Effect on the body

Take a look at the graph on the left. Gradually, Human Growth Hormone secretion diminishes with age. Starting in the 20's, hormone secretion declines about 14% a decade, by 60 you only secrete 25% as much HGH as an average 20 year old. This human growth hormone reduction, greatly contributes to the acceleration of the aging process.

Human Growth Hormone (HGH) is produced by somatropes, which are the cells that make up 50% of the pituitary gland. It is first converted to growth factors in the liver. IGF-1 is the most effective growth factor, causing the majority of the age-reversing effect of HGH. IFG-1 is sent to all parts of the body, affecting every bodily function sex and reproduction, growth and development, mood and metabolism. HGH is produced in largest amounts during childhood and adolescence, the "peak" of our physical well being, and then gradually diminishes as we age. By age 61 our growth hormone levels decrease to 80% less than when we were 21. The signs and symptoms of depleting HGH levels in our bodies are the common signs of aging we all experience today. They include: poor general health, increased body fat, increased anxiety and social isolation, lack of positive well-being. Low levels of HGH result in reduced energy and vitality, exercise performance, decreased muscle strength, increase in LDL cholesterol, decreased bone mineral density.

Diagnosis of GHD in adults

Definition of adult GHD

Severe GHD should be defined biochemically within an appropriate clinical context. In patients with hypothalamic–pituitary disease, the syndrome of adult GHD characteristically presents with alterations in body composition, including reduced lean body mass and bone mineral density, and increased fat mass with a preponderance of abdominal adiposity (increased waist circumference). The skin is thin and dry, and sweating is reduced. Muscle strength and exercise performance are reduced. An impaired sense of well-being and other psychological complaints are common. Partial GHD exists, but further research is needed to distinguish it from physiological causes of reduced GH secretion, for example, aging. Furthermore, the benefits of treatment of partial GHD remain to be established.

Patients who should be tested for adult GHD

An evaluation for GHD should be considered in patients with evidence of hypothalamic–pituitary disease, subjects who have received cranial irradiation, or in patients with childhood-onset GHD. In patients with organic hypothalamic–pituitary disease, the likelihood of GHD increases with increasing number of pituitary hormone deficits, from approximately 45% if no other deficits are present to nearly 100% if three or four pituitary hormone deficits are present. It may not be necessary to evaluate patients with pituitary microadenomas for GHD unless other pituitary hormone deficits are present or unless a strong clinical suspicion for GHD exists. Patients with childhood-onset GHD should be re-tested as adults before committing them to long-term GH replacement.

Biochemical diagnosis of adult GHD

Dynamic tests of GH secretion

The diagnosis of adult GHD is established by provocative testing of GH secretion. Patients should be on stable and adequate hormone replacement for other hormonal deficits prior to testing. At present, the insulin tolerance test (ITT) is the diagnostic test of choice. Provided adequate hypoglycemia is achieved, this test distinguishes GHD from the reduced GH secretion that accompanies normal aging and obesity. The ITT should be performed in experienced endocrine units where the test is performed frequently. The test is contraindicated in patients with electrocardiographic evidence or history of ischemic heart disease, or in patients with seizure disorders. Given these precautions, the ITT is safe; however, there is less experience of its use in patients over the age of 60 years.

Most normal subjects respond to insulin-induced hypoglycemia with a peak GH concentration of greater than 5 m g/l. Severe GHD is defined by a peak GH response to hypoglycemia of less than 3 m g/l. These cut-off values were defined in GH assays employing polyclonal competitive radioimmunoassays (RIAs). However, GH immunoassay results vary between different methods and, therefore, the cut-off value may need to be adjusted appropriately (see below for standardization of assays).

In patients with contraindications to the ITT, alternative provocative tests of GH secretion must be used with appropriate cut-offs. At present, the combined administration of arginine and GH-releasing hormone is the most promising alternative. Administration of arginine alone or glucagon alone can be considered but these tests have less established diagnostic value compared with the ITT. Other stimulatory tests may prove to be useful but require further validation. Present data indicate that the clonidine test is less useful in adults than in children.

Adult patients with hypothalamic–pituitary disease and one or more additional pituitary hormone deficits require only one provocative test of GH secretion for the diagnosis of GHD. Childhood-onset GHD requires reconfirmation in adulthood. In order to establish the diagnosis of isolated GHD in adults, it is recommended that, in addition, a second biochemical test of GH status be abnormal.

Biochemical markers of GH action

Several biochemical markers of GH action have been studied to determine their diagnostic potential in adult GHD. Serum insulin-like growth factor I (IGF-I) concentrations are only useful when age-adjusted normal ranges are available. In adults, normal serum IGF-I does not exclude the diagnosis of GHD. A serum concentration of IGF-I below the normal range is suggestive of GHD in the absence of other conditions known to lower serum levels of IGF-I; for example, malnutrition, hepatic disease, poorly controlled diabetes mellitus and hypothyroidism. In the presence of multiple (two or more) pituitary hormone deficiencies, low serum IGF-I indicates a high probability of GHD. However, it is recommended that the diagnosis of adult GHD be confirmed by a provocative test of GH release.

Measurement of serum levels of IGF-binding protein-3 (IGFBP-3) or acid-labile subunit (ALS) has to date not proven to offer any advantage over the measurement of serum IGF-I.

Standardization of assays

GH immunoassay results vary between different assay methods. The above recommendations for cut-off values for the ITT are based on results obtained with polyclonal competitive RIAs calibrated against the pituitary-derived preparation International Reference Preparation (IRP) 80/505 (1 mg = 2.6 IU). The GRS advocates future use of the recombinant human GH preparation IRP 88/624 (1 mg = 3.0 IU). Further comparative studies are necessary, both at a national and international level, to achieve standardization of GH assays.

The presence of IGFBPs interferes with measurement of serum IGF-I. At present, removal of IGFBPs before immunoassay is essential. However, new IGF-I assays are being developed which may not require extraction procedures. The current international reference standard for IGF-I assays is IRP 87/518. GH and IGF-I results should be expressed in mass units.

Treatment of GHD in Adults

Patients to be treated

All patients with documented severe GHD are eligible for GH replacement. The goal for GH replacement in adults is to correct the abnormalities associated with adult GHD.

Dose selection

The objective of treatment is to maximize benefit and minimize side-effects. Experience has shown that sensitivity varies considerably between individuals, with elderly individuals being most sensitive. It is recommended that therapy should start with a low dose, 0.15-0.30 mg/day (0.45-0.90 IU/day). The dosage should be increased gradually on the basis of clinical and biochemical responses and no more frequently than at monthly intervals. The maintenance dose may vary considerably from person to person and seldom exceeds 1.0 mg/day (3 IU/day).

In healthy adults, it is known that premenopausal women secrete more GH than age-matched men, and that GH secretion is reduced with advancing age and with obesity. In adults aged 30-50 years, the reported daily production of GH in women was approximately 0.2 mg/day, whereas the production rate in men was approximately 0.1 mg/day. Clinical experience has demonstrated that the variability in subcutaneous absorption and individual responsiveness to GH make dosing based on body weight or body surface area less helpful than anticipated. Furthermore, some adult patients experience side-effects even with a low dose.

In accordance with the clinical practice of treating GH-deficient children, we recommend GH to be administered as daily subcutaneous self-injections in the evening.

Monitoring treatment efficacy

A physical examination and a careful clinical history with particular attention to quality of life related questions are of great value in monitoring treatment. Where appropriate, questioning the patient’s partner may also assist with the evaluation.

At present, the best biochemical marker of GH action is serum IGF-I. An important use of IGF-I measurements is to avoid over-replacement, and values should be kept in the age-related normal range. IGFBP-3 has been found to be less useful, while ALS, although promising, needs further validation. In the initial stages of dose titration, frequent measurements are required (every 1 or 2 months). Once a stable dose has been reached, once- or twice-yearly measurements are sufficient.

Simple anthropometric measures, such as weight and waist circumference, may be supplemented by bioelectrical impedance analysis and dual-energy X-ray absorptiometry, the latter being particularly valuable when bone mineral density is reduced. Lipids should be monitored annually.

Safety issues

Adult GHD is associated with reduced extracellular fluid volume. Fluid retention during GH treatment is therefore to be expected and the patient should be informed. Edema and, occasionally, carpal tunnel syndrome may be seen. These symptoms are usually transient and dose dependent, but may require a dose reduction. Mild arthralgias may occur but are usually self-limiting. Because GH may reduce insulin sensitivity, markers of glycemia should be monitored periodically.

The risk of certain malignancies, in particular colon cancer, is increased in acromegaly. It is, however, inappropriate to extrapolate from the acromegalic data to the GH-replaced adult with hypopituitarism. Nonetheless, current recommendations for cancer prevention and early detection in the general population should be implemented.

Good clinical practice requires regular imaging of residual pituitary tumor; GH replacement does not impose a need for intensifying this follow-up. A baseline scan is recommended before starting treatment.

GH influences the metabolism of many substances, including other hormones and medications; therefore, alterations in dose requirements of such compounds should be anticipated.

Contraindications

Absolute contraindications include active malignancy, benign intracranial hypertension and proliferative or preproliferative diabetic retinopathy. Early pregnancy is not a contraindication, but GH should be discontinued in the second trimester, as GH is produced by the placenta.

Long-term care

Although insufficient information is currently available, GH replacement (as with other hormones) is most likely for life. It is possible that the dose requirement may decrease over time. Replacement therapy in the elderly should be monitored particularly carefully as the patient ages, with special emphasis on dosage and perceived benefit. If any patient perceives no benefit, then a trial of withdrawal should be considered.

It is recommended that patients with hypopituitarism receiving GH replacement should remain under long-term surveillance by an endocrinologist with special experience in pituitary disease; this can be undertaken in partnership with an internist or general practitioner.