New hypogonadism tests aim to fill Androgen Deficiency in the Aging Male questionnaire deficiencies

By: Louise Gagnon

Toronto, 02 feb 2009—Researchers are developing promising new tools to improve the diagnosis of hypogonadism.

An established method of screening for hypogonadism is the Androgen Deficiency in the Aging Male (ADAM) questionnaire. The questionnaire, first devised in 2000, consists of 10 questions that require "yes" or "no" responses. However, in many cases, ADAM has proved inadequate for capturing the population of men with hypogonadism, and researchers are vying to find an evaluation instrument that more accurately identifies these men, allowing early treatment.

"Although the questionnaire has good sensitivity, up to 88%, the specificity can be as low as 60%," Mohit Khera, MD, MBA, MPH, assistant professor of urology at the Baylor College of Medicine in Houston, told Urology Times. "With the ADAM questionnaire, it is difficult to quantitatively assess any improvement in hypogonadal symptoms when patients are started on testosterone therapy."

Consequently, Dr. Khera and colleagues have proposed a means of quantifying the ADAM questionnaire by assigning a grade to each of the questions contained in it. The responses are graded on a Likert scale from one to five, and the questionnaire has been referred to as the quantitative ADAM or qADAM.

In research by Dr. Khera's team, presented at the Sexual Medicine Society of North America Fall Scientific Meeting, Baylor patients who were scheduled to have a radical prostatectomy were administered the qADAM, the Sexual Health Inventory for Men (SHIM), and Expanded Prostate Cancer Index Composite (EPIC). In addition, patients also had their serum testosterone drawn.

In total, 58 patients completed the qADAM questionnaire. Of those, testosterone values were available for 34 patients. Investigators found 11 patients were hypogonadal, with testosterone levels measuring less than 300 ng/dL.

Researchers found that the qADAM questionnaire significantly correlated with serum testosterone measurements (r=.34, p=.023). It also correlated with SHIM questionnaire responses (r=.44, p=.005). Moreover, qADAM significantly correlated with patient responses within the sexual and hormonal domains of the EPIC questionnaire (r=.57, p≤.0001) and (r=.32, p=.008), respectively.

"The higher your qADAM score, the more likely you were to have better erections and the less likely you were to be hypogonadal," Dr. Khera said.

A limitation of the research is that an insufficient number of patients were available to validate the questionnaire, particularly since testosterone values were available for only 34 patients, Dr. Khera admitted.

Screening tool in development

Another new tool, a brief screening test for detecting hypogonadism, is being developed by scientists at the New England Research Institutes in Watertown, MA, including Andre Araujo, PhD, and Raymond Rosen, PhD.

"Current screening tests are not specific enough," said Dr. Araujo, director of epidemiology. "There is an unacceptably high rate of false positives. Men frequently test positive on the current screening tests when many of them have clinical depression, a sleep disorder, or chronic fatigue.

Increasingly, data are emerging linking low testosterone to comorbidities such as diabetes, metabolic syndrome, and cardiovascular illness, suggesting that the presence of low testosterone is not just a question of diminished quality of life, said Dr. Araujo.

In developing a new screening tool based on current FDA guidelines, Dr. Araujo's team has conducted extensive qualitative interviews with a group of carefully selected hypogonadal patients and age-matched controls. These interviews form the basis on which questionnaire items are developed and subsequently validated in a prospective, multicenter study. Results were presented at the SMSNA meeting.

Based on the results of the qualitative interviews and expert advice from a panel of urologists, endocrinologists, and primary care physicians, a draft of a screening instrument has been developed. It includes multiple questions in several domains of patient function, including physical health, bodily appearance, emotional experiences, sexual function, and cognitive function.

The draft questionnaire is expected to be completed in mid-2009. It will be available for use in clinical and research settings later in 2009.

ENDO: Low Testosterone May Be All-Cause Mortality Marker

SAN DIEGO, June 5 -- Men older than 50 with androgen deficiency are at a greater risk for all-cause mortality than their peers with age-appropriate testosterone, reported investigators here.
Among nearly 800 men followed for an average of 18 years, those in the lowest third of endogenous testosterone levels had a 33% greater risk for death from any cause than men in the highest third, reported Elizabeth Barrett-Connor, M.D., of the University of California at San Diego, and colleagues.
The difference in mortality risk between in the lowest and highest tertiles of testosterone could not be explained by smoking, drinking, physical activity level, diabetes, or cardiovascular disease, the investigators said at the Endocrine Society meeting.
But the association between androgen levels and death was attenuated when the investigators controlled for metabolic syndrome, and was eliminated when they also controlled for inflammatory cytokines, the authors reported.
"The study is only the second report linking deficiency of this sex hormone with increased death from all causes, over time, and the first to do so in relatively healthy men who are living in the community," said co-author Gail Laughlin, Ph.D., also of UCSD.
The data emerged from a substudy on endogenous testosterone of men enrolled in the Rancho Bernardo Heart and Chronic Disease Study, a longitudinal follow-up study now in its 35th year.
The investigators looked at 794 men from the ages of 50 to 91 years who had had serum testosterone measured at baseline (from 1984 to 1987). The men were followed through July 2004 or until their deaths. The authors defined androgen deficiency as lower than 250 ng/dL, generally agreed to be the lower limit of normal.
They found that among the 143 men in the cohort who met the definition of metabolic syndrome (waist circumference greater than 40 inches, low HDL, high triglycerides, hypertension, hyperglycemia), testosterone levels were 22% lower than that of others in the cohort (P<0.001). In addition, in men with the metabolic syndrome, the lower the testosterone levels the higher the levels of the inflammatory markers plasma interleukin-6 (IL-6) and high-sensitivity C-reactive protein (CRP ) (P for both <0.01).
There were 538 deaths during an average 18 years of follow-up. In unadjusted data and in an analysis adjusting for age, body mass index, and waist girth there were no differences in baseline testoserone levels (geometric means: 300 ng/dL versus. 298 ng/dl, respectively, P=0.84).
But when the authors conducted Cox regression analyses using testosterone tertiles, they noticed a low threshold effect of testosterone on mortality. Specifically, in an analysis adjusted for age, BMI, waist girth, and lifestyle choices, the 229 men with levels below 250 ng/dL had an odds ratio for death of 1.33 (95% confidence interval, 1.10 to 1.62) compared with men in with higher testosterone levels.
"This association was independent of diabetes and prevalent cardiovascular disease, but was attenuated by adjustment for the metabolic syndrome, and eliminated by further adjustment for IL-6 and high-sensitivity CRP levels," the authors reported.
When they further adjusted for serum creatinine or weight loss as markers of overall health status, the results did not change, and the addition of either total or bioavailable levels of estradiol had only minimal effects on results.
In multivariate logistic regression models that included age, BMI, lifestyle characteristics, the metabolic syndrome, and IL-6 and CRP levels, only the metabolic syndrome were associated with odds of low testosterone. Men with the metabolic syndrome had a three-fold risk for lower testosterone (odds ratio 3.05, 95% CI 1.88 to 4.95) and men who had one or more drinks per day compared with less or none had a nearly two-fold risk for low testosterone (odds ratio 1.95, 95% CI 1.32, to 2.86).
The authors cautioned that the results do not suggest a protective effect of exogenous testosterone on mortality risk.
"We are very excited about these findings, which have important implications, but we are not ready to say that men should go out and get testosterone to prolong their lives," said Dr. Barrett-Connor. "We're not ready to take this to the prescribing pharmacist."
"Conventional wisdom is that women live longer because estrogen is good and testosterone is bad. We don't know. Maybe the decline in testosterone is healthy and comes with older age. Maybe the decline is bad and is associated with chronic diseases of aging."