RESEARCH

The New England
Journal of Medicine

Abstract. Background. The declining activity of the growth hormone-insulin-like growth factor 1 (IGF-1) axis with advancing age may contribute to the decrease in lean body mass and the increase in mass of adipose tissue that occur with aging.

Methods. To test this hypothesis, we studied 21 healthy men from 61 to 81 years old who had plasma 1GF-1 concentrations of less than 350 U per liter during a six-month base-line period and a six-month treatment period that followed. During the treatment period, 12 men (group 1) received approximately 0.03 mg of biosynthetic human growth hormone per kilogram of body weight subcutaneously three times a week, and 9 men (group 2) received no treatment. Plasma 1GF-1 levels were measured monthly. At the end of each period, we measured lean body mass, the mass of adipose tissue, skin thickness (epidermis plus dermis), and bone density at nine skeletal sites.

Results. In group 1, the mean plasma 1GF-1 level rose into the youthful range of 500 to 1500 U per liter during treatment, whereas in group 2 it remained below 350 U per liter. The administration of human growth hormone for six months in group 1 was accompanied by an 8.8 percent increase in lean body mass, a 14.4 percent decrease in adipose-tissue mass, and a 1.6 percent increase in average lumbar vertebral bone density (Proximal femur. In group 2 there was no significant change in lean body mass, the mass of adipose tissue, skin thickness, or bone density during treatment.

Conclusions. Diminished secretion of growth hormone is responsible in part for the decrease of lean body mass, the expansion of adipose-tissue mass, and the thinning of the skin that occurs in old age. (New England Journal of Medicine, 1990; 323:1-6).

Medical Abstract:
Journal of Clinical Endocrinology & Metabolism

The long term effects of GH replacement in adult GH-deficient (GHD) patients have not yet been clarified. We studied 21 GHD adults who originally took part in a randomized, double blind, placebo-controlled trial of GH treatment in 1987. After completion of that trial, ten patients received continuous GH replacement for the subsequent ten years, whereas 11 did not. A group of 11 age-and sex-matched normal controls were also studied in 1987 and 1997. Lean body mass, as assessed by total body potassium measurement and computed tomography scanning of the dominant thigh, increased in the GH-treated group (P<0.01 for both) only (P<0.05 between groups for total body potassium). Low-density lipoprotein cholesterol decreased in the GH-treated group (P<0.05) only. Carotid intima media thickness was significantly greater (P<0.05) in the untreated group than in the GH-treated group. Assessment of psychological well-being, using the Nottingham Health Profile, revealed improvement in overall score, energy levels, and emotional reaction in the GH-treated group compared with those in the untreated group (P<0.02). In conclusion, GH treatment for ten years in GHD adults resulted in increased lean body and muscle mass, a less atherogenic lipid profile, reduced carotid intima media thickness, and improved psychological well-being.

Medical Abstract:
Journal of Clinical Endocrinology & Metabolism

The role of insulin-like growth factor 1 (IGF-1) in prostate development is currently under thorough investigation because it has been claimed that IGF-1 is a positive predictor of prostate cancer. To assess the effect of GH and IGF-1 levels on prostate pathophysiology, 46 acromegalic (30 in active disease, ten cured from acromegaly, and six affected from GH deficiency) and 30 aged-matched controls, free from previous or concomitant prostate disorders, underwent pituitary, androgen, and prostate hormonal assessments and transrectal ultrasonography. Compared to control values, GH (P<0.0001), IGF-1 (P<0.0001), and IGFBP-3 (P<0.001) levels were increased, whereas testosterone (P<0.0001) and dihydrotestosterone levels (P<0.0001) were reduced in active acromegalic patients. Hypogonadism was present in 28 of the 46 acromegalic patients (60.8%). The anteroposterior (P<0.05, and transverse (P<0.0001) prostate diameters and the transitional zone volume (P<0.05) were increase in acromegalic patients compared to those in controls. Prostate Volume (PV) was significantly higher in untreated acromegalic patients than in controls (41.7 + 3.2 vs. 21.9 + 1.4 mL; P<0.0001), cured patients (23.6 + 1.6 mL; P<0.0001), and GH-deficient patients (17.5 +1.1 mL; P<0.0001). In the patients, PV was correlated with disease duration (r=0.606; P<0.0001) and age (r=0.496; P<0.0001), whereas in controls it was correlated with age (r=0.476; P<0.01) and IGF-1 levels (r=-0.448; <0.05). Benign prostate hyperplasia (PV > 30mL) was found in 58% of the acromegalics and 26.6% of the controls. When grouped by age (<40, 40-60, and >60 yr), PV was increased in elderly patients compared to younger patients (P<0.05) and to controls (P<0.01). The prevalence of structural abnormalities, including calcifications, nodules, cysts, and vesicle inflammation, was significantly increased in patients compared to controls (78.2% vs. 23.3%; x2=5.856; P<0.05). No clinical, transrectal ultrasonography or cytological evidence of prostate cancer was detected in acromegalic or control subjects. In conclusion, chronic excess of GH and IGF-1 cause prostate overgrowth and further phenomena of rearrangement, but not prostate cancer.

Medical Abstract:
Insulin-Like Growth Factor-1 (IGF-1, Somatomedin C) Blood Levels are not Associated with Prostate Specific Antigen (PSA) Levels or Prostate Cancer:
A Study of 749 Patients

IGF-1, also known as somatomedin C, is a polypeptide hormone about the same size as insulin. It is produced in the liver in response to growth hormone (GH) release from the pituitary gland. Many of the growth promoting effects of GH are due to its ability to release IGF-1 from the liver, which in turn acts on several different tissues to enhance growth. IGF-1 belongs in the "superfamily" of substances known as "growth factors," along with epidermal, transforming, platelet derived, fibroblast, nerve, and ciliary neurotrophic growth factors. These agents have in common the ability to stimulate cell division, known as mitogenesis, and cell differentiation. Because IGF-1 is mitogenic to prostate epithelial cells, as well as other cell lines in tissue culture, its role , if any, in prostate cancer has been considered and raises the question as to whether high levels of circulating IGF-1 might increase the risk of prostate cancer. The best and most sensitive screening test available for prostate cancer is prostate specific antigen (PSA), a serine protease secreted by prostate epithelial cells.

The incidence of prostate cancer increases with age in men, whereas, blood levels of IGF-1 decline significantly with age, about 14% per decade after 30. It therefore seemed unlikely that IGF-1 would have any causative relationship with prostate cancer, however, it does raise the question as to whether supplementation with recombinant human GH (rhGH), as a deterrent to the aging process, might increase the risk.

The purpose of this study was to determine whether IGF-1 blood levels in men receiving rhGH supplementation had any relationship to blood PSA levels, as an indicator of prostate cancer. To accomplish this goal, PSA and IGF-1 levels were measured in 749 blood samples from men with ages ranging from 22 to 86 years old. Age, IGF-1, and PSA were matched in 544 individuals. Also, IGF-1 levels were measured in six patients with known prostate cancer prior to rhGH administration. [Laboratory data were generously supplied by Michael Bray and Jeff Budge from MedQuest Laboratories, Salt Lake City, UT.]

The mean age of all men was 55.1 + 0.5 year with a median of 55 and mode of 64. Mean PSA was 2.2 + 0.1ng/ml with median of 1.1, mode of 0.7, and range of <0 to 63.7. Trend line analysis demonstrated a clear increase in PSA levels with increasing age, as expected. Mean IGF-1 was 218.8 + 3.4ng/ml with a median of 211, mode of 183, and range of 20 to 498. There was no correlation between IGF-1 and PSA levels. IGF-1 levels were further broken down into quartiles and compared with PSA levels in each. This resulted in the following data:

The data were then grouped by normal (<4.1ng/ml) and abnormal (>4.0) ng/ml) PSA levels resulting in the data below:

Also, the mean IGF-1 level, before rhGH treatment, in six cases of known prostate cancer was 121.5 + 30.0ng/ml, which places this group in the lowest quartile of IGF-1 levels.