Check Homocysteine Before Considering Testosterone?

Pauline Anderson

April 17, 2014

Older white men considering testosterone replacement therapy (TRT) should perhaps first have homocysteine levels checked to determine their oxidative stress status, new research suggests.

Investigators led by Rebecca L. Cunningham, PhD, assistant professor, Pharmacology and Neuroscience, North Texas Health Science Center, Fort Worth, report study results showing that although endogenous testosterone may be beneficial under conditions of low oxidative stress, it appears to have negative consequences for cognition when oxidative stress is elevated, although only among white men.

Dr. Rebecca L. Cunningham

Interestingly, they found that in older Mexican-American men, testosterone levels were not associated with any deleterious effects on cognitive function, regardless of oxidative stress status.

The results provide a strong argument that ethnicity and oxidative stress levels should be considered when prescribing TRT to older men, the researchers conclude.

"Our study shows oxidative stress determines how testosterone is going to behave," Dr. Cunningham told Medscape Medical News. "It's almost as if a perfect storm happens: If you have high oxidative stress, the testosterone is going to interact with it and you have a higher risk of dementia, but if you have low oxidative stress, testosterone is actually really good for you because it's increasing your antioxidants."

Their preliminary, in press results were published online in the Journal of Alzheimer's Disease.

Strong Argument

Testosterone therapy has been the focus of some scrutiny of late. In February, the US Endocrine Society called for a fuller assessment of the risks and benefits of testosterone treatment in older men with declining levels of the hormone, hard on the heels of the decision of the US Food and Drug Administration to evaluate the safety of testosterone therapy.

The 2 decisions came in the wake of studies that have raised concerns about testosterone therapy in older men with a history of cardiovascular disease. The most recent one showed that men treated with testosterone were significantly more likely to have a myocardial infarction in the first 90 days after starting the medication. The second study, of Veterans Affairs patients, published last year, also found that testosterone therapy in older men was linked with an increased risk for death, myocardial infarction, or ischemic stroke.

"Interestingly, TRT effects on the central nervous system have not been thoroughly examined; even though cognition is one of the purported benefits of TRT, and advanced age along with male gender are 2 of the clinical risk factors for many neurodegenerative disorders," the authors of the current study write.

In this new study, the researchers looked at the effects of endogenous testosterone on cognitive function to see whether any neuroprotective effect of testosterone may be related to levels of oxidative stress. A previous report by this group suggested that variability in previous findings on testosterone effects may be mediated by levels of oxidative stress.

Participants were a subset of the Texas Alzheimer's Research Care and Consortium (TARCC) cohort and included 116 white men (mean age, 74.5 years), 23.3% of whom had Alzheimer's disease (AD) and 19% of whom had mild cognitive impairment (MCI), and 117 Mexican-American men (mean age, 68.9 years), 8.5% of whom had AD and 22% of whom had MCI.

Researchers divided the men into 3 groups according to their testosterone level: hypogonadal (≤2.5 ng/mL), borderline (2.6 - 3.5 ng/mL), and normal (≥3.6 ng/mL).

They also divided them into those with low (≤12 μmol/L) and high (>12.1 μmol/L) levels of homocysteine. Homocysteine is an indicator of low folate and vitamin B-12 status and can be used as a marker for oxidative stress.

The researchers selected homocysteine to determine oxidative stress because it is a blood test clinicians are familiar with, said Dr. Cunningham. "We wanted to make it easy for them, instead of adding in a new test that they may not have had any experience with."

The investigators also categorized the men into normal (≤8 ng/mL) and high (≥8.1 ng/mL) levels of luteinizing hormone, a regulator of testosterone secretion, and measured 2 antioxidants: superoxide dismutase 1 and glutathione S-transferase alpha (GST).

As a measurement of cognitive functioning, researchers used scores on the Clinical Dementia Rating Sum of Boxes (CDRSUM), which tests dysfunction resulting from cognitive decline in 6 domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care.

Interesting Associations

"When we started separating the men according to their oxidative stress and their testosterone levels, we started seeing some interesting associations in cognitive measures," commented Dr. Cunningham.

The analysis revealed no deleterious effects of testosterone on CDRSUM in men with low oxidative stress. "With low oxidative stress, testosterone wasn't associated with cognition at all," said Dr. Cunningham.

The study also showed that in low oxidative stress, testosterone was positively associated with GST, and there were no deleterious effects of testosterone. However, with high oxidative stress, "we get something completely different" in white men — an association between testosterone and dementia — said Dr. Cunningham.

As testosterone levels rose from low to borderline to normal, so did worse dementia scores, increasing in a step-wise pattern, commented Dr. Cunningham. "It almost looked like a concentration response curve."

When oxidative stress reaches a certain level, testosterone seems to increase the damage oxidative stress causes to neurons, she said.

In contrast, the study did not find a relationship between testosterone and cognitive impairment in Mexican-American men with high oxidative stress. This lack of relationship could have been a result of their relatively abundant levels of the GST antioxidant, the authors note.

Another interesting finding was that oxidative stress increased with age in white but not Mexican-American men. This could also be related to their higher levels of antioxidants.

More Obesity

Dr. Cunningham noted that obesity was more prevalent in the study's Mexican-American population (43.6% vs 18.1%), but this population had similar rates of hyperlipidemia (64.1% vs 60.3%) and hypertension (65.8% vs 63.8%).

"Other studies show obesity is more of a metabolic syndrome, so maybe what's going on in Mexican-American men who have AD and MCI is that it's not oxidative stress that's underlying it, but a metabolic disorder," Dr. Cunningham said.

The researchers found elevated levels of luteinizing hormone in white men with MCI compared with cognitively intact men. This is consistent with past research suggesting that increased luteinizing hormone is an initial event in AD pathology.

The new results support measuring serum homocysteine levels to prescreen patients for whom testosterone replacement therapy may be indicated.

Dr. Cunningham pointed out that oxidative stress is a key component of neurodegenerative diseases such as AD and Parkinson's disease, as well as sleep apnea. However, having these conditions does not preclude a prescription for TRT. At this time, the only contraindications for TRT are breast and prostate cancer and heart, liver, and kidney disease, said Dr. Cunningham.

This is of concern, as testosterone clinics are "popping up" in major American cities, she said. There has been a 3-fold increase in TRT prescription sales for men older than 40 years during the last decade.

Men with a homocysteine level above 12.1 μmol/L should try to lower their oxidative stress, she said. Strategies could include a diet high in antioxidant-rich foods such as blueberries and nuts, as well as getting regular physical activity.

Complex Relationship

Invited to comment, Keith N. Fargo, PhD, director of scientific programs and outreach, Alzheimer's Association, said the study illustrates the complexity of the relationship between race or ethnicity and the risk for AD.

"This paper seems to support the idea that oxidative stress might be one factor here, but I don't know that you can say that it's the most important factor," said Dr. Fargo. "It's one piece of the puzzle."

So it might be too early to systematically check oxidative stress levels of every patient before getting a TRT prescription, added Dr. Fargo. All patients should follow the advice of their physician as to what therapies they should take, and this includes older patients who might have comorbid disorders such as heart disease and diabetes.

The Alzheimer's Association applauds any research that tries to "untangle the factors" related to the correlation between ethnicity and AD risk, he said, adding that he would like to see larger studies. "It would be nice to see longitudinal studies where groups are followed over time and measured for various factors that may be related to the risk."

Dr. Fargo noted that a group of experts convened by the Alzheimer's Association in 2010 determined that Hispanics have 1.5 times the risk of developing AD than non-Hispanic whites.

This study was supported by the TARCC, funded by the state of Texas through the Texas Council on Alzheimer's Disease and Related Disorders. Research reported in this publication was supported by the National Institute on Aging, Garvey Texas Foundation, University of North Texas Health Science Center Young Investigator Intramural Funding, and American Heart Association, and National Institutes of Health/National Institute on Aging awards. Dr. Cunningham has disclosed no relevant financial relationships.

J Alzheimers Dis. 2014; in press. Abstract

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