David R. Clemmons

THE insulin-like growth factors were discovered on the basis of their ability to stimulate cartilage sulfation and to replace the “sulfation factor activity” of GH, as determined using an in vivo assay, in an in vitro test system (1). The biological significance of this finding was quickly expanded beyond the study of cartilage sulfation to include stimulation of DNA synthesis (2), proteoglycan synthesis (3), glycosaminoglycan synthesis (4), and protein synthesis (5). Most of these studies used tissue preparations such as isolated diaphragm, cartilage, or epididymal fat pads to study biologicalactivity. In recognition of its generalized pleiotypic actions, in the early 1970's sulfation factor was renamed somatomedin (mediator of the effects of somatotropin) and was included in the emerging classification of broad spectrum growth factors along with platelet derived growth factor, fibroblast growth factor, and epidermal growth factor (6). During the period in which the biological actions of sulfation factor were being characterized, parallel studies were initiated that attempted to define factors in serum that could stimulate insulin-like effects. Because these factors were known to be distinct from immunoreactive insulin, their bioassay was based on insulin-like actions that could not be abolished by the simultaneous addition of anti-insulin antibody, and the factors were termed nonsuppressible insulin-like activity (NSILA) (7). Initial biological studies of both NSILA and somatomedin were based on the use of crude serum extracts. Early attempts to extract these factors from tissues were generally not successful, and by 1970 it had been concluded that no concentrated organ source for them existed (8). However, highly purified preparations of both factors were prepared from serum extracts.

OBJECTIVE: The aim was to update The Endocrine Society Clinical Practice Guideline on Evaluation and Treatment of Adult Growth Hormone Deficiency (GHD) previously published in 2006. CONSENSUS PROCESS: Consensus was guided by systematic reviews of evidence and discussions through a series of conference calls and e-mails. An initial draft was prepared by the Task Force, with the help of a medical writer, and reviewed and commented on by members of The Endocrine Society. A second draft was reviewed and approved by The Endocrine Society Council. At each stage of review, the Task Force received written comments and incorporated substantive changes. CONCLUSIONS: GHD can persist from childhood or be newly acquired. Confirmation through stimulation testing is usually required unless there is a proven genetic/structural lesion persistent from childhood. GH therapy offers benefits in body composition, exercise capacity, skeletal integrity, and quality of life measures and is most likely to benefit those patients who have more severe GHD. The risks associated with GH treatment are low. GH dosing regimens should be individualized. The final decision to treat adults with GHD requires thoughtful clinical judgment with a careful evaluation of the benefits and risks specific to the individual.

BACKGROUND: Patients with acromegaly are currently treated with surgery, radiation therapy, and drugs to reduce hypersecretion of growth hormone, but the treatments may be ineffective and have adverse effects. Pegvisomant is a genetically engineered growth hormone-receptor antagonist that blocks the action of growth hormone. METHODS: We conducted a 12-week, randomized, double-blind study of three daily doses of pegvisomant (10 mg, 15 mg, and 20 mg) and placebo, given subcutaneously, in 112 patients with acromegaly. RESULTS: The mean (+/-SD) serum concentration of insulin-like growth factor I (IGF-I) decreased from base line by 4.0+/-16.8 percent in the placebo group, 26.7+/-27.9 percent in the group that received 10 mg of pegvisomant per day, 50.1+/-26.7 percent in the group that received 15 mg of pegvisomant per day, and 62.5+/-21.3 percent in the group that received 20 mg of pegvisomant per day (P<0.001 for the comparison of each pegvisomant group with placebo), and the concentrations became normal in 10 percent, 54 percent, 81 percent, and 89 percent of patients, respectively (P<0.001 for each comparison with placebo). Among patients treated with 15 mg or 20 mg of pegvisomant per day, there were significant decreases in ring size, soft-tissue swelling, the degree of excessive perspiration, and fatigue. The score fortotal symptoms and signs of acromegaly decreased significantly in all groups receiving pegvisomant (P< or =0.05). The incidence of adverse effects was similar in all groups. CONCLUSIONS: On the basis of these preliminary results, treatment of patients who have acromegaly with a growth hormone-receptor antagonist results in a reduction in serum IGF-I concentrations and in clinical improvement.

"GH DEFICIENCY in the human adult most commonly results from pituitary or peripituitary tumors and their treatment (1). The majority of these tumors are benign, and in a large series, pituitary adenoma was the commonest cause of adult hypopituitarism (2). The incidence of adultonset (AO) GH deficiency is not known, but indirect estimates based on the incidence of pituitary tumors suggest an incidence of 10 people/million annually. In contrast, childhood- onset (CO)GHdeficiency is most commonly idiopathic and is not necessarily associated with other pituitary hormone deficiencies. The limited supplies of pituitary-derived GH restricted research into the use of GH in adults and limited knowledge of the role ofGHafter the cessation of linear growth. An early study, in which a 35-yr-old hypopituitary adult reported increased vigor, ambition, and well-being after GH replacement, suggested that GH may have biological actions in adulthood (3). More recent evidence suggests that adults with hypopituitarism have reduced life expectancy (2, 4), possibly related to GH deficiency (5). The availability of recombinant GH has led to intensive investigation of the effects ofGHin health and disease, and over the past decade, numerous studies have focused on the effects of GH replacement in the adult with GH deficiency. The first placebo-controlled trials ofGHreplacement in the GH-deficient adult were reported in 1989 (6, 7). These and subsequent investigations have led to the recognition of a specific clinical syndrome in adults with long standing GH deficiency. This syndrome is associated with characteristic symptoms, signs, and investigative findings. The main features are listed in Table 1. Many studies have assessed the effects of GH replacement on these symptoms and signs. The majority of these data has resulted from both formal randomized placebo-controlled trials and smaller open studies. Consistently, these studies have demonstrated that adults with GH deficiency are both physically and psychologically less healthy than their age-matched peers, and that GH replacement results in substantial and sustained benefits. This review details the important features resulting from GH deficiency and summarizes the information, available up to the beginning of 1997, relating to the effects of GH replacement."

OBJECTIVE: The Acromegaly Consensus Group reconvened in November 2007 to update guidelines for acromegaly management. PARTICIPANTS: The meeting participants comprised 68 pituitary specialists, including neurosurgeons and endocrinologists with extensive experience treating patients with acromegaly. EVIDENCE/CONSENSUS PROCESS: Goals of treatment and the appropriate imaging and biochemical and clinical monitoring of patients with acromegaly were enunciated, based on the available published evidence. CONCLUSIONS: The group developed a consensus on the approach to managing acromegaly including appropriate roles for neurosurgery, medical therapy, and radiation therapy in the management of these patients.