Rheumatoid arthritis (RA) is a disease characterized by chronic inflammation of the joints, especially in the hands and feet. It is an often-painful condition, which in advanced stages can be associated with significant damage and deformity to the bones and joints. Rheumatoid arthritis is classified as an autoimmune disorder, which involves the body’s immune system attacking and damaging it own tissues. Though it occurs in both sexes, the disease is predominantly found in women. Sex steroids have long been believed to play some role in RA, given the strong gender disparity, as well as the known influence sex steroids have on the immune system. A new study published in the journal Annals of the Rheumatic Diseases seems to strengthen this association.

Previous studies have found men with RA to have lower levels of testosterone than healthy controls. It has been unclear, however, if such hormonal deficiencies come about as a result of the disease, or precede its onset. In this paper, researchers at Lund University in Sweden addressed the question with the help of stored blood samples from a population-based health survey (1). The samples were cross-linked to national RA registers, and those of a matched set of controls. After controlling for smoking and body mass, the researchers found a significant association between low testosterone and the later onset of rheumatoid arthritis. This research suggests that testosterone may play a role in protecting men from the disease. Further research is needed into the link between hypogonadism (low testosterone) and RA.
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References:
(1) Association between testosterone levels and risk of future rheumatoid arthritis in men: a population-based case-control study. Pikwer M, Giwercman A. et al. Ann Rheum Dis. 2013 Apr 3. [Epub ahead of print]

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HRT-RX is a nationwide advocacy group that represents THOUSANDS of men that are suffering with low testosterone and eager to enter treatment. We need more doctors! If you are an HRT physician, or know of a progressive doctor in the U.S. that understands the needs of today’s active aging men, please contact us.

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Catherine Llewellyn
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Metabolic Syndrome

Metabolic syndrome comprises a group of pathologies including abdominal fat accumulation, insulin resistance, hypertension, and dyslipidaemia (reduced HDL, elevated LDL and triglycerides). This syndrome is considered a strong risk factor for diabetes and cardiovascular disease (CVD). Research over the last five years has established a strong link between metabolic syndrome and hypogonadism. The interplay between the two is often described as a vicious cycle. As the process goes, reduced testosterone levels support the accumulation of fat around the abdominal region. The increased abdominal adiposity contributes to a host of adverse metabolic changes including insulin resistance, increased androgen-to-estrogen metabolism, and elevated inflammatory markers. Serum testosterone is further suppressed by these changes, which only propagates the cycle.

While links between metabolic syndrome and hypogonadism had been established prior, the past year has produced the most compelling research concerning the use of testosterone therapy to treat this disorder. For example, one study examined the effects of androgen supplementation in 184 men with combined hypogonadism and metabolic syndrome[iii]. The men were given parenteral testosterone (1000 mg testosterone undecanoate at 0, 6, and 18 weeks) or placebo, and monitored for 30 weeks. Androgen supplementation significantly reduced body mass index (BMI), waist circumference, and serum glucose compared to placebo. Serum insulin and leptin levels were also reduced, as were the inflammatory markers IL-1 beta, TNF-alpha, and C-reactive protein. Testosterone replacement therapy had significantly improved several markers of metabolic syndrome.

A second study followed 50 patients with both metabolic syndrome and hypogonadism for 24 months[iv]. It compared the effects of testosterone undecanoate (1,000 mg every 12 weeks) to placebo for the first 12 months, followed by 12 months of testosterone therapy for all patients. An analysis of the data found that testosterone supplementation significantly improved waist circumference, visceral fat mass, and insulin resistance, all key components of metabolic syndrome. After two years, only 35% or 58% of patients retained a positive diagnosis for metabolic syndrome as defined by NCEP-ATPIII and IDF criteria, respectively. Under the controlled experimental conditions, testosterone therapy reversed metabolic syndrome in a high percentage of patients.

CVD and Mortality

The favorable effects of testosterone therapy on metabolic syndrome have strong implications for cardiovascular health. Maintaining normal youthful hormone levels can thus be an effective strategy to improving CVD risk. More than that, however, our very understanding of the relationship between testosterone, cardiovascular health, and mortality has been changing. It has long been known that men are more likely to suffer from sudden cardiac arrest than women are. For many years, this tendency was attributed to the atheroprotective effects of estrogen, or negative influence of androgens. New evidence, however, suggests that testosterone has a direct atheroprotective effect, independent of its aromatization to estrogen[v]. Furthermore, the data is pointing to hypogonadism as a fundamental contributor to cardiovascular disease in men[vi].

One recurring finding this past year has been a link between hypogonadism and mortality from cardiovascular event. For example, one study followed 1,954 men aged 20-79 years for 7.2 years. Hormone levels were recorded at baseline and at the time of death for 195 participants[vii]. After controlling for factors such as waist circumference, smoking, alcohol use, and physical activity, low serum testosterone levels (< 250 ng/dL) were associated with increased rate of mortality from cardiovascular disease and cancer. Another study examined 126 male patients admitted to the hospital for myocardial infarction[viii]. Free testosterone, C-reactive protein, NT-pro-BNP, and hemoglobin levels were measured at the time of admission. The 30-day mortality rate was later analyzed. All of the men that died (n=16) had a testosterone level below 300 ng/dL. A third study followed 930 patients with coronary disease for two years[ix]. Once again, low testosterone (bioavailable) was associated with a significantly increased rate of mortality.

Testosterone replacement therapy in adult hypogonadism is now well understood to have favorable effects on many cardiovascular disease risk factors. It has previously been shown to improve lipid profiles, lower certain inflammatory markers, reduce abdominal fat stores, and enhance insulin sensitivity and glycemic control[x]. Testosterone therapy has also been shown to exert positive effects in some patients with cardiac ischemia, angina, and even chronic heart failure. These most recent findings only serve to further solidify a relationship between testosterone and cardiovascular health. Furthermore, they are forcing medicine to look even more closely at the potential atheroprotective value of hormone replacement therapy in aging men.

Alzheimer’s Disease

This past couple of years has also seen a stronger association established between low testosterone levels and Alzheimer’s disease. One recent paper concerns a one-year cohort study of 153 ambulatory community-living men aged 55 years and over (the mean age was 72.7 years)[xi]. None of the men had been previously diagnosed with Alzheimer’s disease. Various serum markers were taken at baseline including total and bioavailable testosterone. At their one-year follow up, the cognitive health of all subjects was re-evaluated. Ten subjects (6.5%) had developed Alzheimer’s disease during this time. After adjusting for age, education, BMI, fasting glucose, and HDL-cholesterol, bioavailable testosterone was found to be a strong independent predictor for the later development of Alzheimer’s disease.

A second study, published the year earlier, examined brain sex steroid levels in post-mortem tissue samples of men and women diagnosed with Alzheimer’s disease[xii]. In men aged 60-79 years at the time of death, testosterone levels (but not estrogens) were lower in cases where mild neuropathological changes or advanced AD neuropathology were present. There was also an inverse relationship between testosterone levels and soluble beta-amyloid (Abeta), the major constituent of amyloid plaque in Alzheimer’s. These studies add to earlier works suggesting a link between sex steroids and this disease[xiii]. While not conclusive, the data is promising. More research is clearly needed to determine if hormone replacement therapy in aging men can reduce the risk of developing Alzheimer’s disease.

Looking Forward

The past couple of years have brought fourth many compelling studies on the hormone testosterone. As we further review the results of hormone replacement therapy, we are finding significant potential in not only traditional treatment areas such as the loss of muscle mass with aging (sarcopenia) and sexual dysfunction, but in fundamental areas of metabolic, cardiovascular, and cognitive health. Cardiovascular disease remains the most common cause of death, and Alzheimer’s a growing concern in a population that seems to be growing older. While treatment rates below 10% for testosterone deficiency as discouraging, they also suggest great potential for medicine to change the health landscape for men given the proper education and support.

Testosterone is an important hormone for maintaining the health of the cardiovascular system. This is an association we are now seeing continually in the medical literature. One of the most recent studies was published in the Asia Journal of Andrology, and examines the relationship between the testosterone level in men and their severity of coronary artery disease. The researchers looked at more than 800 individuals that underwent elective coronary angiography, which is a diagnostic test using special dyes and x-rays to image the arteries. It is often used to help detect blockages and plaque buildup., or access the severity of disease.

The men also had their testosterone levels measured, and were divided into three groups based on the result. The groups were then compared to each other with regard to their coronary angiography readings. The investigators found a strong (statistically significant) relationship between the level of testosterone and the severity of heart disease. However, the association was negative, meaning that men with the highest testosterone level (upper 1/3 of subjects) had better angiography readings. Likewise, the group with the lowest testosterone demonstrated the most advanced disease. While this study did not attempt to establish causality, it certainly does invite further investigation into the potential health benefits of testosterone and hormone replacement therapy.

Study referenced: Testosterone is negatively associated with the severity of coronary atherosclerosis in men. Li L, Guo CY et al. Asian J Androl. 2012 Oct 8.

Testosterone replacement therapy had no statistically significant effect on PSA levels or the likelihood of a positive cancer diagnosis in this study. The researchers here made an additional conclusion in this study, however. While hormone therapy did not influence the rate of cancer in these men, it did have a secondary benefit. By placing these men in the regular care of physicians, including periodic prostate examinations, detection of the disease was earlier than expected (mean 6.3 years). In all 14 cases, the cancers appeared to be localized and suitable for removal. The paper closes by suggesting that the monitoring that comes with male HRT may improve prostate cancer detection and treatment rates. This is worth considering whenever physicians and patients discuss the potential risks and benefits of HRT.

Source: J Sex Med 2012 Jun 6 [ePub]

Researchers at the Aretaieion Hospital in Athens Greece recently completed a study comparing the use of Femara (letrozole) and Arimidex (anastrozole) in men with low testosterone, which are two of the more potent and modern aromatase inhibitors. The study involved infertile men (n=29), all having testosterone concentrations below 300 ng/dL and a T/E ratio under 10. The men were divided into two groups, each given either 1 mg of anastrozole or 2.5 mg of letrozole per day. The medications were continued for six months. At the end of therapy, basic health markers were compared to baseline, including hormone levels and sperm density. The data is presented in the tables below.

The results in this study appeared to be promising for both drugs. Sperm density was improved in 73.4% of the men taking letrozole, and 78.6% for those using anastrozole. Testosterone was substantially improved for both groups as well. With men taking letrozole, testosterone increased from 275 ng/dL to 495 ng/dL on average, an 80% bump. With anastrozole, the average testosterone level went from 265 ng/dL to 513 ng/dL, or a 94% increase. Side effects were mild and transient, including GI upset, lethargy, headache, and liver enzyme elevations in a small number of patients. Both drugs were deemed “well tolerated”, and none of the participants were forced to discontinue treatment.

No comparative conclusions could be drawn in this study. Letrozole and anastrozole appeared equally effective at treating men with low testosterone, infertility, and low T/E ratio. There are still questions that need to be answered, especially when it comes to the long-term safety of this type of therapy. In particular, there are some concerns with a potential loss of bone mineral density, or elevations in serum cholesterol and cardiovascular disease risk. Still, the results here were promising, and add to a series of other positive studies with men taking AI drugs for low testosterone. The present researchers have furthered this discussion by recommending the use of T/E ratio as an additional diagnostic tool. A ratio below 10:1 would identify those hypogonadal men that might benefit from aromatase inhibitor therapy.

Source: Fertil Steril. 2012 May 11. [Epub ahead of print]

Clinical studies supporting a health-protective role of testosterone in aging men are growing in number. This latest study examines the relationship between the serum bioavailable testosterone level and calcification within the arteries. Calcification, or the placement of calcium deposits along the artery lining, is an indicator of atherosclerosis (hardening of the arteries). This change shows up easily during CT scan, which facilitates data collection. The men studied for this paper did not have any apparent history of cardiovascular or metabolic disease. Therefore, this group may better represent an average healthy male population, many of whom may not know they are developing atherosclerosis.

This study involved 291 non-obese male participants, with an average age of 52 years. Biomarkers measured included total testosterone, sex hormone-binding globulin, bioavailable testosterone, free testosterone, and coronary calcium score. After controlling for age, body mass index, smoking, alcohol consumption, exercise status, blood pressure, heart rate, C-reactive protein, fasting plasma glucose, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, hypertension medication, and hyperlipidemia medication(s), only a strong (inverse) relationship remained between bioavailable testosterone and the concentration of calcium within the arteries.

In this study, higher bioavailable testosterone was associated with less calcium deposited within the arteries, and thus a lower risk of developing atherosclerosis. More research is needed to determine the exact nature of any protective role bioavailable testosterone may have with regard to artery calcification, and further, how long-term testosterone replacement therapy (TRT) may improve the CVD risks of otherwise healthy aging men. At this point, however, it can be said that the positive data on testosterone and the aging male heart has been highly consistent. All clinicians that deal with male patients should be taking note of these studies.

Source: Inverse relationship between bioavailable testosterone and subclinical coronary artery calcification in non-obese Korean men. Park BJ, Shim JY, Lee YJ, Lee JH, Lee HR. Asian J Androl. 2012 Apr 23. doi: 10.1038/aja.2012.19.

The paper concerns the recent study of 1,031 male veterans over the age of 40. Each of the men began the study with testosterone levels below 250 ng/dL, regarded as the very low limit of the “normal” range for testosterone (they had clinical hypogonadism). Approximately 400 of the men were then given testosterone medications to correct the hypogonadism. The two groups (treated and untreated) were followed for at least 3 years, during which time health and mortality were assessed. The results were quite startling. Testosterone treatment cut the mortality rate in half (20.7% vs. 10.3%). After assessing other factors such as age, diabetes, and CVD status, only a strong association remained between testosterone treatment status and reduced death rate.

This study further underlines what we’ve been finding with short-term health markers, and long-term studies of hypogonadism; low testosterone appears to be a strong risk factor for increased mortality. In this case, which examined a substantial population of men; treatment had a remarkable influence over mortality. More research in this area is sorely needed. However, this positive trend seems to be gaining in strength. Common TRT drugs such as AndroGel, Testim, or Axiron may be much more important to men than for just treating physical (muscle, strength) or sexual (erectile dysfunction, low libido) issues. These medicines may turn out to be some of the most effective ways to protect our health when our levels of natural testosterone drop.

Source: J Clin Endocrinol Metab 2012 Apr 11. Testosterone Treatment and Mortality in Men with Low Testosterone Levels.

The potential health benefits of testosterone replacement therapy in men suffering from low testosterone levels are mounting in the medical literature. This latest study examined the potential effects of TRT after a heart attack, or myocardial infarction (1). During the investigation, castrated rats were subject to ligation of the left anterior descending coronary, which is used as a model for myocardial infarction. Some were then given doses of testosterone to replace normal physiological levels. The two groups (HRT treated and untreated) were followed for 4 weeks, and then compared to see how well each recovered from the myocardial infarction.

Rats that had untreated hypogonadism (low testosterone due to castration) noticed reduced capillary density, cardiac function that was more notably impaired, and a greater level of heart tissue damage 28 days post-infarction. When the hypogonadal rats were given testosterone, however, these negative cardiac effects were reversed. In this study, testosterone administration (replacement) promoted a greater level of angiogenesis (formation of new blood vessels). This pro-angiogenesis effect was also associated with an enhanced expression of HIF-1a (hypoxia-inducible factor 1a), SDF-1a (stromal cell-derived factor 1a) and VEGF (vascular endothelium growth factor). While more research is needed, this study suggests testosterone replacement may be beneficial for men following heart attack.

References:

(1) Eur J Pharmacol. 2012 Mar 30. [Epub ahead of print]

The article in question reviews a recent phase 3 clinical trial with 71 hypogonadal men. The study ran for 180 days, during which time they applied Axiron 2% testosterone gel daily. The tail end of the study (60 days) was specifically focused on evaluating the skin safety of the medication. The men did well with the testosterone, though skin irritation was reported in a moderate percentage of patients. The most common dermatological side effect was application-site irritation, with 12 men reporting. All cases were mild except one, classified as moderate. Ten patients reported transient erythema (skin redness). Again, all cases were mild except one. Water retention (3 cases), acne (2 cases), and inflammation of the hair follicles (1 case) were reported as well. Overall, Axiron was well tolerated, leading to mild transient side effects in a minority of patients, and rarely at a level warranting drug cessation.

References:
(1) Skin reactions in a phase 3 study of a testosterone topical solution applied to the axilla in hypogonadal men. Muram D, Melby T, Kingshill EA. Curr Med Res Opin. 2012 Mar 29. [Epub ahead of print]

Nebido (testosterone undecanoate injection) is a relatively new long-acting testosterone injection, which is already available in many other parts of the world. It is currently under investigation in the United States. On that subject, the results of a three-year study into the safety and effectiveness of this drug in middle-aged men was just published in the journal Aging Male (1). Sixty men (mean age of 57 years) were selected for the study, each suffering from late-onset hypogonadism (low testosterone), obesity, and metabolic syndrome. Forty of these men were given a recommend course of Nebido to correct the hormone deficiency, which involved four injections per year. The remaining twenty men were not candidates for testosterone treatment, and thus were used as controls.

At the start of the study, the men (in general) suffered from mild osteopenia. This refers to a reduced level of bone mass, though less severe than osteoporosis. After testosterone treatment, BMD significantly improved at a rate of approximately 5% per year. There was also a significant reduction in C-reactive protein (hs-CRP), a marker of inflammation. This should reflect a substantial improvement in symptoms or diagnosis of metabolic syndrome. No serious side effects were reported during the study, though the adherence to the testosterone injections over the three-year period was only about 50%.

Some patients in Europe have been complaining about uncomfortable injections with Nebido. For them, the 4 mL volume is perhaps a bit too much. Others find that their hormone levels are better stabilized with more frequent injections of drugs like testosterone cypionate or enanthate. These reports may underline an issue with patient compliance. Testosterone undecanoate was still well tolerated, and resulted in significant metabolic and physical improvements in the men that remained in treatment. Therefore, this study does continue to support the potential efficacy and safety of Nebido for testosterone replacement therapy. The future of this drug in the U.S., however, remains uncertain.

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References:

(1) Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study. Aversa A, Bruzziches R et al. Aging Male. 2012 Mar 23