What Is the Role of “Growth Hormone” When You Have Stopped Growing?
Growth hormone clearly plays a key role in development during youth, but research in adults implicates it as an agent in cellular aging processes. Shlomo Melmed, MD, ChB, the first recipient of the Transatlantic Alliance Award, co-sponsored by the Endocrine Society and the European Society of Endocrinology, discusses the misconceptions of administering growth hormone in adults.
Children need growth hormone to grow into their adult height, but the hormone’s function among adults is unclear. The pituitary secretes less growth hormone as a person ages, but new research is elucidating a potentially important role for nonpituitary growth hormone generated in the periphery in regulating cellular proliferation associated with aging.
- Growth hormone levels decline with age — which may be a protective mechanism in slowing some of the effects of aging.
- Nonpituitary growth hormone in the colon epithelium has been shown to inhibit the tumor suppressor gene p53, resulting in pro-proliferative effects.
- Low levels of growth hormone in adulthood appear to be associated with greater longevity, whereas higher levels are associated with the adverse effects of aging.
Unraveling the effects of this mysterious hormone has been a focus of the work of Shlomo Melmed, MB ChB, dean of the faculty of medicine at Cedars-Sinai in Los Angeles. Melmed is the inaugural winner of the Transatlantic Alliance Award, an honor co-sponsored by the Endocrine Society and the European Society of Endocrinology to recognize an international leader who has made significant advancements in endocrine research on both sides of the Atlantic. As part of the award, Melmed gave a presentation at both ENDO 2022 in Atlanta in June, and at the European Congress of Endocrinology 2022 in Milan entitled, “Growth Hormone: An Adult Endocrine Misnomer?”
Dangers of Too Little or Too Much
The growth hormone level declines dramatically with age such that it is barely detectable in the circulation by age 80, but even at low levels it is clearly playing an important role. “Adults deficient in pituitary growth hormone have a unique phenotype,” Melmed says. “They develop central obesity and may have high blood pressure and lethargy. Growth hormone in adulthood is needed to maintain body homeostasis, i.e., the appropriate ratio between lean body mass and fat mass. When these GH-deficient adults [receive] very low doses of growth hormone, body changes are recalibrated and homeostatic changes that occur with hormone deficiency may be reversed.”
On the other hand, the deleterious effects of too much growth hormone from an over-secreting pituitary adenoma are well-known. “Patients with acromegaly have phenotypic features often associated with aging,” Melmed says. “They have heart disease, diabetes, hypertension, and osteoporosis, and may develop tumors. Many afflictions of aging are present, and the linkage of too much growth hormone with adverse effects on the aging process is clinically intuitive.”
Nonpituitary Growth Hormone
However, evidence is mounting that growth hormone that originates not from the pituitary but in the periphery could have significant effects. Melmed and others have been conducting cellular, animal, and human studies on the effects of autocrine and paracrine growth hormone.
“We found that growth hormone locally suppresses p53, thereby unleashing the cell to become more pro-proliferative. We performed a series of cellular and animal experiments to show that the molecular profile of aging may be accelerated by increasing growth hormone signaling, and if you block growth hormone action you may suppress deleterious aging effects on the cell cycle, including attenuation of DNA repair.”Shlomo Melmed, MB ChB, dean, faculty of medicine, Cedars-Sinai, Los Angeles, California
For example, the hormone appears to be produced by the epithelial cells of the colon and neighboring cells, where it acts locally to activate the growth hormone receptor, to engender cell cycle changes and DNA damage, and to promote pro-proliferative changes, Melmed says. One of its most important actions may be to inhibit the tumor suppressor gene p53, which is a powerful constraint on cell proliferation and tumor formation. “We found that growth hormone locally suppresses p53, thereby unleashing the cell to become more pro-proliferative,” Melmed says.
“We performed a series of cellular and animal experiments to show that the molecular profile of aging may be accelerated by increasing growth hormone signaling, and if you block growth hormone action you may suppress deleterious aging effects on the cell cycle, including attenuation of DNA repair,” Melmed says.
For example, their experiments showed that the drug pegvisomant, a growth hormone receptor inhibitor used to treat patients with acromegaly, can elevate p53 levels and enable a protective environment in the colon epithelium. “The role of growth hormone in regulating proliferation of colon cells could explain why patients with acromegaly have an abundance of colon polyps,” he tells Endocrine News.
Evidence from Families
Melmed says that other tantalizing clues implicating growth hormone in aging include the pioneering work of Endocrine Society Koch Awardee Anderzj Bartke, who showed that GH-deficient mice live longer. Furthermore, a Netherlands study of the relatives of centenarians found that these long-lived individuals and their family members have very low growth hormone levels.
There have also been studies of several families around the world who have inactivating growth hormone receptor mutations with short stature and an extremely low incidence of cancer. “We re-introduced a normal growth hormone receptor into the mutated fibroblasts, and down-regulated their high p53 expression, another proof of principle in humans that local growth hormone may enable a pro-proliferative micro-environment,” Melmed says.
“We propose, based upon the body of cellular, animal, and human data that have been generated by other colleagues and ourselves, that blocking growth hormone action may protect from adverse cellular effects of aging. We have no evidence that aging could be reversed, but blocking growth hormone signaling could mitigate pro-proliferative cell cycle events and DNA damage associated with aging,” Melmed says.
“Adults deficient in pituitary growth hormone have a unique phenotype. They develop central obesity and may have high blood pressure and lethargy. Growth hormone in adulthood is needed to maintain body homeostasis, i.e., the appropriate ratio between lean body mass and fat mass. When these GH-deficient adults [receive] very low doses of growth hormone, body changes are recalibrated and homeostatic changes that occur with hormone deficiency may be reversed.”
He notes that these findings have an immediate practical application as a counter to the large illicit market in which people, especially athletes, are taking growth hormone as a performance-enhancing drug “in an attempt to enhance athletic performance or to improve their longevity” when the evidence indicates that “the opposite is true, and growth hormone may in fact be harmful.”
Seaborg is a freelance writer based in Charlottesville, Va. He wrote about the Endocrine Society’s latest Clinical Practice Guideline, “Management of Hyperglycemia in Hospitalized Adult Patients in Non-Critical Care Settings: An Endocrine Society Guideline,” in the July issue.