[endoc.] Acromegaly
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THE ENDOCRINE SYSTEM
ACROMEGALY A 48-year-old man complaining of impotence sought medical attention. Over the years, he experienced increasing difficulty with maintaining and, more recently, achieving an erection. Further questioning revealed that he was also shaving less frequently. The patient’s shoe size had increased from 9-C to 11-EEE over the past 5 years, and his dental plate had to be altered three times in 6 years. Recently, friends have remarked on changes in his appearance. The patient also admitted to tingling of his fingers and joint pains. On physical examination, he had coarse facial features with a bulbous nose and a beetle-browed look. The tongue was enlarged and teeth were wide spaced. Testing of visual fields showed a loss of both lateral (temporal) fields. The hands and feet were enlarged with spadelike fingers. The liver was enlarged. Laboratory studies showed a fasting plasma glucose level of 150 mg/dl. Fasting growth hormone (GH) was 40ng/ml, and it did not decrease after administration of an oral glucose load. On magnetic resonance imaging, a large pituitary mass protruded upward from the sella turcica. 1. Why did the physician measure the GH? 2. The concentration of what other peptide is certainly elevated in this patient’s plasma, and what is the source of this peptide? 3. What has caused the changes in the patient’s facial features, tongue, hands, feet, and liver? 4. What has caused the neurologic and joint symptoms? 5. What is the normal effect of glucose administration on the plasma GH levels, and why did it not change in this patient? 6. Why is the fasting plasma glucose level elevated, and what changes in the plasma insulin level would you expect to find? 7. What is the most likely cause of the patient’s impotence, and what hormonal abnormalities explain it? 8. What effects might this pituitary tumor mass have on other anterior and posterior pituitary functions, and by what mechanisms? 9. What has caused the impairment of visual fields? 10. What molecule made in the hypothalamus might be therapeutically useful in this patient? 11. If the tumor mass were removed surgically, what physical changes would you expect to see in the patient? 12. If the normal anterior pituitary gland were removed surgically along with the tumor, what would be the consequences for the patient? How would you correct the situation? 13. If the patient wished to restore gonadal function, what hormonal replacement therapy would be needed?
[ANSWER]
Created by Karla Sanchez
Page 1 of 3
10/15/2008
1. The features of this patient and the history of the changes in his appearance and shoe size strongly suggest an excess of growth hormone (GH). This is usually caused by a tumor of pituitary somatotrophs, and this disease is called acromegaly. 2. GH stimulates the synthesis of a peptide mediator called somatomedin or insulin-like growth factor-l (IGF-l). This is produced in the liver, but also in many other tissues that contain GH target cells. Plasma somatomedin levels will be high in patients with GH-secreting tumors. 3. GH via somatomedin (and its plasma membrane receptor) stimulates proliferation of chondrocytes (cartilage cells), osteoblasts and connective tissue cells. This causes excess linear growth in children and giantism results. In adults whose bone growth centers are already closed, appositional bone growth is stimulated. This causes widening of digits, thickened vertebrae, ribs, skull bones, and mandible, with resultant alteration in facial features and position of the teeth. Proliferation of muscle cells increases lean body mass, as exemplified by enlargement of the muscular tongue. The visceral parenchymal cell growth is stimulated, which causes enlargement of organs such as the liver and kidneys. 4. Stimulation of the growth of connective tissue and synovium and cartilage causes osteoarthritis. Also, nerves can be compressed by the growing bone at points where the nerves pass through grooves in the bone. 5. Glucose normally suppresses GH release. When GH is created autonomously by a somatotrophic tumor, there is usually no response to glucose administration. 6. GH is an insulin antagonistic hormone that inhibits insulin-stimulated glucose uptake by muscle cells as well as the insulin effects on the liver. Thus the fasting plasma glucose level rises. In response to the high glucose levels, plasma insulin levels will also be elevated. In addition, GH directly stimulates growth of pancreatic islet beta cells. 7. There are three possible causes of the patient's impotence, which reflect a low plasma testosterone level. First, the pituitary tumor may have destroyed gonadotropin-producing cells by exerting pressure on them. The resultant loss of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) decreases the secretion of testosterone by the Leydig cells of the testes. Second, the tumor may have compressed the hypophyseal stalk and cut off transport of gonadotropin-releasing hormone (GnRH) down the pituitary portal veins from the median eminence to the anterior pituitary gonadotrophs; this process would decrease LH and FSH secretions. Third, such tumors may secrete prolactin, a hormone structurally related to GH. High prolactin levels inhibit GnRH release from the hypothalamus and thus would decrease LH and FSH secretion. 8. Similarly, ACTH and/or TSH secretion might be impaired by the same two mechanisms described above for LH and FSH. This would in turn cause cortisol and thyroxine deficiencies. 9. The optic nerves cross just above the pituitary gland on their route to the occipital cortex. Pressure from a tumor on this crossing point causes a characteristic defect in the visual fields. 10. Growth hormone secretion is normally under dual regulation from the hypothalamus. It is stimulated by GnRH and inhibited by somatostatin. The latter, in a long-acting analog form, can reduce the elevated GH levels in patients with acromegaly because their tumors contain plasma membrane receptors for the hypothalamic inhibitory peptide. 11. The swelling of soft tissues would resolve promptly. However, the bone changes caused by excess GH would resolve very slowly (and perhaps not at all) because of the relatively slow rate of normal bone turnover.
Created by Karla Sanchez
Page 2 of 3
10/15/2008
12. Inadvertent removal of the anterior pituitary gland would cause permanent deficiencies of TSH, ACTH, FSH, LH, MSH, and prolactin. Replacement therapy with thyroxine and cortisol would be necessary. Aldosterone would not be needed because its secretion would be maintained by the reninangiotensin system. Lack of MSH action might cause pale skin and the inability to get a tan upon exposure to ultraviolet light. There are no known consequences of prolactin deficiency in males. Removal of the posterior pituitary gland would not ordinarily cause ADH deficiency as long as the suprahypophyseal portion of the axons from the hypothalamic neurons that synthesize ADH remained intact. 13. If the patient still wished to father a child, and his gonadotrophic cells were not significantly damaged, then treatment with daily pulsatile administration of GnRH would be effective. If his gonadotrophic cells were destroyed, he would require regular administration of LH and FSH. If the patient only wished to restore sexual potency, he would require only testosterone replacement therapy.
Impotence Poor erection Shaves less frequently Hand and feet enlargement with spadelike fingers Finger tingling Joint pains Coarse facial features Loss of lateral (temporal) visual fields Enlarged liver Fasting plasma glucose level of 150 mg/dl Fasting growth hormone (GH) of 40ng/ml GH not decreasing after administration of an oral glucose load Pituitary mass
Created by Karla Sanchez
Page 3 of 3
10/15/2008
ACROMEGALY A 48-year-old man complaining of impotence sought medical attention. Over the years, he experienced increasing difficulty with maintaining and, more recently, achieving an erection. Further questioning revealed that he was also shaving less frequently. The patient’s shoe size had increased from 9-C to 11-EEE over the past 5 years, and his dental plate had to be altered three times in 6 years. Recently, friends have remarked on changes in his appearance. The patient also admitted to tingling of his fingers and joint pains. On physical examination, he had coarse facial features with a bulbous nose and a beetle-browed look. The tongue was enlarged and teeth were wide spaced. Testing of visual fields showed a loss of both lateral (temporal) fields. The hands and feet were enlarged with spadelike fingers. The liver was enlarged. Laboratory studies showed a fasting plasma glucose level of 150 mg/dl. Fasting growth hormone (GH) was 40ng/ml, and it did not decrease after administration of an oral glucose load. On magnetic resonance imaging, a large pituitary mass protruded upward from the sella turcica. 1. Why did the physician measure the GH? 2. The concentration of what other peptide is certainly elevated in this patient’s plasma, and what is the source of this peptide? 3. What has caused the changes in the patient’s facial features, tongue, hands, feet, and liver? 4. What has caused the neurologic and joint symptoms? 5. What is the normal effect of glucose administration on the plasma GH levels, and why did it not change in this patient? 6. Why is the fasting plasma glucose level elevated, and what changes in the plasma insulin level would you expect to find? 7. What is the most likely cause of the patient’s impotence, and what hormonal abnormalities explain it? 8. What effects might this pituitary tumor mass have on other anterior and posterior pituitary functions, and by what mechanisms? 9. What has caused the impairment of visual fields? 10. What molecule made in the hypothalamus might be therapeutically useful in this patient? 11. If the tumor mass were removed surgically, what physical changes would you expect to see in the patient? 12. If the normal anterior pituitary gland were removed surgically along with the tumor, what would be the consequences for the patient? How would you correct the situation? 13. If the patient wished to restore gonadal function, what hormonal replacement therapy would be needed?
[ANSWER]
Created by Karla Sanchez
Page 1 of 3
10/15/2008
1. The features of this patient and the history of the changes in his appearance and shoe size strongly suggest an excess of growth hormone (GH). This is usually caused by a tumor of pituitary somatotrophs, and this disease is called acromegaly. 2. GH stimulates the synthesis of a peptide mediator called somatomedin or insulin-like growth factor-l (IGF-l). This is produced in the liver, but also in many other tissues that contain GH target cells. Plasma somatomedin levels will be high in patients with GH-secreting tumors. 3. GH via somatomedin (and its plasma membrane receptor) stimulates proliferation of chondrocytes (cartilage cells), osteoblasts and connective tissue cells. This causes excess linear growth in children and giantism results. In adults whose bone growth centers are already closed, appositional bone growth is stimulated. This causes widening of digits, thickened vertebrae, ribs, skull bones, and mandible, with resultant alteration in facial features and position of the teeth. Proliferation of muscle cells increases lean body mass, as exemplified by enlargement of the muscular tongue. The visceral parenchymal cell growth is stimulated, which causes enlargement of organs such as the liver and kidneys. 4. Stimulation of the growth of connective tissue and synovium and cartilage causes osteoarthritis. Also, nerves can be compressed by the growing bone at points where the nerves pass through grooves in the bone. 5. Glucose normally suppresses GH release. When GH is created autonomously by a somatotrophic tumor, there is usually no response to glucose administration. 6. GH is an insulin antagonistic hormone that inhibits insulin-stimulated glucose uptake by muscle cells as well as the insulin effects on the liver. Thus the fasting plasma glucose level rises. In response to the high glucose levels, plasma insulin levels will also be elevated. In addition, GH directly stimulates growth of pancreatic islet beta cells. 7. There are three possible causes of the patient's impotence, which reflect a low plasma testosterone level. First, the pituitary tumor may have destroyed gonadotropin-producing cells by exerting pressure on them. The resultant loss of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) decreases the secretion of testosterone by the Leydig cells of the testes. Second, the tumor may have compressed the hypophyseal stalk and cut off transport of gonadotropin-releasing hormone (GnRH) down the pituitary portal veins from the median eminence to the anterior pituitary gonadotrophs; this process would decrease LH and FSH secretions. Third, such tumors may secrete prolactin, a hormone structurally related to GH. High prolactin levels inhibit GnRH release from the hypothalamus and thus would decrease LH and FSH secretion. 8. Similarly, ACTH and/or TSH secretion might be impaired by the same two mechanisms described above for LH and FSH. This would in turn cause cortisol and thyroxine deficiencies. 9. The optic nerves cross just above the pituitary gland on their route to the occipital cortex. Pressure from a tumor on this crossing point causes a characteristic defect in the visual fields. 10. Growth hormone secretion is normally under dual regulation from the hypothalamus. It is stimulated by GnRH and inhibited by somatostatin. The latter, in a long-acting analog form, can reduce the elevated GH levels in patients with acromegaly because their tumors contain plasma membrane receptors for the hypothalamic inhibitory peptide. 11. The swelling of soft tissues would resolve promptly. However, the bone changes caused by excess GH would resolve very slowly (and perhaps not at all) because of the relatively slow rate of normal bone turnover.
Created by Karla Sanchez
Page 2 of 3
10/15/2008
12. Inadvertent removal of the anterior pituitary gland would cause permanent deficiencies of TSH, ACTH, FSH, LH, MSH, and prolactin. Replacement therapy with thyroxine and cortisol would be necessary. Aldosterone would not be needed because its secretion would be maintained by the reninangiotensin system. Lack of MSH action might cause pale skin and the inability to get a tan upon exposure to ultraviolet light. There are no known consequences of prolactin deficiency in males. Removal of the posterior pituitary gland would not ordinarily cause ADH deficiency as long as the suprahypophyseal portion of the axons from the hypothalamic neurons that synthesize ADH remained intact. 13. If the patient still wished to father a child, and his gonadotrophic cells were not significantly damaged, then treatment with daily pulsatile administration of GnRH would be effective. If his gonadotrophic cells were destroyed, he would require regular administration of LH and FSH. If the patient only wished to restore sexual potency, he would require only testosterone replacement therapy.
Impotence Poor erection Shaves less frequently Hand and feet enlargement with spadelike fingers Finger tingling Joint pains Coarse facial features Loss of lateral (temporal) visual fields Enlarged liver Fasting plasma glucose level of 150 mg/dl Fasting growth hormone (GH) of 40ng/ml GH not decreasing after administration of an oral glucose load Pituitary mass
Created by Karla Sanchez
Page 3 of 3
10/15/2008
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