0.46], risk of MI (HR: 0.76, CI 0.63–0.93), and stroke (HR: 0.64, CI 0.43–0.96) were significantly lower in Gp1 (n = 43 931, median age = 66 years, mean follow-up = 6.2 years) vs. Gp3 (n = 13 378, median age = 66 years, mean follow-up = 4.7 years) in propensity-matched cohort. Similarly, the all-cause mortality (HR: 0.53, CI 0.50–0.55), risk of MI (HR: 0.82, CI 0.71–0.95), and stroke (HR: 0.70, CI 0.51–0.96) were significantly lower in Gp1 vs. Gp2 (n = 25 701, median age = 66 years, mean follow-up = 4.6 years). There was no difference in MI or stroke risk between Gp2 and Gp3.
Conclusion In this large observational cohort with extended follow-up, normalization of TT levels after TRT was associated with a significant reduction in all-cause mortality, MI, and stroke.
13) Muraleedharan, Vakkat, et al. “Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes.” European Journal of Endocrinology 169.6 (2013): 725-733.
Objective Men with type 2 diabetes are known to have a high prevalence of testosterone deficiency. No long-term data are available regarding testosterone and mortality in men with type 2 diabetes or any effect of testosterone replacement therapy (TRT). We report a 6-year follow-up study to examine the effect of baseline testosterone and TRT on all-cause mortality in men with type 2 diabetes and low testosterone.
Research design and methods A total of 581 men with type 2 diabetes who had testosterone levels performed between 2002 and 2005 were followed up for a mean period of 5.8±1.3 s.d. years. Mortality rates were compared between total testosterone >10.4 nmol/l (300 ng/dl; n=343) and testosterone ≤10.4 nmol/l (n=238). The effect of TRT (as per normal clinical practise: 85.9% testosterone gel and 14.1% intramuscular testosterone undecanoate) was assessed retrospectively within the low testosterone group.
Results Mortality was increased in the low testosterone group (17.2%) compared with the normal testosterone group (9%; P=0.003) when controlled for covariates. In the Cox regression model, multivariate-adjusted hazard ratio (HR) for decreased survival was 2.02 (P=0.009, 95% CI 1.2–3.4). TRT (mean duration 41.6±20.7 months; n=64) was associated with a reduced mortality of 8.4% compared with 19.2% (P=0.002) in the untreated group (n=174). The multivariate-adjusted HR for decreased survival in the untreated group was 2.3 (95% CI 1.3–3.9, P=0.004).
Conclusions Low testosterone levels predict an increase in all-cause mortality during long-term follow-up. Testosterone replacement may improve survival in hypogonadal men with type 2 diabetes.
Several longitudinal population studies have reported that a low testosterone at baseline is associated with an increase in all-cause mortality (1). Some individual studies have specifically identified increases in cardiovascular, respiratory and cancer deaths (2, 3, 4). A meta-analysis of published research papers with a mean follow-up period of 9.7 years confirmed that low testosterone was associated with increased risk of all-cause and cardiovascular mortality in community based studies (1). Men with specific co-morbidities such as proven coronary artery disease and renal failure have also found that low testosterone predicts an increased risk of earlier death than those with the same condition and are testosterone replete (5, 6).
In summary, this is the first study to demonstrate that low testosterone levels are associated with an increase in all-cause and cardiovascular mortality in men with type 2 diabetes. This study demonstrates that long-term testosterone replacement is not only safe in terms of mortality but may also improve survival in men with type 2 diabetes and hypogonadism.
14) Shores, Molly M., et al. “Testosterone Treatment and Mortality in Men with Low Testosterone Levels.” (2012). J Clin Endocrinol Metab. 2012 Jun;97(6):2050-8. Shores Testosterone-Treatment mortality-in-men-with-hypogonadism J Clin Endocrinol Metab. 2012
Low testosterone levels in men have been associated with increased mortality. However, the influence of testosterone treatment on mortality in men with low testosterone levels is not known.
OBJECTIVE:The objective of the study was to examine the association between testosterone treatment and mortality in men with low testosterone levels.
DESIGN:This was an observational study of mortality in testosterone-treated compared with untreated men, assessed with time-varying, adjusted Cox proportional hazards regression models. Effect modification by age, diabetes, and coronary heart disease was tested a priori.
SETTING:The study was conducted with a clinical database that included seven Northwest Veterans Affairs medical centers.
PATIENTS:Patients included a cohort of 1031 male veterans, aged older than 40 yr, with low total testosterone [≤250 ng/dl (8.7 nmol/liter)] and no history of prostate cancer, assessed between January 2001 and December 2002 and followed up through the end of 2005.
MAIN OUTCOME MEASURE:Total mortality in testosterone-treated compared with untreated men was measured.
RESULTS:Testosterone treatment was initiated in 398 men (39%) during routine clinical care. The mortality in testosterone-treated men was 10.3% compared with 20.7% in untreated men (P<0.0001) with a mortality rate of 3.4 deaths per 100 person-years for testosterone-treated men and 5.7 deaths per 100 person-years in men not treated with testosterone. After multivariable adjustment including age, body mass index, testosterone level, medical morbidity, diabetes, and coronary heart disease, testosterone treatment was associated with decreased risk of death (hazard ratio 0.61; 95% confidence interval 0.42-0.88; P = 0.008). No significant effect modification was found by age, diabetes, or coronary heart disease.
CONCLUSIONS:In an observational cohort of men with low testosterone levels, testosterone treatment was associated with decreased mortality compared with no testosterone treatment. These results should be interpreted cautiously because residual confounding may still be a source of bias. Large, randomized clinical trials are needed to better characterize the health effects of testosterone treatment in older men with low testosterone levels.
Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Florida 33314
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