Andropause?

Everyone has heard of menopause, but is there a male equivalent? Two weeks ago at Personalized Primary Care Atlanta we discussed treatment of testosterone deficiency, or so called "andropause," in an evening health talk. PPC was happy to host Dr. Wayland Hsiao, Assistant Professor of Urology from Emory University as our discussant. Dr. Hsiao pointed out that declining testosterone levels are normal as men age and that while some men may be asymptomatic, others may suffer with symptoms that may negatively impact quality of life.

What are the symptoms of testosterone deficiency?  Loss of energy, decreased strength, reduced exercise capacity and erectile dysfunction are some. Testosterone deficiency may also contribute to metabolic syndrome, loss of lean muscle mass, and osteoporosis.  The ADAM questionnaire is a validated tool that can help identify symptomatic men.  Morley et al. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism. 2000;49(9):1239-1242.

Testosterone deficiency may be diagnosed on the basis of blood tests. Dr. Hsaio pointed out that saliva tests are not accurate.  Typically total testosterone and free testosterone levels are measured.  Free testosterone is the active version of the hormone.  If levels are low and men are deemed symptomatic treatment involves supplementation with testosterone, which is available in various delivery systems including transdermal gels, patches and pellets (implanted beneath the skin of the buttocks). Dr. Hsiao is of the opinion that injections of testosterone are not as well tolerated as the other delivery methods as they produce hormonal peaks and troughs that are associated with more adverse effects including flushes. 

Given the common nature of some of the described symptoms of testosterone deficiency it is not always clear who should be treated. One approach, for symptomatic men who have low or borderline testosterone levels, is a three month trial of treatment to see if symptoms improve.

What is the downside of testosterone replacement? One large clinical trial reported in the New England Journal of Medicine in 2010 demonstrated increased cardiovascular events in men who were randomized to treatment, and the trial was terminated early because of these adverse outcomes. However, Dr. Hsiao is skeptical that these risks translate to all men, and he noted that the population studied was primarily elderly, frail, and immobile.

Another concern with testosterone therapy is whether it has potential to promote prostate cancer growth in a man who may have subclinical prostate cancer or prostate cancer that has not yet been detected, and also whether it can cause enlargement of benign prostate tissue and contribute to worsening of urinary symptoms in men. Benign prostatic hypertrophy is another common condition that impacts quality of life in men as they age by causing reduced ability to urinate.  Dr. Xiao felt that evidence is lacking to suggest that either of these prostate conditions is affected much by testosterone therapy and sited data supporting this viewpoint.

It’s good to know that testosterone therapy exists as an option to help men with symptoms of andropause, which can adversely affect quality of life. However, those of us who have doctored through the era of the Women’s Health Initiative, which studied the effects of hormonal therapy for menopause, have to be somewhat cautious about prescribing treatment for a condition that affects a huge segment of the population. In the case of estrogen and progestin therapy in women, as discussed in a recent blog,  the pendulum has swung for, then against, and now recently partially back in favor of a cautionary approach to post-menopausal hormone replacement for symptom management during the time immediately following menopause in women.

To date testosterone therapy has been less well studied, and it could be years before the safety data for testosterone replacement in men is as good as the data for hormone replacement in women, which has been the subject of intense research in the previous decade.

Osteoporosis: What about Men?

Treating reduced bone density in women is a big business—from its detection with bone density screening (DXA), to its treatment with medications, such as the blockbuster bisphosphonates, to the medical care that the condition generates through referrals to specialists.  It seems curious to me that men have been neglected as the objects of this frenzy.  

It’s estimated that the lifetime risk of an osteoporotic fracture in women is 1 in 2, and in men that it’s 1 in 5. With our aging population, hip, femoral and vertebral fractures are a significant source of morbidity and mortality in the elderly.  I’ve written about treating bone loss in women: “Osteopenia: to treat or not to treat.”  A study published last year in the Annals of Internal Medicine demonstrated that although hip fractures are more common in women, they lead to higher mortality in men. In general, the onset of osteoporosis is ten year delayed in men compared with women.

Recently a middle-aged man consulted with me about osteoporosis.  Several years prior a gastroenterologist had been worried about my patient’s chronic use of omeprazole, a proton pump inhibitor. Proton pump inhibitors reduce acid secretion in the stomach. Their use has been linked to reduced absorption of calcium and possibly to an increased risk of osteoporotic fractures, though this is still controversial.  A bone density test was ordered and my patient’s bone density was found to be low, in fact, in the “osteoporosis” range (T score <-2.5).  My patient was sent to an endocrinologist and was determined to have no secondary risk factors for osteoporosis.  However, my patient was prescribed alendronate.  With no clear end in sight for treatment with this medication, he asked me whether I felt it was necessary to continue.

The fact is little is known about treating men’s bones--that is, the ones in their skeletons.  

A few trials have looked at DXA screening in men and found that T-scores, the measurement used to define bone loss (a “T-score” is the standard deviations from the mean for peak bone density), are as predictive of fracture risk in men as they are in women. However, the data is very limited. Bisphosphonate use has not been widely studied in male patients, particularly not in younger men with idiopathic osteoporosis.  A couple of trials have looked at alendronate use in men with secondary risk factors and found it to have efficacy in preventing fractures.  Best practice guidelines for treating osteoporosis in men were published in April 2011 by Gielen in BEST PRACTICE & RESEARCHCLINICAL ENDOCRINOLOGY & METABOLISM , which states:

 “With the ageing of the population, male osteoporosis is an increasingly important health problem:  from age 50 onward, one in three osteoporotic fractures occurs in men and fracture-related morbidity and mortality is higher than in women. In men with low BMD, 50% have an underlying cause, most often glucocorticoid excess, hypogonadism or alcohol abuse.  DXA is recommended in all men from 70 years of age on and in men age 50–70 with a prior fragility fracture or clinical risk factors.  Treatment decisions should be based on assessments of absolute fracture risk and not on  BMD alone.  Supplementation of calcium and vitamin D is essential in ageing men to prevent age-related secondary hyperparathyroidism.  Bisphosphonates and PTH seem to be as effective in men as in women and should be given to men with DXA-documented osteoporosis, a prior fragility fracture or high absolute fracture risk as assessed by FRAX.  Testosterone replacement can only be recommended in older men with osteoporosis who have symptoms of hypogonadism as well as total testosterone values below 250 ng/dL(9 nmol/l).”

Experts acknowledge that while bone mineral density testing may be useful, it is just one piece of the equation when it comes to assessing a person’s fracture risk. Clinical risk calculators take into account clinical risk factors and project a person’s ten year risk of suffering an osteoporotic fracture. The most widely known risk calculator is called FRAX,  a tool developed by the World Health Organization.  Clinical factors that contribute to fracture risk include age, body mass index, tobacco use, glucocorticoid use, alcohol use (>3 drinks per day), parental history of hip fracture, “secondary” causes of osteoporosis (low testosterone, hyperparathyroidism, hyperthyroidism and certain drugs),  and the presence of rheumatoid arthritis.

In their recently released Guidelines on the Treatment of Osteoporosis the USPSTF concludes that there is insufficient evidence to support screening men for osteoporosis. 

The case of my patient is a good example of how the well-intentioned use of testing may lead to information that we just don’t have good answers for yet.  In the absence of firm data, the question becomes, does one opt to treat with medication, for how long, and with what sort of monitoring? And if not, then what should one suggest?  Frankly, I find the relative lack of data about male osteoporosis surprising.