Clinical Presentation and Diagnosis: Growth Hormone Deficiency in Adults

Published Online: October 01, 2004
Gary Owens, MD; Donald Balfour, MD, FACP; Beverly MK Biller, MD; Jay Cohen, MD, FACE; Michael Jacobs, RPh; Michael Lease, MS, PharmD, FASCP; Rajendra Ratnesar, MD; Kenneth L. Schaecher, MD; and David E. Wilcox, MD, FACEP

In the United States, growth hormone deficiency (GHD) affects 50 000 adults, with 6000 new cases yearly.1 Patients with GHD have decreased or absent growth hormone (GH) production as a result of hypothalamic or pituitary disorders resulting in underactive pituitary gland function (ie, hypopituitarism). GHD is distinct from somatopause, a term that describes the gradual decline in GH production through normal adulthood. Adults with hypopituitarism routinely receive replacement cortisol, thyroid hormone, and gonadal hormone replacement therapy. Until the past decade, GH replacement therapy had been primarily reserved for pediatric use. GHD in adults, however, represents a serious clinical disorder, which is distinct from pediatric GHD and can be treated with recombinant human GH replacement therapy.

GH is produced in the pituitary gland, which is located at the base of the brain behind the sphenoid sinus in a small bony cavity called the sella turcica (Figure 1). The pituitary gland secretes hormones from 2 distinct lobes, each derived from different embryonic tissue (Figure 2). These hormones affect numerous body systems.



The posterior lobe of the pituitary gland, an extension of the hypothalamus, secretes 2 hormones: arginine vasopressin (also called antidiuretic hormone), which stimulates the kidney to reduce urine output, and oxytocin, which causes uterine contractions. The anterior lobe secretes 6 hormones: luteinizing hormone, which stimulates the secretion of sex steroids from the gonads; follicle-stimulating hormone, which stimulates ovulation and sperm production; prolactin (PRL), which targets the mammary glands to stimulate milk production; adrenocorticotropic hormone, which targets the adrenal cortex to cause glucocorticosteroid production; thyrotropin influences the production of thyroid hormones; thyroid stimulating hormone (TSH) targets the thyroid; and, finally, GH (also called somatotropin), which targets many tissues to promote growth and control protein, lipid, and carbohydrate metabolism. Of all the anterior pituitary hormones, only GH and PRL act independently and not through a target endocrine gland. The effects of an excess or deficiency in hormone production are listed in Table 1. The typical managed care organization formulary includes drug therapies for all of the hormone deficiency states, and for several of the hormone excess states.


The pituitary is the master gland, but it is also controlled by hormones originating in the hypothalamus, an area of the brain just above the pituitary. Anatomically linked to the pituitary through a funnel-shaped structure called the infundibulum, the hypothalamus controls pituitary function by secretion of releasing and inhibiting factors. GH release is stimulated by GH-releasing hormone (GHRH) and inhibited by somatostatin. During a 24-hour period, pulses of GHRH and somatostatin stimulate or inhibit the pituitary to release GH in discrete bursts, with a distinct diurnal phase resulting in most of the 24-hour GH secretion during sleep. Most healthy individuals, therefore, have little measurable GH secreted during much of the daylight hours. Measurement of a single blood sample for GH is therefore not helpful in making the diagnosis of GH excess or deficiency. When GH deficiency is considered, stimulation testing (sometimes termed "provocative testing" or "dynamic hormone testing") is usually performed. When GH enters the circulatory system it attaches to GH receptors in virtually all body tissue to produce and stimulate local insulin-like growth factor 1 (IGF-1) production. At the tissue level, many of the effects of GH are mediated by IGF-1. In addition, regulation of GH production by the pituitary is controlled by negative feedback from IGF-1.

The level of GH production normally varies among individuals and groups of individuals. For example, premenopausal women produce more GH, and, as people age, production of GH gradually declines. Further, the extent of excessive visceral fat is negatively correlated with GH production, whereas exercise appears to be positively correlated.2 There are many different etiologies for GHD in adults. Table 2 describes the causes of pituitary or hypothalamic damage that results in a decrease in GH secretion. The majority of patients with pituitary hormone abnormalities present initially with a pituitary tumor or other sellar lesions. Pituitary tumors may secrete an excess of 1 pituitary hormone or be clinically nonfunctioning, producing clinical problems by mass effect, such as headaches or visual field abnormalities accused by compression of the optic chiasm. Pituitary hormone deficiencies may be secondary to compression of the normal gland by a cyst or tumor, or from treatment of the tumor, which may include surgery and radiation. Hypopituitarism may also result from other causes, such as head trauma, infiltrative hypothalamic disorders, or infection. In addition, for some children with GHD, the disorder persists in adulthood.


In adults, GHD can produce metabolic disturbances that may compromise the patient's health and quality of life and increase cardiovascular (CV) risk. The most salient features of GHD in adults include decreased lean body mass, increased visceral fat and subcutaneous fat, decreased bone mass, and hyperlipidemia.2 GHD has been linked to a higher risk of bone fractures, an increase in carotid artery intimal thickness, and elevations in certain markers of CV risk, among them Creactive protein and homocysteine. It has been shown that the degree of elevation in lipid level3 and the severity of bone mineral loss correlate with the severity of GHD.4 Epidemiologic studies have clearly shown that adults with hypopituitarism, including GHD, display an increased risk for CV and cerebrovascular disease and premature mortality (Figure 3).5,6


In the transitional patient, GHD can induce deleterious metabolic events similar to those in adults. A 2-year, placebo-controlled trial examined 64 young adults (mean age, 23 years) who had pediatric GHD, current GH levels of less than 5 μg/L, and were not taking GH for an average of 5.6 years.7 At baseline, 22% of these patients demonstrated evidence of below average bone mineral density, 59% were overweight or obese, and 45% had total cholesterol levels of more than 200 mg/dL.

For the clinician, diagnosing GHD can be a daunting process. Because GH is secreted in a diurnal pulsatile manner and has a short half-life of only 19 minutes, it is frequently undetectable in blood samples without provocative testing. Numerous pharmacologic agents can be used to assess GH production and secretion by the pituitary in adults (Table 3). These include insulin, arginine, levodopa (L-dopa), arginine plus L-dopa, arginine plus GHRH, and the glucagon test. None display perfect sensitivity and specificity; however, the insulin tolerance test (ITT) and arginine-GHRH are excellent tests. A cut point of <5 μg/L has been suggested to optimize sensitivity of detection of GHD without sacrificing too much specificity.2 The choice of diagnostic test by the endocrinologist depends on many factors and relates to the clinical setting.


The ITT is considered the gold standard for determining GHD.2 Insulin-induced hypoglycemia provokes the pituitary to secrete GH. Once basal glucose levels are lowered, GH levels are assessed at 30, 45, and 60 minutes after insulin administration. However, with ITT, the plasma glucose level suggested as an optimal GH stimulus, <40 mg/dL, is a level well below normal (70-120 mg/dL) and may produce symptoms and signs of hypoglycemia and some serious side effects such as seizures. The ITT requires stable and adequate hormonal replacement for other hormone deficiencies and the presence of obesity may result in false positives. The ITT is also contraindicated in patients older than 55 years of age and in patients with an abnormal electrocardiogram, a history of ischemic heart disease, or seizure disorder. Because the ITT is technically demanding, the physician's personal experience with this test is critical to its success as a diagnostic tool.8,9

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