Gh somatotropin

Somatotropin or GH is the most abundant hormone produced by the anterior pituitary lobe. The GH-secreting somatotropes account for 50% of hormone-secreting cells in the anterior pituitary. GH is regulated primarily by the hypothalamic-pituitary axis. The hypothalamus releases growth hormone-releasing hormone (GHRH) to stimulate GH synthesis and secretion, whereas somatostatin inhibits it.1 Upon stimulation by GHRH, somatotropes release GH into the circulation, thereby stimulating the liver and other peripheral target tissues to produce insulin-like growth factors (IGFs). These IGFs, also known as somatomedins, are the peripheral GH targets. There are two types of IGFs: IGF-I and IGF-II. IGF-II is responsible primarily for regulating fetal growth, whereas IGF-I is the hormone responsible for growth of bone and other tissues. High levels of IGF-I inhibit GH secretion through somatostatin, thereby inhibiting GHRH secretion.1 The hypothalamus also may stimulate the release of somatostatin to inhibit GH secretion. Effects of IGF-I in peripheral tissues are both GH-dependent and GH-independent.2 GH is an anabolic hormone with direct "anti-insulin" metabolic effects. By stimulating protein synthesis and shifting the body's energy source from carbohydrates to fats, GH promotes a diabetic state (Table 46-1). GH controls somatic growth and has a critical role in the development of normal skeletal muscle, myocardial muscle, and bone.

In healthy individuals, GH is secreted in a pulsatile pattern throughout a 24-hour period, with several short bursts occurring mostly during the night. The most intense period of GH secretion occurs within the first 1 to 2 hours of slow-wave sleep (stage 3 or 4 deep sleep).1 In between these bursts, basal concentration of GH falls to very low or undetectable levels because of its short half-life in the blood (approximately 19 minutes). The amount of GH secretion fluctuates throughout a person's lifetime. Secretion of GH is lowest during infancy, increases during childhood, peaks during adolescence, and then declines gradually during the middle years.1 These changes are parallel to an age-related decline in lean muscle mass.

Table 46-1 Effects of Growth Hormone




Increases the use of



fat by stimulating

breakdown of fat



breakdown and

Increases circulating

oxidation of

fatty acid levels


Increases lean body mass


Stimulates protein

Increases muscle


anabolism by increasing amino acid uptake and protein synthesis and decreasing oxidation of proteins



Suppresses the

Decreases glucose


ability of insulin to stimulate uptake of glucosc in peripheral tissues


Decreases insulin

Insulin resistance

receptor sensitivity

Impairs postreceptor


insulin action

Stimulates glucose

Increases hepatic

synthesis in the liver

glucose output


GH Excess

Epidemiology and Etiology

Acromegaly affects both genders equally, and the average age of presentation is 44 years. Approximately 50 to 70 people per 1 million population are affected, with an es-

timated annual incidence of 3 to 4 cases per 1 million people. In more than 95% of the cases, overproduction of GH is due to a benign pituitary tumor (adenoma), whereas malignant tumors occur in less than 1%. Most pituitary adenomas occur spontaneously as a result of a genetic mutation acquired during life. Depending on the size of the tumor, pituitary adenomas are classified as: (a) microadenomas if they are 10 mm or less in diameter; or (b) macroadenomas if they are greater than 10 mm. Rarely, nonpituitary tumors cause acromegaly. These tumors can produce GH, but more commonly they secrete GHRH and result in excessive GH and IGF-I production.


Acromegaly is a rare, insidious disorder that manifests gradually over time. It is caused by an adenoma of the pituitary that overproduces GH and stimulates excessive production of IGF-I during adulthood. This typically occurs after fusion of the epi-physes (growth plates) of the long bones. The facial features of an acromegalic patient are depicted in Figure 46-2. Gigantism refers to GH excess that occurs during childhood before epiphyseal closure and results in excessive linear growth.

Diagnosis of acromegaly is based on both clinical and biochemical findings. Because secretion of GH fluctuates throughout the day, a single random measurement is never reliable for diagnosing GH excess.1 However, GH-mediated IGF-I production results in relatively stable serum IGF-I concentrations during the day, which correlate positively with 24-hour mean GH levels.1 This makes elevated IGF-I levels an ideal screening test for acromegaly and a reliable monitoring biochemical marker to assess disease activity and response to therapy.6,7 Because IGF-I levels may fluctuate with age and gender, it is important to compare IGF-I levels with age- and sex-matched population values.6,7 Other conditions such as nutritional status, liver dysfunction, insulin levels, and illness also can affect IGF-I levels. The measurement of serum GH secreted by the pituitary in response to an oral glucose tolerance test (OGTT) is the primary biochemical test for diagnosing acromegaly. GH is suppressed after administration of a 75 g oral glucose challenge because postprandial hyperglycemia inhibits secretion of GH for at least 1 hour. If the GH level does not decline to less than 1 ng/

mL (1 mcg/L) during the test, the patient is diagnosed with acromegaly. In addition to clinical presentation, elevated IGF-I serum concentration helps to confirm the diagnosis.

Acromegaly Treatment Goals

Patients with untreated acromegaly experience a twofold increase in mortality rate primarily due to cardiovascular and pulmonary diseases.10 Normalization of GH and IGF-I levels reverses the mortality risk and alleviates significant comorbid complications, especially cardiovascular, pulmonary, metabolic, and respiratory abnormalit-ies.11 Reduction of IGF-I levels alone does not appear to be a reliable predictor of

/r 1 ^ i if long-term outcome. , The goals of therapy are as follows , - :

• Normalize biochemical markers.

• Reduce GH to less than 1 ng/mL (1 mcg/L) after OGTT. When using the older GH assay, suppression of GH levels to less than 1 ng/mL (1 mcg/L) after OGTT is the biochemical target. Lower cut off levels have been suggested using the more sensitive GH assays.13-15

• Normalize IGF-I levels to age- and sex-matched control values.

• Ablate or reduce tumor size to relieve tumor mass effect.

• Prevent tumor recurrence and control tumor size.

• Preserve normal pituitary function.

• Improve clinical signs and symptoms.

• Alleviate significant morbidities.

• Reduce mortality rates to that of the general population.

General Approaches to Treatment

The American Association of Clinical Endocrinologists published medical guidelines for the diagnosis and treatment of acromegaly (Fig. 46-3). According to these guidelines, surgical resection of the pituitary tumor through transsphenoidal pituitary microsurgery is the treatment of choice for most patients with GH-producing pituitary adenomas.3 When performed by experienced surgeons, approximately 70% to 80% of patients with microadenomas and less than 50% of patients with mac-roadenomas achieve biochemical control.10 Complete resection of a macroadenoma may be difficult if the tumor has already invaded the surrounding nerves and tissues. In such cases, debulking of the tumor along with adjunctive radiation and/or pharma-cotherapy may improve treatment outcome. Infrequent surgical complications include meningitis, serious visual impairment, cerebrospinal fluid leakage, diabetes insipidus, and permanent hypopituitarism. Relative contraindications to surgery include patient frailty, acromegaly-associated comorbidities, and medically unstable conditions such as airway difficulties, severe hypertension, or uncontrolled diabetes.

Acromegaly Pictures Before After

FIGURE 46-2. Before and after photographs of an acromegalic patient. Compare the photographs of an acromegalic woman (A) before the onset of acromegaly and (B) after approximately 20 years, when the diagnosis was well established. Notice the coarsening of facial features, with enlarged nose, lips, and forehead.

FIGURE 46-2. Before and after photographs of an acromegalic patient. Compare the photographs of an acromegalic woman (A) before the onset of acromegaly and (B) after approximately 20 years, when the diagnosis was well established. Notice the coarsening of facial features, with enlarged nose, lips, and forehead.

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