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A 36-year-old male comes into the physicians office because his hands and
feet are swelling, and his face has coarse features with oily skin. On examination, he is above the 95th percentile for height at his age. He is noted to have
some coarse facial features including large nose, large tongue, and frontal
bossing of his forehead. His hands are enlarged with soft tissue swelling, and
his heel pad is thickened. He is noticed to have a slightly enlarged liver and
spleen. The remainder of the examination was otherwise normal.
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Diagnosis: Acromegaly
Biochemical mechanism: Excess and autonomous secretion of growth
hormone
CLINICAL CORRELATION
Acromegaly is a disorder with excessive growth hormone (GH), usually as a
result of autonomous secretion from a nonmalignant anterior pituitary tumor.
When acromegaly affects individuals prior to bone growth plate closure,
giantism may result; after the bone growth plates close, the patients usually
develop coarse features and large hands and feet. The diagnosis is confirmed
by demonstrating the failure of GH suppression within 1 to 2 hours of an oral
glucose load (75 gm), because GH is usually decreased with glucose. As a consequence of the pulsatility of GH secretion, a single random GH level is not
useful for diagnosis. Morbidity can ensue because of diabetes or hypertension.
The most feared complications are cardiac in nature, which may affect up to
30 percent of patients. Cardiac arrhythmias, cardiomyopathy, left ventricular
hypertrophy, hypertension, and coronary heart disease can be present.
Arrhythmias can be associated with cardiomyopathy or coronary heart disease.
The primary therapy of acromegaly is surgical, but there is often only partial
response. Thereafter somatostatin analogues or dopamine agonists are used,
and as a last line of therapy, radiation.
Definitions
Ghrelin: A 28-amino acid peptide that is octanoylated on serine-3. Ghrelin
is synthesized and secreted by endocrine cells in the stomach and will
bind to somatotrophic cells in the anterior pituitary to promote the
release of growth hormone (somatotropin).
CLINICAL CASES
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DISCUSSION
Growth hormone (somatotropin) is a polypeptide synthesized and secreted
by somatotrophs in the anterior pituitary. Growth hormone synthesis and
secretion is stimulated by the hypothalamic peptide growth hormone
releasing hormone (GHRH). Somatostatin, a polypeptide produced by several tissues including the hypothalamus, opposes GHRH stimulation of
growth hormone release. High levels of insulin-like growth factor-1 (IGF-1)
directly suppress growth hormone production in somatotrophs and also act
indirectly by stimulating somatostatin release from the hypothalamus.
Furthermore, growth hormone itself directly feedback inhibits its synthesis in
the somatotroph and also inhibits GHRH production by the hypothalamus.
A potent stimulator of growth hormone release is ghrelin, a polypeptide hormone
secreted by the stomach that acts directly on somatotrophs. In general, many
environmental factors including stress, exercise, nutrition, and sleep influence circulating levels of growth hormone. The overall effect is a pulsatile pattern of
growth hormone release reaching a maximum in children and young adults
shortly after the onset of deep sleep. Levels of growth hormone fluctuate dramatically and are suppressed in normal individuals after oral glucose administration.
Growth hormone plays a major role in cell proliferation and in regulating protein, lipid, and carbohydrate metabolism. It stimulates protein synthesis and the accompanying amino acid uptake in many tissues. In adipocytes,
it increases fat utilization by stimulating triglyceride breakdown and oxidation.
It opposes effects of insulin by suppressing its ability to stimulate glucose
uptake and by stimulating gluconeogenesis. Interestingly, injection of growth
hormone stimulates insulin secretion, leading to hyperinsulinemia.
In most of these examples, growth hormone acts at two levels. Growth hormone acts directly by binding its receptors in the plasma membrane of target
cells to influence cell proliferation and metabolism. Binding of growth hormone
to its receptor triggers receptor dimerization. In the absence of bound hormone,
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COMPREHENSION QUESTIONS
[47.1] A 30-year-old female of normal weight was recently diagnosed with
type II diabetes and hypertension. Menstrual cycles were irregular. In
appearance she had unusually coarse features; a noticeable enlargement of the tongue, hands, and feet; and a deep voice. Although not
pregnant or nursing, she unexpectedly began producing breast milk
(galactorrhea). Which one of the following possibilities is most likely
to explain all of these symptoms?
A.
B.
C.
D.
E.
CLINICAL CASES
427
[47.2] A 7-year-old child who was very small for his age began receiving
treatment with growth hormone. Which one of the following metabolic
alterations is most likely to be observed after beginning this treatment?
A.
B.
C.
D.
E.
ACTH
Epidermal growth factor
Growth hormone
Insulin
Nerve growth factor
Answers
[47.1]
B. The symptoms are consistent with acromegaly, or GH overproduction, in the adult. This condition usually is caused by a pituitary
tumor. In the female, breast milk secretion is sometimes observed,
either as a result of GH overproduction or an accompanying overproduction of prolactin. Growth hormone opposes insulin action resulting in decreased glucose utilization and symptoms of diabetes
mellitus. Growth hormone also increases IGF-1 production by the
liver, leading to stimulation of cartilage synthesis and muscle mass.
Excessive bone and tissue growth lead to the characteristic coarse
facial features, enlarged tongue and heart, bone thickening, and other
characteristics associated with this syndrome.
[47.2]
[47.3]
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BIOCHEMISTRY PEARLS
REFERENCES
Litwack G, Schmidt TJ. Biochemistry of hormones I: polypeptide hormones. In:
Devlin TM, ed. Textbook of Biochemistry with Clinical Correlations, 5th ed.
New York: Wiley-Liss, 2002.
Pathophysiology of the endocrine system. An online textbook from Colorado State
University: http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/