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ADULT HORMONE DEFICIENCY (AGHD) - PART 2

NATURE AND CLASSIFICATION OF GHD/AGHD

“Growth hormone deficiency” (GHD) may be classified broadly into four categories based on the source of the GH deficiency: (1) pituitary or “classic” GHD, (2) “hypothalamic GHD,” (3) “functional GHD,” and (4) “idiopathic GHD.” Pituitary GHD is the incapacity of the pituitary to produce growth hormone. Hypothalamic GHD is the failure of the hypothalamus to produce and/or transmit the neuroendocrine messaging hormone, GHRH, which directs a properly functioning pituitary to produce GH. Functional GHD is the failure of other hormone and of metabolic functions, caused by various and often unknown etiologies that result in the failure of the pituitary to produce, uptake, and/or utilize GH. “Idiopathic GHD” is GHD of unknown origin or etiology.

“Adult growth hormone deficiency” (AGHD) may be classified broadly into three categories based on the stage of life the GH deficiency became manifest: (1) child-onset, (2) adult-acquired onset, and (3) child-onset idiopathic GHD which can be divided into organic and idiopathic causes.

Child-onset GHD is caused by different genetic defects in various genetic components and by Prader-Willi syndrome (a congenital disorder characterized by obesity, short stature, lack of muscle tone, hypogonadism, and central nervous dysfunction); associated brain structural defects, and associated mid-line facial defects. Children with brain tumors are at high risk of developing growth hormone deficiency (GHD) from the effects of cranial radiation on the hypothalamus/pituitary (HP) axis (pathway)alls within the fields of irradiation. It is possible that a significant number of patients develope hypothalamic radiation-induced damage to the GHRH secreting neurons, which results in the pituitary gland developing decreased responsiveness to GHRH following CI in childhood. In the transition period from GH in childhood to adulthood, the emphasis is on completion of the development of bone and muscles. Thre is increasing recognition of the need to continue GH therapy beyond final height in young adults with severe GHD on retesting.

In the middle years, adult acquired onset is caused by trauma at or soon after birth, central nervous system infection, tumors of the hypothalamus or pituitary glands, infiltrative or granulomatous disease, cranial irradation, surgery; or, from idiopathic causes. The chief concerns are increased cardiovascular risk risk involving GHD-related dyslipidemia, increased fat mass, reduced insulin sensitivity, and increased mortality markers, especially in women as compared with the general population.

In the elderly, GHD becomes manifest in decreased quality of life, fatigue, and alteration of body composition differently than in normal persons. Abnormalities in body composition, bone metabolism, and lipid profile in GH-deficient and hypopituitary adults are distinct from those that occur as the result of normal aging. As people with GHD age, they retain the ability to respond to GH; at the same time peripheral sensitivity to GH remains, as does the capacity of the liver to secrete IGF-I. Thus, growth hormone has significant benefits in adults with GHD or hypopituitarism throughout each stage of adult life.

EPIDEMIOLOGY OF GHD/AGHD

In the United States commencing in the mid-1960s through April of 1985, natural human growth hormone (nGH) was used to treat child-onset GHD. In 1985, the FDA approved the use of Protropin brand of recombinant human (biosynthetic) growth hormone (rhGH) (somatropin [rDNA origin], manufacturered by Genentech, to treat child-onset GHD. Since then, similar, but not identical brands, of rhGH have come to the marketplace. In 1996, rhGH was approved or use in GHD adults. In the last 15 years, it has been recognized that growth hormone deficiency (GHD) in the adult leads to increased morbidity (metabolic syndrome, osteoporosis, muscle wasting, impaired quality of life) and increased incidence of cardiovascular events, a main cause of the increased mortality observed in this population. Pituitary adenomas and their treatment (surgery, radiation) are the most common cause of GHD in adults. In the United States, it is estimated that the incidence of growth hormone deficiency in children is between 1 in 4,000 and 1 in 10,000. More than 50,000 adults in the United States are growth hormone deficient, and 6,000 new cases are reported each year, including GHD children who transition to GHD as an adult.

DIAGNOSIS OF AGHD

Until several years ago, the growth hormone stimulation test (GHST), which measures the capacity of the the pituitary to produce growth, was considered the principal biochemical test for the diagnosis of AGHD. During the past several years, the accuracy of the GHST to determine whether a person has AGHD has been increasingly questioned because of test variability and and increasing acceptance of IGF-I being of significant diagnostic value in combination with the GHST, the phenotype (physical and mental characteristics, the medical history, as described above; and, increased understanding that, in the absence of a clearly defined organic cause for AGHD, the unique physiology of each person being evaluated, makes the diagnosis of AGHD complex and varied.

Adult growth hormone deficiency (GHD) is a multifactorial disorder in which pituitary dysfunction associated with pituitary adenomas or their treatment plays a major role. The concept of partial GHD, recognized by paediatric endocrinologists for many years, is being now being examined in adults for an association between hypothalamic-pituitary disease and metabolic and anthropometric abnormalities in persons whose GH range from severe GHD to non-GHD levels. Partial GHD, however, becomes more difficult to diagnosis in the presence of obesity, increasing age, and in the absence of additional pituitary hormone deficits.

Adults with GHD can have a variety of signs and symptoms, which include abnormality body composition with increased fat mass (especially central adiposity), decreased lean muscle mass, extracellular fluid volumn, dimished muscle strength, physical energy and stamina, lack of motivation, lethargy, lability (changes in mood), depression, and impairment of congitive functions.

Comprehensive biochemical testing may reveal the following conditions that are also markers for AGHD: lipid imbalance, athersclerosis, obesity, increased LDL cholesterol and reduced insulin sensitivity, and metabolic syndrome. An MRI scan may reveal a structural abnormality or tumor in the brain. A pulmonary function test may reveal dimished lung respiratory muscle capacity. A DEXA (dual-energy X-ray absorptiometry) scan may reveal osteoporosis and increased risk of fracture. All those conditions are consistent with AGHD. Hypopituitarism and GHD are associated with an increased mortality.

Comprehensive biochemical testing initally includes, but is not limited to: complete blood count (CBC) with differential platelets, comprehensive metabolic panel, thyroid panel, IGF-I, HbA1c, lutenizing hormone, follicle stimulating horomone, testosterone, estrogen (for women only), DHEAS, androstenedione. Biochemical testing can also reveal deficiences in thyroxin, testosterone, and androgenic steriods (DHEAS and androstenedione), diseases and disorders of metabolism, and genetic defects that can interfere with the secretion, uptake, and utilization of GH and IGF-I.

When the IGF-I is low, further investigation is warranted to determine the cause of the low IGF-I, which can include (1) the testing of IGF-II, and the IGF binding proteins; (2) growth hormone stimulation tests to determine whether the pituitary has the capacity to produce growth hormone; (3) the levels of zinc, magnesium, and selenium, which minerals are necessary for the proper functioning of certain enzymes that are essential for the metabolic processes involved in with IGF-I and its various binding proteins; and, possibly testing for metabolic diseases and disorders.

The diagnosis of AGHD is often challenging because of the absence of growth parameters as diagnostic factors in addition factor, and the effects of other disorders that adults acquire over time. Other markers are therefore needed to identify adults who have GHD and could potentially benefit from GH replacement therapy. Consensus guidelines for the diagnosis and treatment of adult GHD include patients who have evidence of hypothalamic-pituitary disease or disorder, patients with childhood-onset GHD, and patients who have undergone cranial ablation, or have a history of head trauma. Suspicion of GHD is also heightened in the presence of other pituitary hormone deficits. Tests for GHD include measurement of GH upon conducting growth hormone stimulation tests (GHSTs) with provoking agents that have high sensitivity and sensitivity including, but not limited to, the insulin tolerance test (ITT), GHRH plus arginine or GHRH and GHRP-6. The results of several studies have found that non-stimulated serum or urine measurements of GH levels do not reliably predict deficiency in adults. Also, the ITT has some potential risks involved its administration and is of questionable reproducibility, which have prompted the development of the previously mentioned tests. Thus, in cases where ITT is contraindicated or inconclusive, the combination of arginine and GHRH is an effective alternative.

The signs and symptoms of growth hormone deficiency can be masked by testosterone or thyroxin; or caused by deficiencies in those hormones or by other hormone dysfunction or by metabolic disorders. In such cases, rhGH can cause other hormone deficiencies (e.g., cortisol), or in combination with testosterone in males can cause (1) secondary polycythemia via the hormone erythropietin, resulting in serious and even grave conditions (i.e. hemochromotosis, cardiac infarction, stroke and paralysis, liver damage). rhGH can also stimulate coagulation of prothrombin and activated partial thromboplastin time in GHD adults. Excessive GH/rhGH also causes a significant increase in the risk of cancer and the recurrance of cancer, and diabetes mellitus. It is, therefore, important to identify and rule out any such conditions before diagnosing and treating GHD/AGHD. The patient’s medical history, as well as physical examination, biochemical testing and appropriate scans of the brain are critical to the diagnosis and treatment of the patient for AGHD.

TREATMENT OF AGHD AND HYPOPITUITARISM

The current treatment for AGHD in the United States is rhGH that is approved as safe and efficacious by the U.S. Food and Drug Administration. Although made by various manufacturers, rhGH contains DNA sequencing that is identical to natural GH, regardless of the source material from which it is made. The manufacturing processes, pH (alkalinity/acidity) index of preservatives contained in the diluent (fluid part) of the rhGH, storage and stability properties, and delivery technologies and devices differ with each manufacturer. Therefore, with the possibility of a minimal difference bioequivalancy among the rhGH products, all those products and their delivery devices are safe and efficacious. Generally, rhGH treatment is monitored by testing a periodic intervals determined by the endocrinologist, changes in body composition, and bone remodeling, and lipid values.

In the beginning years of treating AGHD, rhGH was dosed by by body weight, which resulted in relatively high levels of IGF-I. Based on patient experience in recent years, with minor but aggravating adverse events such as edema and joint pain, lower doses have been found to be efficacious, but safer, with a reduction in the IGF-I levels. Also, the older a person is, the more sensitive he/she is to IGF-I and requires less rhGH to achieve a safe and effective level of IGF-I. Experience on the HGF Discussion Forum shows that for middle age adults, a dose of 0.4 mg to 0.8 mg of rhGH daily, and for older adults, a dose of 0.2 to 0.4, may be sufficient to treat AGH. These estimates are consistent with the dosage regimens found to be adequate in recent studies on dosage regimen.

BENEFITS OF TREATMENT

One daily subcutaneous injection of rhGH can reverse many of the symptoms and signs of growth hormone deficiency. Not to be overlooked is that rhGH, independently of its correlation with IGF-I, rhGH has important benefits in the elimination or reduction of lability (emotional ups and downs) and depression at relatively low levels, regardless of the mg/kg/wk determined by a persons weight. Experience on the HGF Discussion Forum shows that regardless of weight, at least for “older” adults, 0.2 mg of rhGH daily can eliminate or significant reduce lability and depression. The pathophysiology for this positive results appears to be the natural mediatory and regulatory effects of rhGH on the neurotransmitters of the central nervous system (CNS), which seem to perform better than psychotropic drugs. (natural physiology).

RESULTS: After 3 and 6 months of rhGH treatment in the closed label phase a significant improvement of attentional performance was observed compared to baseline in the rhGH group but not in the placebo group. After 6 months scores of attention were significantly different between rhGH and placebo treatment for the digit cancellation test and marginally different for the trail-making test. In contrast, long-term verbal memory and non-verbal intelligence did not improve compared to baseline during therapy and short-term memory improved both in the GH and the placebo group after 3 and 6 months. This was considered as a placebo or practice effect. In the open-label phase a further improvement of attention was found in the GH group and subsequent treatment with rhGH for 3 and 6 months in the placebo group also significantly improved attentional performance supporting the results of the rhGH group in the first 6 months of the double-blind phase. CONCLUSION: RhGH treatment appears to have a beneficial effect on attentional performance in adult hypopituitary patients with GH deficiency when treated for at least 3 months. Our study does not support a role for GH in influencing verbal memory or non-verbal intelligence.

The introduction of recombinant growth hormone (GH) for the treatment of GHD has opened up new treatment avenues but has also raised concerns about possible untoward long-term metabolic effects of GH, such as the potential effect of GH on insulin sensitivity and a deterioration in glucose tolerance. Research has shown that GH induces insulin resistance by the stimulation of lipolysis and a concomitant switch from oxidation of glucose to oxidation of lipids, during both acute and chronic treatment. However, although this is a consistent effect of GH therapy, it does not mean per se that it leads to abnormal glucose tolerance and diabetes mellitus. This article discusses this and other potential long-term metabolic effects of GH, and raises a number of questions to be addressed by future research.

LDL-cholesterol abnormalities appear to improve with GH replacement even if maintained within physiological dose range; the greatest improvement occurs in those subjects with higher baseline total and LDL cholesterol values and in female patients with adult onset GHD compared with male patients with childhood onset GHD. In contrast, hypertriglyceridaemia is not corrected by GH replacement. The majority of the reports suggest GH replacement increases Lipoprotein-a levels. Long-term observation will be required to determine whether GH replacement reduces cardiovascular morbidity and mortality in GHD adults. The reduced muscle mass and strength associated with GHD has been shown to improve after GH replacement. GH treatment also improves maximal and sub-maximal exercise performance in GHD adults. The effects on protein metabolism, energy expenditure and thyroid metabolism in GHD adults are also critical.

GH replacement has a long-term beneficial effect on muscle mass and function in patients with GHD of all ages, although there appears to be a greater effect in normalizing muscle mass and function in young males and in adults with adult-onset GHD compared with those with childhood-onset GHD. Results also suggest that concomitant exercise training might further improve the outcome of GH replacement therapy. Copyright © 2006 S. Karger AG, Basel Vol. 50, No. 4, 1998

The beneficial effects of rhGH replacement, described after short-term rhGH replacement, are sustained in the long term up to 7 years

Understanding the mechanisms by which GH antagonizes insulin-stimulated glucose disposal in muscle is an important future research field, with implications for a variety of clinical conditions ranging from malnutrition to obesity and type 2 diabetes mellitus.

It was concluded that individuals with GHD do show cognitive impairment and that this is ameliorated to some extent by GH treatment.

Most of the available studies indicate that GHD can lead to small, but clinically relevant changes in memory, processing speed and attention. Some of these changes may be reversed by GH replacement, although the number of reliable intervention studies is limited. In addition to the possible clinical relevance of neuropsychological improvement following GH replacement in patients with GHD, the observed findings may be of interest for studies in neurocognitive performance in other conditions associated with changes in the activity of the somatotrophic axis, and in the understanding of underlying pathophysiological mechanisms.

One study of GH-deficient adults found that, after 33 months of GH treatment, BMD and BMC increased to a greater extent in men with GHD than in women. There is also a gender difference in the increases in serum levels of insulin-like growth factor I and biochemical bone markers during GH treatment. The reason for these findings is unknown, and the role of sex steroids in determining the response to GH therapy remains to be fully elucidated.

A significant positive correlation was observed between BMD (z-scores) and age at all skeletal sites studied. Overall, few patients, except those aged less than 30 years, had significantly reduced bone mass (i.e. a BMD z-score of less than -2); correction of BMD to provide a pseudo-volumetric measure of BMD suggested that reduced stature of the younger patients may explain, at least in part, this higher frequency of subnormal BMD z-scores. Despite normal BMD, however, an increase in fracture prevalence may still be observed in elderly GHD adults as a consequence of increased falls related to muscle weakness and visual field defects.

GHD patients with AO-IGHD and AO-MPHD present with a similar clinical expression and respond similarly to GH replacement. Patients with CO-IGHD are less severely affected by GHD than CO-MPHD patients, but, nevertheless, both groups show a comparable adverse lipid profile and poor quality of life and respond favourably to GH replacement. These findings support the concept that GH alone is responsible for most if not all metabolic aspects of hypopituitary patients receiving conventional replacement therapy, regardless of age of onset or aetiology. As a consequence, GH replacement therapy not only has potential benefit in GHD patients with additional hormonal deficits, but also the indication of treatment must be extended to patients with isolated GHD.

GH therapy may increase cortisol metabolism, which in turn, may precipitate adrenal insufficiency in hypopituitary patients who have partial deficiency of the pituitary messaging hormone, adrenocorticotropic hormone. But GHD also increases cortisol production in key target tissues including liver and adipose tissue, which result in insulin resistance and visceral adiposity. However, beneficial effects of GH on cardiovascular risk factors in patients with hypopituitarism may be an indirect effect of the alterations in cortisol metabolism. Further, GH/IGF-I modulation of cortisol metabolism may underpin the pathogenesis of common diseases such as central obesity and idiopathic osteoporosis.

MEDICAL INSURANCE FOR COVERAGE OF AGHD

Insurance coverage of rhGH for the treatment of AGHD is separate matter for the diagnosis of AGHD. In the United States, many insurance companies cover rhGH only for severe AGHD, as evidenced by one or two GHST, each with a different stimulating agent, with a cut-off point of 5 ng/mL of nGH on any the five samples of blood taken over a three hour period, except in the case of panhypopituitarism, trauma, or ablation of the pituitary. In these latter instances, the condition, plus low IGF-I, and signs and symptoms consistent with AGHD usually accepted by insurance companies for coverage of rhGH.

PRINCIPAL SOURCE INFORMATION
1. American Association of Clinical Endocrinologists (AACE) Medical Guidelines for the Clinical Practice for Growth Hormone Use in Adults and Children- 2003 update
2. Update of Guidelines for the Use of Growth Hormone in Children: The Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee-2003

 

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