- Email: [email protected]
Hypothalmic neurohumors and pituitary tumors
J Chron Dis 1974, Vol. 27, pp. 325-327. PergamonPress. Printed in Great Britain
Editorial HYPOTHALMIC NEUROHUMORS PITUITARY TUMORS
AND
INSIGHTS into initiating and controlling determinants of a neoplastic process are fundamental toward the development of a rational approach to prevention and therapy. Recently, specific, precise and highly sensitive radioimmunoassay methodologies have been evolved to quantitate pituitary protein hormones in blood. Application of these techniques in patients with functional pituitary tumors has provided new observations that have revolutionized current concepts about pituitary tumor secretory behavior and have stimulated innovative avenues of medical therapy. The excessive secretion of human growth hormone (HGH) in acromegaly had been assumed to be an unregulated and constant process from an autonomous pituitary adenoma. In 1969, frequent measurements of circulating HGH throughout 24 hr periods in acromegalic subjects revealed that HGH concentrations not only varied considerably, but often showed qualitatively normal responses to provocative stimulation by arginine or hypoglycemia [l]. Since the effects of these maneuvers upon HGH are presumed to be mediated through the hypothalamic secretion of growth hormonereleasing hormone (GRH) in normal subjects, the concept was proposed that HGH secreting tumors can exhibit hypothalamic dependency. Subsequently, many pharmacologic and physiologic agents that have been discovered to either augment (e.g. p--adrenergic blocking agents, hypoglycemia, arginine, L-DOPA) or inhibit (e.g. a-adrenergic blockers, glucose, progesterone, phenothiazines, glucocorticoids). HGH secretion in normal subjects have also been administered to acromegalic patients. Four patterns of response have been identified: (1) qualitatively normal HGH excursions, (2) ‘paradoxical’ responses (elevations after glucose; inhibition by L-DOPA), (3) HGH release by hypothalamic hormones (e.g. Thyrotropin-releasing hormone (TRH)) that fail to activate HGH secretion in most normals, and (4) blunted or absent changes. A high degree of correlation has been shown between the magnitude of HGH rise after insulin-induced hypoglycemia in individual acromegalic subjects with the magnitude of HGH reduction by glucocorticoids, suggesting a clinical spectrum from hypothalamic dependency to complete autonomy from central nervous influences. That an abnormality in hypothalamic GRH release constitutes the initial event in the hypersecretion of HGH and eventual tumor formation in acromegaly has been hypothesized [2]. One line of evidence supporting this concept is that elevations in serum HGH produced in normals by exogenous administration, comparable to those encountered in acromegaly, inhibit subsequent responses to provocative stimuli. Thus, further increases in serum HGH after arginine administration in acromegaly are inappropriate, in the presence of an already elevated serum HGH, and are compatible
325
326
JOHN F. WILBER
with the notion that the hypothalamic regulation of HGH in acromegaly has been perturbed quantitatively. Whether or not such a concept is valid must await direct measurements of GRH in man. In any event, the discovery of partial or complete hypothalamic dependency in many acromegalics has lead to adjunctive medical therapies with progestins, phenothiazines, L-DOPA, and with the newly discovered hypothalamic tetradecapeptide (somatostatin) that may be a physiologic inhibitor of HGH secretion [3]. Undoubtedly, alternative and more efhcacious therapies will emerge as further knowledge accrues about HGH secretory physiology. An analogous set of observations has been made now in patients with prolactin (HPr) secreting tumors often associated with galactorrbea. The release of prolactininhibiting factor (PIF) which lowers HPr in normals is thought to be under dopaminergic control, since circulating HPr can be reduced following administration of oraI L-DOPA, a dopamine precursor. Qualitatively similar inhibition has been demonstrated in patients with HPr secreting tumors [4]. Moreover, other pharmacologic agents, which raise HPr (TRH, phenothiazines) stimulate HPr release from prolactin-secreting tumors. Whether or not chronic administration of agents that can inhibit HPr secretion can ameliorate galactorrhea, or prevent pituitary tumor growth, is under study. Perhaps the classic example of inappropriate hypothalamic stimulation of pituitary function is bilateral adrenocortical hyperplasia (Cushing’s Disease). Since the slightly increased concentrations of serum ACTH can be suppressed by supraphysiologic quantities of glucocorticoids, it has been inferred that the ‘set point’ of the glucocorticoid responsive hypothalamic negative feedback center has become elevated. Thus, elevations in circulating hydrocortisone are being misinterpreted centrally as ‘normal’. Similarly, following bilateral adrenalectomy, when normal serum cortisol concentrations have been restored by exogenous replacement therapy, further increases in serum ACTH occur. Since enhanced pituitary ACTH release is mediated presumably by increased secretion of the hypothalamic hormone, corticotropin-releasing hormone (CRH), the emergence of pituitary ACTH secreting tumors (Nelson’s syndrome) following surgery may be the result of chronic pituitary stimulation by excessive CRH. Finally, an instance where pituitary growth would appear to be initiated in man by hypothalamic stimulation is the phenomenon of pituitary enlargement in the context of chronic primary (1”) hypothyroidism in adults. Since serum thyroxine (TJ and triiodothyronine (TJ inhibit TRH action upon TSH secreting cells (thyrotrophs), a sustained reduction in serum T1 and T, permits augmented TRH expression and attendant thryotroph hyperplasia. This phenomenon has had clinical implications in differential diagnosis, since the presence of hypothyroidism with sella turcica enlargement has been erroneously interpreted in the past to signify hypothyroidism secondary to a pituitary chromophobe adenoma. The documentation of an elevated serum TSH, however, the hallmark of (1”) myxedema, suppressible by appropriate exogenous thyroid hormone replacement, allows this distinction, and has precluded unwarranted neurosurgical intervention [5]. JOHN F. WILBER,
Northwestern University McGaw Medical Center
M.D.
Hypothalmic
Neurohumors
and Pituitary Tumors
REFERENCES 1. 2. 3. 4. 5.
Cryer PE, Daughaday WH: J Clin Endow Metab 29: 386, 1969 Lawrence AM, Goldfine ID, Kirsteins L: J Clin Endocr Metab 31: 239, 1970 Brazeau P et al.: Science 179: 77, 1973 Malarkey WB, Jacobs LS, Daughaday WH: N Eng J Med 285: 1160, 1971 Lawrence AM, Wilber JF, Hagen TC: Arch Int Med 132: 327, 1973
327
Editorial HYPOTHALMIC NEUROHUMORS PITUITARY TUMORS
AND
INSIGHTS into initiating and controlling determinants of a neoplastic process are fundamental toward the development of a rational approach to prevention and therapy. Recently, specific, precise and highly sensitive radioimmunoassay methodologies have been evolved to quantitate pituitary protein hormones in blood. Application of these techniques in patients with functional pituitary tumors has provided new observations that have revolutionized current concepts about pituitary tumor secretory behavior and have stimulated innovative avenues of medical therapy. The excessive secretion of human growth hormone (HGH) in acromegaly had been assumed to be an unregulated and constant process from an autonomous pituitary adenoma. In 1969, frequent measurements of circulating HGH throughout 24 hr periods in acromegalic subjects revealed that HGH concentrations not only varied considerably, but often showed qualitatively normal responses to provocative stimulation by arginine or hypoglycemia [l]. Since the effects of these maneuvers upon HGH are presumed to be mediated through the hypothalamic secretion of growth hormonereleasing hormone (GRH) in normal subjects, the concept was proposed that HGH secreting tumors can exhibit hypothalamic dependency. Subsequently, many pharmacologic and physiologic agents that have been discovered to either augment (e.g. p--adrenergic blocking agents, hypoglycemia, arginine, L-DOPA) or inhibit (e.g. a-adrenergic blockers, glucose, progesterone, phenothiazines, glucocorticoids). HGH secretion in normal subjects have also been administered to acromegalic patients. Four patterns of response have been identified: (1) qualitatively normal HGH excursions, (2) ‘paradoxical’ responses (elevations after glucose; inhibition by L-DOPA), (3) HGH release by hypothalamic hormones (e.g. Thyrotropin-releasing hormone (TRH)) that fail to activate HGH secretion in most normals, and (4) blunted or absent changes. A high degree of correlation has been shown between the magnitude of HGH rise after insulin-induced hypoglycemia in individual acromegalic subjects with the magnitude of HGH reduction by glucocorticoids, suggesting a clinical spectrum from hypothalamic dependency to complete autonomy from central nervous influences. That an abnormality in hypothalamic GRH release constitutes the initial event in the hypersecretion of HGH and eventual tumor formation in acromegaly has been hypothesized [2]. One line of evidence supporting this concept is that elevations in serum HGH produced in normals by exogenous administration, comparable to those encountered in acromegaly, inhibit subsequent responses to provocative stimuli. Thus, further increases in serum HGH after arginine administration in acromegaly are inappropriate, in the presence of an already elevated serum HGH, and are compatible
325
326
JOHN F. WILBER
with the notion that the hypothalamic regulation of HGH in acromegaly has been perturbed quantitatively. Whether or not such a concept is valid must await direct measurements of GRH in man. In any event, the discovery of partial or complete hypothalamic dependency in many acromegalics has lead to adjunctive medical therapies with progestins, phenothiazines, L-DOPA, and with the newly discovered hypothalamic tetradecapeptide (somatostatin) that may be a physiologic inhibitor of HGH secretion [3]. Undoubtedly, alternative and more efhcacious therapies will emerge as further knowledge accrues about HGH secretory physiology. An analogous set of observations has been made now in patients with prolactin (HPr) secreting tumors often associated with galactorrbea. The release of prolactininhibiting factor (PIF) which lowers HPr in normals is thought to be under dopaminergic control, since circulating HPr can be reduced following administration of oraI L-DOPA, a dopamine precursor. Qualitatively similar inhibition has been demonstrated in patients with HPr secreting tumors [4]. Moreover, other pharmacologic agents, which raise HPr (TRH, phenothiazines) stimulate HPr release from prolactin-secreting tumors. Whether or not chronic administration of agents that can inhibit HPr secretion can ameliorate galactorrhea, or prevent pituitary tumor growth, is under study. Perhaps the classic example of inappropriate hypothalamic stimulation of pituitary function is bilateral adrenocortical hyperplasia (Cushing’s Disease). Since the slightly increased concentrations of serum ACTH can be suppressed by supraphysiologic quantities of glucocorticoids, it has been inferred that the ‘set point’ of the glucocorticoid responsive hypothalamic negative feedback center has become elevated. Thus, elevations in circulating hydrocortisone are being misinterpreted centrally as ‘normal’. Similarly, following bilateral adrenalectomy, when normal serum cortisol concentrations have been restored by exogenous replacement therapy, further increases in serum ACTH occur. Since enhanced pituitary ACTH release is mediated presumably by increased secretion of the hypothalamic hormone, corticotropin-releasing hormone (CRH), the emergence of pituitary ACTH secreting tumors (Nelson’s syndrome) following surgery may be the result of chronic pituitary stimulation by excessive CRH. Finally, an instance where pituitary growth would appear to be initiated in man by hypothalamic stimulation is the phenomenon of pituitary enlargement in the context of chronic primary (1”) hypothyroidism in adults. Since serum thyroxine (TJ and triiodothyronine (TJ inhibit TRH action upon TSH secreting cells (thyrotrophs), a sustained reduction in serum T1 and T, permits augmented TRH expression and attendant thryotroph hyperplasia. This phenomenon has had clinical implications in differential diagnosis, since the presence of hypothyroidism with sella turcica enlargement has been erroneously interpreted in the past to signify hypothyroidism secondary to a pituitary chromophobe adenoma. The documentation of an elevated serum TSH, however, the hallmark of (1”) myxedema, suppressible by appropriate exogenous thyroid hormone replacement, allows this distinction, and has precluded unwarranted neurosurgical intervention [5]. JOHN F. WILBER,
Northwestern University McGaw Medical Center
M.D.
Hypothalmic
Neurohumors
and Pituitary Tumors
REFERENCES 1. 2. 3. 4. 5.
Cryer PE, Daughaday WH: J Clin Endow Metab 29: 386, 1969 Lawrence AM, Goldfine ID, Kirsteins L: J Clin Endocr Metab 31: 239, 1970 Brazeau P et al.: Science 179: 77, 1973 Malarkey WB, Jacobs LS, Daughaday WH: N Eng J Med 285: 1160, 1971 Lawrence AM, Wilber JF, Hagen TC: Arch Int Med 132: 327, 1973
327