Acromegaly and GH deficiency

GH

GH is the most abundant anterior pituitary hormone, and GH-secreting somatotrope cells constitute up to 50% of the total anterior pituitary cell population. Mammosomatotrope cells, which co-express PRL with GH, can be identified using double immunostaining techniques. The pituitary GH gene (hGH-N) produces two alternatively spliced products that give rise to 22-kDa GH (191 amino acids) and a less abundant 20-kDa GH molecule, with similar biologic activity. Placental syncytiotrophoblast cells express a GH variant (hGH-V) gene; the related hormone human chorionic somatotropin (HCS) is expressed by distinct members of the gene cluster.

GH secretion is controlled by complex hypothalamic and peripheral factors. GHRH is a 44-amino-acid hypothalamic peptide that stimulates GH synthesis and release. Ghrelin, an octanoylated gastric-derived peptide, as well as synthetic agonists of the GHRP receptor, induce GHRH and also directly stimulate GH release. Somatostatin [somatotropin-release inhibiting factor (SRIF)] is synthesized in the medial preoptic area of the hypothalamus and inhibits GH secretion. GHRH is secreted in discrete spikes that elicit GH pulses, whereas SRIF sets basal GH tone. SRIF is also expressed in many extrahypothalamic tissues, including the CNS, gastrointestinal tract, and pancreas, where it also acts to inhibit islet hormone secretion. IGF-I, the peripheral target hormone for GH, feeds back to inhibit GH; estrogen induces GH, whereas chronic glucocorticoid excess suppresses GH release.

GH secretion is pulsatile, with highest peak levels occurring at night, generally correlating with sleep onset. GH secretory rates decline markedly with age so that hormone levels in middle age are about 15% of pubertal levels. These changes are paralleled by an age-related decline in lean muscle mass. GH secretion is also reduced in obese individuals, though IGF-I levels may not be suppressed, suggesting a change in the setpoint for feedback control. Elevated GH levels occur within an hour of deep sleep onset as well as after exercise, physical stress, trauma, and during sepsis. Integrated 24-h GH secretion is higher in women and is also enhanced by estrogen replacement.

GH induces protein synthesis and nitrogen retention and impairs glucose tolerance by antagonizing insulin action. GH also stimulates lipolysis, leading to increased circulating fatty acid levels, reduced omental fat mass, and enhanced lean body mass. GH promotes sodium, potassium, and water retention and elevates serum levels of inorganic phosphate. Linear bone growth occurs as a result of complex hormonal and growth factor actions, including those of IGF-I. GH stimulates epiphyseal prechondrocyte differentiation. These precursor cells produce IGF-I locally and are also responsive to the growth factor.

Longer-term subcutaneous IGF-I injections enhance protein synthesis and are anabolic

GH Deficiency in Children

GH Deficiency

Isolated GH deficiency is characterized by short stature, micropenis, increased fat, high-pitched voice, and a propensity to hypoglycemia due to relatively unopposed insulin action

GHRH Receptor Mutations, Growth Hormone Insensitivity, Nutritional Short Stature

The sequential order of hormone loss is usually GH- FSH/LH -TSH -ACTH.

Adult

Impaired quality of life, Decreased energy and drive, Poor concentration, Low self-esteem, Social isolation, Body composition changes, Increased body fat mass, Central fat deposition, Increased waist-hip ratio, Decreased lean body mass, Reduced exercise capacity, Reduced maximum O₂ uptake, Impaired cardiac function, Reduced muscle mass, Cardiovascular risk factors, Impaired cardiac structure and function, Abnormal lipid profile, Decreased fibrinolytic activity, Atherosclerosis, Omental obesity.

Evoked GH <3 name="2877130">IGF-I and IGFBP3 low or normal, Increased LDL-cholesterol, Concomitant gonadotropin, TSH, and/or ACTH reserve deficits may be present.

predisposing factors: (1) pituitary surgery, (2) pituitary or hypothalamic tumor or granulomas, (3) history of cranial irradiation, (4) radiologic evidence of a pituitary lesion, (5) childhood requirement for GH replacement therapy, or, rarely, (6) unexplained low age- and sex-matched IGF-I levels.

Dx: After glucose reduction to ~40 mg/dL, most individuals experience neuroglycopenic symptoms (Chap. 339), and peak GH release occurs at 60 min and remains elevated for up to 2 h. About 90% of healthy adults exhibit GH responses >5 g/L; AGHD is defined by a peak GH response to hypoglycemia of <3>.

The starting dose of 0.1–0.2 mg/d should be titrated (up to a maximum of 1.25 mg/d) to maintain IGF-I levels in the mid-normal range for age- and gender-matched controls.

Acromegaly

GH hypersecretion is usually the result of a somatotrope adenoma but may rarely be caused by extrapituitary lesions (Table 333-10). In addition to more common GH-secreting somatotrope adenomas, mixed mammosomatotrope tumors and acidophilic stem-cell adenomas secrete both GH and PRL. In patients with acidophilic stem-cell adenomas, features of hyperprolactinemia (hypogonadism and galactorrhea) predominate over the less clinically evident signs of acromegaly

Clinical manifestations: Protean manifestations of GH and IGF-I hypersecretion are indolent and often are not clinically diagnosed for 10 years or more. Acral bony overgrowth results in frontal bossing, increased hand and foot size, mandibular enlargement with prognathism, and widened space between the lower incisor teeth. In children and adolescents, initiation of GH hypersecretion prior to epiphyseal long bone closure is associated with development of pituitary gigantism (Fig. 333-8). Soft tissue swelling results in increased heel pad thickness, increased shoe or glove size, ring tightening, characteristic coarse facial features, and a large fleshy nose. Other commonly encountered clinical features include hyperhidrosis, deep and hollow-sounding voice, oily skin, arthropathy, kyphosis, carpal tunnel syndrome, proximal muscle weakness and fatigue, acanthosis nigricans, and skin tags. Generalized visceromegaly occurs, including cardiomegaly, macroglossia, and thyroid gland enlargement.

The most significant clinical impact of GH excess occurs with respect to the cardiovascular system. Coronary heart disease, cardiomyopathy with arrhythmias, left ventricular hypertrophy, decreased diastolic function, and hypertension occur in about 30% of patients, Upper airway obstruction with sleep apnea occurs in more than 60% of patients and is associated with both soft tissue laryngeal airway obstruction and central sleep dysfunction. polyps are diagnosed in up to one-third of patients.

Age- and gender-matched serum IGF-I levels are elevated in acromegaly. The diagnosis of acromegaly is confirmed by demonstrating the failure of GH suppression to <1> Surgical resection of GH-secreting adenomas is the initial treatment for most patients.

Octreotide acetate is an eight-amino-acid synthetic somatostatin analogue. In contrast to native somatostatin, the analogue is relatively resistant to plasma degradation. It has a 2-h serum half-life and possesses fortyfold greater potency than native somatostatin to suppress GH. Octreotide is administered by subcutaneous injection, beginning with 50 g tid; the dose can be gradually increased up to 1500 g/d.

Lanreotide, a slow-release depot somatostatin preparation, is a cyclic somatostatin octapeptide analogue that suppresses GH and IGF-I hypersecretion for 10–14 days after a 30-mg intramuscular injection.

Bromocriptine and cabergoline may suppress GH secretion in some patients, particularly those with cosecretion of PRL. High bromocriptine doses (20 mg/d) are usually required to achieve modest GH therapeutic efficacy