‘Anti-aging’ claims overlook scientific evidence on hormones

In the age of aggressive advertising, those seeking to slow the aging process appear to have a number of promising products at their fingertips, including various drugs and supplements designed to raise hormone levels that naturally decline with age. Growth hormone and testosterone, in particular, are often touted as ideal “anti-aging” drugs for men, but these assertions stand on shaky ground, according to endocrine experts.

One major issue is the imprecise definition of anti-aging, said George R. Merriam, MD, professor of medicine at the University of Washington in Seattle.

“There is a whole variety of symptoms, functional signs and body composition changes that accompany aging,” he told Endocrine Today. “Each one is kind of an endpoint on its own.”

Besides negative effects on muscle, bone and fat mass, alterations in immunological, cardiovascular, neurological and metabolic function occur as people age, according to Marc R. Blackman, MD, associate chief of staff for research and development at the VA Medical Center in Washington, D.C. Although research suggests that age-related declines in GH and testosterone may contribute to these health issues, he said, they are by no means solely responsible.

Further, Blackman, also professor of medicine at Georgetown University School of Medicine and George Washington University School of Medicine, said the scientific evidence is inconclusive, with little data showing that older people reap significant clinical benefits from GH or testosterone therapy. This, however, has not stopped patients from crowding physicians’ office and anti-aging clinics in hopes of finding the key to feeling younger and living longer.

“Many people in the mainstream medical and investigative community are concerned by the proliferation of these anti-aging clinics and programs and the ability of people to either visit these clinics or use the Internet to obtain these powerful hormones and inject themselves in the hopes of becoming more youthful,” Blackman said.

Even so, with a growing population of people aged at least 70 years, this remains an important area of research.

“These powerful hormones, GH and testosterone, are not yet proven to be effective and safe for slowing down the aging process, but the research activities, both nationally and globally, examining these possibilities are hopeful,” Blackman said. “It’s still a promising area of research, but it’s not yet ready for prime time.”

Inaccurate assumptions

The most popular candidates for anti-aging therapy include hormones that rise during puberty, remain elevated in young adult life and then decline with aging, including GH, testosterone and estrogen.

“As we get older, our insulin-like growth factor I levels decline, indicating a decrease in GH production, and then after age 40, testosterone drops by about 1% to 1.5% per year,” Ronald Tamler, MD, PhD, MBA,Endocrine Today Editorial Board member and clinical director of the Mount Sinai Diabetes Center in New York, said in an interview. “This is accompanied by a rise in sex hormone-binding globulin, so that, in the end, aging men have decreasing free testosterone. The question is, as we men get older and our hormone levels decline, can we stay younger and maybe live longer if we normalize these levels or if we bring them back to the levels of young men?”

Currently, Tamler said, the evidence only supports the use of GH and testosterone in patients who have true hormone deficiencies, such as hypogonadism, that are unrelated to age because these treatments have been studied extensively for these indications in which patients may experience real, considerable benefits that outweigh potential risks.

“We know that for all of those different hormones, that if you have a classical bona fide hormone deficiency, such as hypogonadism or a diagnosis of GH deficiency, there generally are net benefits to replacing those hormones until levels are up to whatever is appropriate for a person of that age,” Merriam said. “That, of course, has raised speculation: If it is so beneficial for GH-deficient subjects, wouldn’t it also do equally well for people with the milder form of relative GH deficiency that just comes with the territory with normal aging?”

Unfortunately, this logic is flawed, according to Merriam.

“You can’t necessarily assume that a drug, in this case GH or testosterone, that is good for one indication will be good for a somewhat different indication,” he said

A closer look at GH

Currently, in terms of GH, researchers have evaluated the effects of using recombinant GH, GH-releasing hormones (GHRHs) or GH secretagogues such as ghrelin to replace or augment GH and raise levels in healthy older people to levels that mimic those in healthy younger people.

“Essentially, [all of the trials] yielded similar results. Body composition was improved; amount of muscle was increased; amount of fat was decreased; and bone mass was increased. But, to date, despite vigorous attempts, there’s no convincing evidence that GH actually benefits people in terms of improving key outcomes. For instance, data do not show that it prevents diabetes or cardiovascular disease; that musculoskeletal frailty is improved; that people can walk or perform daily activities better; or that health-related quality of life is enhanced in older people,” Blackman said.

Moreover, treatment-related adverse effects were common in these trials. Although no long-term cancer risks were observed, hormonal issues such as peripheral edema and carpal tunnel syndrome often occurred in patients after administration of GH.

The hormone, however, may have other benefits, according to Merriam, with results from a study published in the Archives of Neurology in 2012 suggesting that GHRH may have a favorable effect on cognition in older adults.

In the randomized, double blind, placebo-controlled trial, Laura D. Baker, PhD, of the VA Puget Sound Health Care System in Seattle, Merriam and colleagues assigned 152 adults (mean age, 68 years) to self-administered daily subcutaneous injections of tesamorelin 1 mg (Egrifta, EMD Serono) or placebo 30 minutes before bedtime for 20 weeks. The intent-to-treat analysis revealed that the GHRH had a positive effect on cognition (P=.03) in adults with mild cognitive impairment (n=66) and healthy older adults (n=76). Other results also suggested a trend toward treatment-related benefit in verbal memory (P=.08) and favorable effects on executive function (P=.005) after GHRH.

Although encouraging, the researchers said there is a need for larger, long-term studies before drawing firm conclusions.

Consequently, despite small signals in the research, Merriam said, current data do not yet delineate a clear benefit of GH treatment in this population.

“At this point, there’s no real consensus, with most of the studies [on the effects of GH administration in older populations] being negative and some of them having suggestions of possible positive effects on physical functional performance and cognition. Nevertheless, all of these studies are relatively short in duration, and it’s not clear that you can reverse 20 to 30 years of decline in 6 months to 1 year of intervention,” Merriam said.

Trials on testosterone

Similar to studies on GH, trials examining testosterone in aging men and women have yielded mixed results. Although testosterone appears to result in positive changes on body composition, according to Blackman, it can come at a price for those who do not have a true testosterone deficiency.

“There are elegant studies to show that if you give enough testosterone to older men with these age-related declines, you can increase not only their amounts of muscle, for example, but also the strength and utility of their muscle as well,” he said. “The problem, however, is that the doses that were used in these studies are higher than those that would be considered prudent or safe in relation to other body systems.”

Additionally, Blackman said, testosterone supplementation failed to exert any other benefits when administered at doses deemed safe in research and clinical practice. Specifically, results suggested no clear effects of testosterone therapy to decrease musculoskeletal frailty, improve CV function or reduce in vasculopathic events in the heart or brain.

As with any true hormone deficiency, however, testosterone therapy may treat certain problems in adults with legitimately low hormone levels that occur with age, according to Mark E. Molitch, MD.

“If you’re testosterone deficient and taking normal amounts, it does bring you back to normal,” Molitch, who is the Martha Leland Sherwin professor of endocrinology at Northwestern University Feinberg School of Medicine, told Endocrine Today. “You do improve your strength, but it only restores it to normal; it’s not excessive. If you take a normal person and give them testosterone in normal amounts, it’s not going to do anything.”

Even when administered in conjunction with GH, testosterone only boosted body composition improvement, according to data from a paper published in JAMA in 2002. The study, conducted by Blackman and colleagues, assessed the effects of combined GH and sex steroids — testosterone in men and estradiol in women — in participants aged 65 to 88 years. Both results from their trial and subsequent studies revealed no improvements in muscle strength and function, quality of life or vasculopathic events.

Similarly, Blackman said the effects of testosterone supplementation also are being evaluated in women because they experience significant declines in ovarian production of testosterone, as well as adrenal production of precursor hormones that are ultimately converted to testosterone, as they age. So far, though, the results mirror those in men, but it remains an interesting area of investigation.

“So, at the doses of testosterone that are relevant to the whole body, the same general sense is out there. Mainly, it’s yet to be proven that testosterone supplementation in healthy aging men with healthy, age-related declines in testosterone are going to make a substantial improvement to retard the aging process, even if they improve body composition and some biochemical functions,” Blackman said.

Estrogen in the spotlight

For women, the endocrinology of aging is similar to that of men in that they experience the same gradual declines in GH and testosterone. Estrogen levels also decrease, but they drop more quickly and around the time of menopause. Unlike with men, however, much more is known about hormone therapy, particularly with estrogen, in this population.

Since the publication of results from the Women’s Health Initiative, the use of estrogen in menopausal women has been a point of contention. Although originally deemed safe and effective, the WHI cast light on some of the risks associated with estrogen. Despite the treatment’s ability to prevent fractures, data linking estrogen with an increased risk for CVD and breast cancer gave many physicians pause, and prescriptions for the drug decreased after the study’s publication in 2002.

Merriam noted that a trend toward individualized care has helped somewhat restore the balance. Although estrogen is still not considered uniformly beneficial for preventive purposes, the treatment has its place in physicians’ armamentarium.

“Looking at a woman’s particular genetic background, whether her family has a high incidence of breast cancer or CVD, is essential in determining if the benefits outweigh the risks. We need more nuanced and balanced care and fewer people herding at the door of anti-aging clinics where everyone comes out with a prescription for something that will make them stay young forever,” Merriam said.

Pinpointing the problem

The fact that studies suggest little clinical benefit raises the question of why so many people seek treatment with these hormones. Unfortunately, the appearance of anti-aging clinics, direct-to-consumer marketing and the natural desire of an ever-growing aging population to recapture their energy form the complex answer.

“The problem is that the so-called anti-aging movement approaches normal aging as if it were a disease rather than part of the continuum of the life cycle, as if aging could be stopped rather than slowed,” Blackman said.

These complications leave physicians who have their patients’ best interests in mind find themselves in a difficult position, according to Tamler.

“There’s a concern that anti-aging clinics may not follow published guidelines and recommendations that are based on our best clinical evidence and rather may use animal experiments or cell culture experiments as the basis for their decision-making,” he said. “Additionally, these clinics are often affiliated with compounding pharmacies and may prescribe drugs essentially to use patients as a revenue stream. So, they benefit by diagnosing patients with hormone deficiencies whereas physicians in a practice usually have an interest in finding out what the underlying cause is, if there is one, and fixing it.”

Moreover, Molitch explained that testing for testosterone and GH levels is variable, leaving physicians or those in anti-aging clinics with room for diagnosis.

“You can make a diagnosis of GH deficiency in a normal man if you use the wrong testing or you can game the system because the insurance companies will pay for GH treatment if you have low results on a GH stimulation test. But generally, they don’t specify the stimulation, so you can diagnose the person as GH deficient when in fact you just didn’t do the right test,” he said.

With no one investigating the root cause of someone’s health problems, however, patients are put at unnecessary risk and mistakes are made, Neil Goodman, MD, FACE, clinical professor of medicine at the University of Miami and chairman of the Reproductive Endocrine Committee for the American Association of Clinical Endocrinologists, told Endocrine Today. Many men actually may have low testosterone, for example, but it is often secondary to other health problems.

“Diabetes, hypertension, obesity and sleep apnea are just a few of the conditions that cause hypothalamic suppression of the gonadal axis,” he said. Simply addressing these problems on their own will allow testosterone levels to return to normal.

Additionally, common conditions can also be mistaken for testosterone deficiency, according to Tamler. For instance, many people associate erectile dysfunction with hypogonadism, but often, the dysfunction is vascular in origin. In other cases, patients complain about a loss of energy that is actually attributable to depression as opposed to low testosterone.

Although overlooking the condition that triggers the hormone deficiency is concerning, so is the unnecessary treatment itself, according to Goodman. Often, he said, patients placed on testosterone or GH by other physicians who are unfamiliar with guidelines and recommendations or by those at anti-aging clinics will feel worse as they withdraw from testosterone once the actual problem is identified because the treatment has interrupted their natural hormone production. They are also at increased risk for adverse events, including prostate cancer.

Nevertheless, physicians are fielding questions from patients seeking these treatments may be the trickiest part of treatment, according to Tamler.

“I represent the kind of interface between the anti-aging and serious aspects of endocrinology, so my biggest job is to prevent these patients from being disgruntled and going to an anti-aging clinic because I didn’t provide them with the medication they wanted,” he said. “I spend a lot of time speaking with patients and explaining that, yes, there are potential upsides, but there are potential downsides, and we must first determine if they need it.”

For the future

At first glance, this area of investigation appears bleak and complicated by direct-to-consumer marketing, but the studies to date actually show some promise and offer insight into the aging process, according to Blackman. Once some of the unanswered questions have been sufficiently explored, physicians will be armed with even more information to treat the rapidly growing geriatric population.

“The question is whether it’s possible to get the right paradigm of hormonal intervention in the right kinds of persons who are otherwise healthy and aging, or even not so healthy and aging, to be able to not only improve body composition but body function as well,” Blackman said. “Also, there has been, understandably, a heavy research focus on musculoskeletal issues, but there are some hints that these hormones can improve CV function, immune function and brain functions such as mood, affect and cognition. All of these things need to be explored as exhaustively as the musculoskeletal piece.”

Blackman identified other areas that require more attention as well. The use of these hormones in unhealthy older adults as opposed to healthy older adults, for instance, or their effects in those aged older than 85 years vs. those aged 65 to 84.9 years — the group that has been the primary focus of recent research — could provide valuable information. Alternatively, no studies have been conducted in younger patients, including those in their 40s and 50s.

Ongoing studies and planned trials are in the works, Blackman said, including a highly anticipated, National Institute on Aging-funded T-Study. This large-scale, placebo-controlled testosterone intervention study will examine the long-term effects of treatment in older men. Primary endpoints include musculoskeletal outcomes, but researchers will look closely at other benefits and risks in this population

“The most important point is that all the knowledge that’s been gained, both in this country and internationally, from the total body of research related to aging and hormones has informed the medical research and practicing community a lot about the aging process,” Blackman said. “That itself is good, and if at the end of the day, it’s shown that they may have beneficial effects, at least for targeted purposes, then that would be even better yet.”–by Melissa Foster

References:

Should an elderly man with symptoms and low testosterone be treated?

Yes

When a man who is 30 years old has a testosterone of 180 ng/dL and symptoms of hypogonadism, including problems with sexual function, low energy levels and decreased strength, we would definitely replace his testosterone and search for the root cause. In an older man who is in his 60s with the same symptoms and testosterone level, however, what is the risk-benefit ratio? Do we diagnose the man as being hypogonadal and treat him or do we just say that he’s getting older and this is what happens? Many older men have testosterone levels of 180 ng/dL or less.

I personally would prescribe testosterone for this particular patient. In my opinion, if the man is symptomatic in addition to having low testosterone, you are not just treating a number. I would treat him with testosterone for a trial period to see if his symptoms improve.

In terms of the risk-benefit ratio, my personal sense is that the risk for prostate cancer in someone with a normal digital rectal exam and PSA, which I would certainly perform before initiating treatment, is very small. We have been worried about the risk for cardiovascular disease, but the jury is still out on whether this is a significant concern. If you look back through the literature, though, there really is not much evidence that implicates bringing testosterone levels back to normal as a risk factor for CVD.

Essentially, I just believe there is more to be gained than to be lost from treating somebody who is truly hypogonadal and symptomatic, even if he’s elderly.

With caution, and only after the diagnosis has been made based on specific symptoms and unequivocally low serum testosterone levels (measured more than once).

The ongoing T-Trial, which is the largest, double blind, randomized, placebo-controlled study, is evaluating various outcomes, such as physical function, sexual function, vitality as well as anemia and cognition in older men. If the T-Trial shows some benefit in these parameters, that would make a strong case for treating these men.

The current literature suggests that the benefits of testosterone therapy in older men are modest. Although improvements in muscle mass and strength have been consistently demonstrated, only a few trials have shown improvement in physical function. Similarly, testosterone therapy improves bone mass, but there are no data that it reduces incidence of fractures. Also, improvement in sexual function has been modest compared with younger hypogonadal men.

Not only are the benefits modest, but the risks of testosterone therapy in older men remain uncertain. Erythrocytosis (polycythemia) is the most commonly encountered adverse effect. Importantly, there are potential cardiovascular and prostate risks that remain unclear. Therefore, until the T-Trial shows clear benefits, caution should be exercised.

Since studies have shown that older men who are healthy and fit maintain normal testosterone levels, promotion of healthy lifestyle and treatment of co-morbidities should be encouraged as it might attenuate testosterone decline with aging.