The Role of the Growth Hormone in the Three Act Play of Life

The growth hormone (GH) is well named. Let's say you are 65 years old — on stage in the third and final act of life. You have a nephew named Jack. Jack is 13 years old, so he is still in Act I: The Age of Growth. You see Jack once a year, at the family reunion and, wow, what a change since last year. He is five inches taller and he beats you at arm wrestling for the first time. Only, the reason for his victory may not be entirely due to his increasing strength. It's true that his GH levels may have increased as much as ten times. Meanwhile, however, yours have taken a dive, dragging with them an increasing tendency toward broken hips, withering muscles and a widening girth.

But what is really going on beneath your thinning, wrinkling skin? Are your hormones decreasing because you are aging or are you aging because your hormones are decreasing? Answering this question is a major area of interest for Mayo endocrinologist and researcher, Johannes Veldhuis, M.D. A faculty member of the Robert and Arlene Kogod Program on Aging, Dr. Veldhuis hopes his research will lead to new opportunities for novel therapies that counter the pathological effects of aging.

Bathtub dynamics

Dr. Veldhuis's group has earned an international reputation for their ability to extract greater understanding from complex data. Dr. Veldhuis explains the complexity of the problem with a bathtub analogy.

"If pituitary hormones were released like water from a faucet into a bathtub, there'd be a constant slow filling of the tub in proportion to its size and whether or not the drain was open — you could solve that with high school physics," explains Dr. Veldhuis. "One of the complexities is that the pituitary squirts out a pulse of hormones at random times."

Back to the problem. Imagine it's your unpredictable nephew, Jack, controlling the faucet. He turns it on and off at a whim, by full force or a trickle, for however long the mood strikes him, and with the drain always open.

"It's a daunting problem," says Dr. Veldhuis. "All we know is the level of water in the bathtub (GH blood levels) checked at 10 minute intervals. From that, we are trying to find out: when the person turned on the faucet, how long it stayed on, how much came out, how often it came on, and how much drained away — and the latter's an additional complication because it varies with each individual we are studying."

Clinical Research Data + Math = New Knowledge

With the help of two study coordinators and the expert team of clinical research specialists in Mayo's Center for Translational Science Activities (CTSA), Dr. Veldhuis measures GH, sequentially, over time and, in the same blood samples, the body's chemical response to it. He also co-directs the Hormone Secretion, Modeling and Assay Core Research Laboratory, where a state-of-the-art robot facilitates endocrine research by running up to 500 samples per hour. The clinical data is then applied to mathematical models that can peer into the human body without needles, radioactive materials or foreign substances.

When Dr. Veldhuis came to Mayo from the University of Virginia, in 2002, he retained his long-time collaboration with UVA statistical probablist, Daniel Keenen, Ph.D., with whom he has several joint National Institutes of Health (NIH) research grants. The team has earned international acclaim for being able to show the random generation of pituitary pulses mathematically.

Two Decades of Studies: It's Not the Drain

In a 20-year collection of studies of different hormones, Dr. Veldhuis's group has reached one important conclusion — it's not the drain. Modeling hormone clearance and elimination patterns is an extremely complex undertaking because such issues as how the hormones are transported and diffused throughout the bloodstream and tissues, and how they bind to carrier proteins and plasma membrane receptors must be considered.

Many of their studies were published in the high profile journal, Proceedings of the National Academy of Sciences and have been copiously cited. Their models allowed them to calculate total daily secretion, daily hypothalamus and pituitary secretion and to estimate the fast and slow half-lives of elimination. Many scientists have since used their models to apply to their own data.

"We blocked the healthy volunteer's ability to make his own hormones with a drug, then injected the recombinant hormone (genetically manufactured) and measured how quickly it was removed," says Dr. Veldhuis. "In older people, when GH enters the blood, it just vanishes. So we know that the removal is not greatly affected ."

Each gush of hormone is generated by a signal from the hypothalamus; identifying them gives Dr. Veldhuis a window into the clock of the brain. He can then observe how it is affected by aging, or other conditions such as head injuries that have disturbed the hypothalamus or the pituitary.

Sex Hormones: Directors of the Pituitary Orchestra

Dr. Veldhuis's studies have led him to conclude that part of the reason that GH levels crash in aging is the waning of sex steroids. There are two main classes of sex steroids, also called sex hormones. They are androgens and estrogens but their study is complicated by the interaction of their many different types.

"It is easier to understand if you think about the sex steroids as the director, the pituitary as the orchestra and the amount of hormone as the sound," muses Dr. Veldhuis, making use of a second analogy. "It turns out, in healthy people, the director charges up the orchestra briefly, 18-20 times per day at intervals that vary from 30 minutes to as much as three hours — it's as if Jack is on amphetamines. No one knows when he will charge the orchestra to play, which sound will come next, or how loud it will be."

Researchers know that the sex steroids decline with age in both men and women. The question is, what is the relationship between these lower testosterone and estrogen levels and the GH crash? Dr. Veldhuis is fascinated by his task of furthering the understanding of how the sex steroids control "this wonderful communication between the brain and the pituitary."

It's Not the Timing

Using mathematical models, Dr. Veldhuis's team has shown that the timing of the bursts does not deteriorate with age.

"We know that the number of times the director leaps up to conduct the orchestra does not change with age," says Dr. Veldhuis. "However, the sound that they produce does decrease, meaning that the key factor is the amount of hormone that is released . The shape of the burst and how long they last often changes with age too , and the sex steroids control several of these points along the pathway."

A Combination of Factors

Still, the question of whether the culprit was age itself, the falling of sex steroids, or a combination of the two factors, remained. To get to the bottom of this question, Dr. Veldhuis conducted clinical studies on young and post-menopausal women.

First, he injected drugs that shut down their reproductive cycles for a period of six weeks to put their sex steroid concentrations at a level playing field — the lower levels of a post-menopausal woman. The result? The post-menopausal group produced only 40% of the GH produced by the younger women. Age must be the culprit because it was the only difference between the two groups.

To confirm his conclusion, Dr. Veldhuis conducted subsequent studies in which he repeated the first step, then replaced the sex steroids to the higher level of the younger women. The results were similar.

"We concluded that 50-60% of the problem is related to some factor associated with aging beyond that of the steroid deficiency," says Dr. Veldhuis. "We currently have fifteen active studies testing very specific aspects of sex steroid differences."

The Incremental Steps of Science

Dr. Veldhuis continues to be humbled by the problems faced by his patients. He is always on the lookout for questions that his research might help to answer. And he understands his role as part of a team that not only includes other scientists at Mayo and those based at other U.S. and international medical centers, but those on whose work his own is built, and those who will come after him.

"Science is about making incremental advances in knowledge," says Dr. Veldhuis. "My view is that excellent work by other scientists, no matter where they are, will bring issues in my work to light that I missed, and make it more interesting and better science. Mayo has a way of instilling excellence in teamwork — and excellence is its own reward."

Dr. Veldhuis's peers understand the excellence of his work. In 2006, they honored his distinguished body of work by awarding him a Mayo Lifetime Research Award.