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Double pituitary adenomas are rare in surgical specimens and the most common clinical feature in reported patients has been acromegaly. We report 3 cases of double pituitary lesions in patients who presented with Cushing's disease. In a 22-year-old man (case 1) with delayed puberty and low testosterone levels, mild hyperprolactinemia was diagnosed and treated with dopamine agonist therapy that reduced the prolactin (PRL) levels to normal. Over a 1-year period Cushing's disease developed gradually and was confirmed with classical endocrine testing. In a 27-year-old woman (case 2) who initially presented with severe depression and morbid obesity there was a gradual onset of Cushing's disease; initially she had minimally elevated serum PRL. In a 33-year-old woman (case 3) there was a 2-year history of Cushing's disease characterized by hirsutism, hypertension and weight gain; serum PRL was normal. Magnetic resonance imaging in all 3 patients revealed a microadenoma that was successfully removed by transsphenoidal pituitary surgery. Histology and immunocytochemistry in case 1 and case 3 revealed a corticotroph cell adenoma and a PRL cell adenoma in separate areas of the pituitary. In case 3 the PRL cell adenoma was "silent" but in case 1 the PRL cell adenoma may have been the cause of the mild hyperprolactinemia. In case 2 nodular corticotroph hyperplasia was the cause of Cushing's disease and a "silent" PRL cell adenoma was also identified. We conclude from these cases and a literature review that double pituitary lesions may occur in patients with Cushing's disease. The corticotroph part of the double lesion may consist of a corticotroph cell adenoma or, as reported in this study, of corticotroph nodular hyperplasia. The counterpart of the double lesion may consist either of a "silent" PRL cell adenoma or a functional PRL cell adenoma causing hyperprolactinemia.

Object: Although transsphenoidal surgery has become the standard of care for Cushing's disease, it is often unsuccessful in normalizing cortisol production. In this study the authors investigate the safety and efficacy of gamma knife radiosurgery (GKRS) for Cushing's disease after failed transsphenoidal surgery., Methods: The records of all patients who underwent GKRS at the authors' institution after unsuccessful transsphenoidal surgery for Cushing's disease were retrospectively reviewed. Successful treatment was considered a normal or below-normal 24-hour urinary free cortisol (UFC) level. Records were also evaluated for relapse, new-onset endocrine deficiencies, interval change in tumor size, and visual complications. Forty-three patients underwent 44 gamma knife procedures with follow up ranging from 18 to 113 months (mean 39.1, median 44 months). Normal 24-hour UFC levels were achieved in 27 patients (63%) at an average time from treatment of 12.1 months (range 3-48 months). Three patients had a recurrence of Cushing's disease at 19, 37, and 38 months, respectively, after radiosurgery. New endocrine deficiencies were noted in seven patients (16%). Follow-up magnetic resonance images obtained in 33 patients revealed a decrease in tumor size in 24, no change in nine, and an increase in size in none of the patients. One patient developed a quadrantanopsia 14 months after radiosurgery despite having received a dose of only 0.7 Gy to the optic tract., Conclusions: Gamma knife radiosurgery appears to be safe and effective for the treatment of Cushing's disease refractory to pituitary surgery. Delayed recurrences and new hormone deficiencies may occur, indicating the necessity for regular long-term follow up.

Radiosurgery for pituitary adenomas is clearly attaining a more prominent position in the spectrum of management of these lesions. It is our belief that improvements in radiosurgical technology can significantly enhance the outcome for patients with these lesions.

Data published in the past decade have demonstrated that adults who are deficient in growth hormone (GH) experience deleterious clinical consequences without treatment. In 1996, the Food and Drug Administration approved the use of GH in adults who were GH deficient as a result of hypothalamic or pituitary disease. However, there are other conditions in adults for which GH treatment has also been approved (acquired immune deficiency syndrome [AIDS]-related wasting) or for which it is being considered, such as aging, catabolic states, and cardiomyopathy. Clinical issues revolve around the rationale for treatment; the diagnostic evaluation; the effects of GH therapy on body composition, bone density, lipids, and cardiac function; and appropriate dosing and follow up. Clearly, the use of GH in adults raises reimbursement issues as well. In this article, Dr. Beverly M.K. Biller provides an overview of the rationale for the treatment of adult-onset GH deficiency and reviews its etiology and clinical features as well as reimbursement and utilization issues related to treatment. Dr. Mary Lee Vance discusses various assays and criteria used in the diagnostic evaluation of the patient with adult-onset GH deficiency. Dr. David L. Kleinberg focuses on the effects of GH therapy on body composition, bone density, lipid profiles, and cardiac function, as well as on reimbursement issues regarding body composition studies. To complete the clinical portion of this session, Dr. David M. Cook addresses dosing and follow up. To address economic implications, Dr. Terry Gordon provides the payer's perspective on the diagnosis and treatment of adult-onset GH deficiency.

Objectives: Treatments for acromegaly, a growth hormone disorder, can be burdensome to patients, often requiring multiple self-administered injections daily. We developed the Impact on Lifestyle Questionnaire (ILQ) to measure the impact on patient's lifestyle imposed by the burden of injectable treatments for acromegaly. The primary objective of this study was to establish the reliability and validity of the ILQ., Methods: The ILQ consists of the SF-12 and 30 additional questions. Thirty-four patients, from two sites, completed the ILQ and scales measuring related concepts. Fourteen patients also completed a retest survey 4 weeks later. Survey sample data were combined with ILQ data from another 56 patients with acromegaly for a factor analysis. Reliability was assessed with Cronbach's alpha and test-retest. Zero-order correlations were examined between ILQ subscales and symptoms, depression, SF-12 mental and physical components, a measure of self-care burden, appraisal of illness, and single-item measures of quality of life and satisfaction., Results: The preconceived subscale structure was supported by factor analysis. These factors were internally consistent and stable over time. Good convergent validity was demonstrated between the Burden and Disruption scales with other measures of the burden of treatment. Patients indicated that they were generally compliant with therapy, and that treatment was not particularly burdensome or disruptive. Results based on the ILQ were consistent with other scales and qualitative responses., Conclusions: The ILQ has three subscales, Burden, Lifestyle Disruption, and Compliance, that are reliable and demonstrate preliminary evidence of construct validity.

Background: Patients with acromegaly are currently treated with surgery, radiation therapy, and drugs to reduce hypersecretion of growth hormone, but the treatments may be ineffective and have adverse effects. Pegvisomant is a genetically engineered growth hormone-receptor antagonist that blocks the action of growth hormone., Methods: We conducted a 12-week, randomized, double-blind study of three daily doses of pegvisomant (10 mg, 15 mg, and 20 mg) and placebo, given subcutaneously, in 112 patients with acromegaly., Results: The mean (+/-SD) serum concentration of insulin-like growth factor I (IGF-I) decreased from base line by 4.0+/-16.8 percent in the placebo group, 26.7+/-27.9 percent in the group that received 10 mg of pegvisomant per day, 50.1+/-26.7 percent in the group that received 15 mg of pegvisomant per day, and 62.5+/-21.3 percent in the group that received 20 mg of pegvisomant per day (P<0.001 for the comparison of each pegvisomant group with placebo), and the concentrations became normal in 10 percent, 54 percent, 81 percent, and 89 percent of patients, respectively (P<0.001 for each comparison with placebo). Among patients treated with 15 mg or 20 mg of pegvisomant per day, there were significant decreases in ring size, soft-tissue swelling, the degree of excessive perspiration, and fatigue. The score fortotal symptoms and signs of acromegaly decreased significantly in all groups receiving pegvisomant (P< or =0.05). The incidence of adverse effects was similar in all groups., Conclusions: On the basis of these preliminary results, treatment of patients who have acromegaly with a growth hormone-receptor antagonist results in a reduction in serum IGF-I concentrations and in clinical improvement.

Objective: Transsphenoidal surgery for Cushing's disease from a pituitary adenoma is an effective and safe treatment. Definitive preoperative diagnosis of Cushing's disease caused by a pituitary adenoma is often difficult, particularly in patients with normal imaging studies and a normal sella turcica. We present the outcome of transsphenoidal surgery in patients with presumed Cushing's disease and a normal pituitary magnetic resonance imaging scan., Methods: Between January 1992 and December 1997, 105 patients underwent transsphenoidal surgery for Cushing's disease at our institution. The criteria for inclusion in this study were clinical and biochemical studies strongly suggestive of Cushing's disease, a normal magnetic resonance imaging scan with normal sella and sellar contents, no previous pituitary surgery, and transsphenoidal surgery performed at this institution. Eighteen patients fulfilled these criteria, and their results were analyzed retrospectively., Results: The average age of the patients was 47.8 years; there were 13 women and 5 men. Inferior petrosal sinus sampling with and without corticotropin-releasing hormone stimulation was performed in 16 patients with correct localization of the lesion in 13 (81%). During surgery, the surgeon identified and removed 17 pituitary tumors; 15 patients had selective adenomectomies, one had a hemihypophysectomy, and two had total hypophysectomies. Thirteen discrete adrenocorticotropic hormone-secreting adenomas were proven histologically, and one pituitary gland had diffuse involvement with tumor. Complications occurred in five patients. Sixteen patients who were followed up for an average of 21.6 months had sustained remission, 12 of whom were profoundly hypocortisolemic immediately after surgery., Conclusion: In patients with Cushing's disease and a normal magnetic resonance imaging scan, an experienced surgeon can perform transsphenoidal surgery resulting in effective removal of very small microadenomas, with clinical and biochemical remission in the majority. Inferior petrosal sinus sampling is helpful in localizing the adenoma.

Active acromegaly is almost always the result of a benign growth hormone (GH)-secreting adenoma of the pituitary gland. Because the same pituitary stem cell can produce both GH and prolactin (PRL), many acromegalic patients also have hyperprolactinemia. The advantages of surgical excision of pituitary adenomas associated with acromegaly include: (1) prompt decrease in GH; (2) reliable and immediate relief of the mass effect from the tumor (decompression of the optic nerves and chiasm), and (3) the opportunity to obtain tumor tissue for characterization and investigative study. Currently, more than 97% of operations for removal of pituitary tumors associated with acromegaly are done using the transsphenoidal approach rather than craniotomy. Technical advances to make the surgery safer continue to evolve, and include endoscopic approaches, computer-guided image-based intraoperative visualization, and intraoperative magnetic resonance imaging. Criteria for satisfactory remission of acromegaly after surgery are the same as those used for medical management. They include normal insulin-like growth factor (IGF)-I and suppression of GH to undetectable levels (<1.0 ng/ml) during an oral glucose tolerance test (OGTT). Data from a recent series of 86 patients operated upon for acromegaly at the University of Virginia and followed for more than 1 year have been reviewed. In patients receiving surgery as the initial procedure, 67% had a normal IGF-I, and 52% suppressed to <1.0 ng/ml in an OGTT. There was one true recurrence of disease diagnosed 81 months after surgery. Results are best in patients with noninvasive microadenomas. Gamma knife radiosurgery has been a valuable adjunct in those patients who fail to achieve postoperative remission. Pathological evaluation of the tumors revealed that 16% expressed GH only, 25% stained for GH and glycoprotein hormones (follicle stimulating hormone, thyroid hormone, thyroid stimulating hormone, alpha-subunit), 21% for GH and PRL, and 33% for GH, PRL and glycoprotein hormones. There was one acidophil stem cell tumor and 10% had the mammosomatotroph subtype. This contemporary series was free of mortality or serious complications. One patient had a transient cerebrospinal fluid leak and 3 developed transient SIADH with hyponatremia. Surgical treatment remains an important aspect of the combined management of patients with acromegaly., (Copyright 2000 S. Karger AG, Basel)

Standard techniques of conventional radiation therapy have been used for many years to treat pituitary adenomas and craniopharyngiomas. These techniques are not always effective and carry with them morbidity in the form of damage to the normal pituitary gland, damage to the hypothalamus, the potential of damage to the visual system and to intellectual functions of the brain and a small but real risk of the development of secondary malignancies. In an effort to avoid these complications and to provide more effective adjunctive radiation therapy, techniques of stereotactic delivery of high-dose radiation to the pituitary region have been developed, known as radiosurgery. The history of the development of radiosurgery and its application to pituitary problems are recounted in this article, as are a number of the controversies that currently exist and need to be considered as these modalities of stereotactic radiosurgery are applied more frequently and to better effect in the future.

The effects of octreotide (up to 5 yr) as primary treatment in 26 patients with acromegaly were compared with those in 81 patients with acromegaly who received octreotide as secondary or adjunctive therapy after previous surgery and/or pituitary radiation. These patients were part of a multicenter study that took place between 1989-1995. The study was divided into 3 phases beginning with a 1-month placebo-controlled treatment period followed by a 1-month washout period. In the second phase, patients were randomized to treatment with either 100 or 250 micrograms octreotide, sc, every 8 h for 6 months. Octreotide was then discontinued for 1 month and reinitiated at the lower dose for a total mean treatment duration of 39 months. The dose was titrated by each investigator to improve each patient's individual response, which included improvement in symptoms and signs of acromegaly as well as reduction of GH and insulin-like growth factor I (IGF-I) into the normal range. In the second phase of the study, in which patients were randomized to either 100 or 250 micrograms octreotide, three times daily, mean integrated GH and IGF-I concentrations after 3 and 6 months were equivalent in the primary and secondary treatment groups. During long term open label treatment, mean GH fell from 32.7 +/- 5.2 to 6.0 +/- 1.7 micrograms/L 2 h after octreotide injection in the primary therapy group and remained suppressed for a mean period of 24 months (range, 3-60 months). The mean final daily dose was 777 micrograms. In the patients receiving secondary treatment, mean GH fell from 30.2 +/- 7.6 to 5.6 +/- 1.1 micrograms/L after 3 months and remained suppressed for the remainder of the study (average dose, 635 micrograms daily). Mean IGF-I concentrations fell from 5.2 +/- 0.5 x 10(3) U/L (primary treatment group) and 4.7 +/- 0.4 x 10(3) U/L (secondary treatment group) to a mean of 2.2 +/- 0.3 x 10(3) U/L in both groups after 3 months of open label treatment and remained suppressed. IGF-I was reduced into the normal range during at least half of the study visits in 68% of the primary treatment group and in 62% of the secondary treatment group. Patients whose GH levels fell to at least 2 SD below the baseline mean GH were considered responders. There was no significant difference in the percentage of responders in the primary and secondary treatment groups (70% vs. 61%), nor was there a statistical difference in the mean GH concentrations between the groups. Symptoms of headache, increased perspiration, fatigue, and joint pain were reported at baseline by 46%, 73%, 69%, and 85%, respectively, of patients in the primary therapy group and improved during 3 yr of octreotide treatment in 50-100%. Similarly, these acromegaly-related symptoms were reported by 62%, 58%, 78%, and 60% of patients in the secondary therapy group, and improvement was noted in 62-88%. Pituitary magnetic resonance imaging scans were available in 13 of 26 patients in the primary treatment group before and after 6 months of octreotide treatment. Tumor shrinkage was observed in 6 of 13 patients, with reduction in tumor volume greater than 25% in only 3. Of 6 patients with documented tumor shrinkage, IGF-I was reduced into the normal range in 4 patients. Of the 7 remaining patients in whom tumor shrinkage was less than 10%, IGF-I was reduced into the normal range in 4 patients. Of the 7 remaining patients in whom tumor shrinkage was less than 10%, IGF-I was reduced into the normal range in 5 patients. The degree of tumor shrinkage did not correlate with the percent reduction in IGF-I or GH. In summary, octreotide was equally effective in 26 previously untreated acromegalic patients (primary treatment group) and 81 patients previously treated with either surgery or pituitary radiation (secondary treatment group). These observations call into question the current practice of surgical resection of all newly diagnosed GH-secreting pituitary adenomas regardless of the likelihood of cure. (AB

Fibrosarcomas involving the sella turcica are rare lesions and, when encountered, have been associated with previous radiation of a pituitary adenoma. Although primary intracranial fibrosarcomas are well recognized, no case of primary fibrosarcoma of the sella turcica has been reported to date. We describe here a patient who presented with a 2-month history of headache, visual disturbances, and diabetes insipidus. Her past medical history was unremarkable, with no radiation therapy. Magnetic resonance imaging revealed a sellar/suprasellar lesion that at surgery appeared firm in consistency. A radical removal of the mass was performed through a transsphenoidal approach. The patient recovered promptly from the operation and 2 weeks later, given the aggressive histologic appearance of the lesion, underwent gamma knife radiosurgery. Seven months after diagnosis, the patient presented with local tumor recurrence. A subtotal surgical resection was performed, and additional postsurgical treatment is still under consideration. Although most often related to previous radiation of the pituitary gland, primary fibrosarcomas can occur in the sella. This possibility should be suspected in the differential diagnosis of sellar masses that lack the classical characteristics of the much more common pituitary adenomas.

The clinical presentation and characterization of the mutation in members of a large kindred with von Hippel-Lindau disease (VHLD) and pheochromocytoma were examined. Twenty-five proven cases of VHLD occurring in four generations of a large kindred have been followed since 1964, and pheochromocytoma has occurred in 17. Symptoms of pheochromocytoma developed at an early age, on average at 12.5 +/- 1.3 yr, and definitive diagnosis and treatment of pheochromocytoma occurred at 19.9 +/- 2.6 yr. Significantly higher urine catecholamine concentrations were observed in younger patients than in older ones. Mutation analysis was performed in 14 family members, and a new mutation in the VHLD gene was identified in 11; this mutation is a G to T change at nucleotide 658 that results in the substitution of a serine for an alanine residue at position 149 of the polypeptide chain. Seven of the 11 patients with the mutation have VHLD; four, all 10 yr old or less, are asymptomatic and have no evidence of disease, but are at high risk for developing VHLD. These children are being followed closely for clinical and biochemical manifestations. The characterization of this new mutation has permitted identification of family members who are likely to develop VHLD.

The modern era of growth hormone research began in 1981 with the characterization and synthesis of the primary stimulator of GH synthesis and secretion, growth hormone releasing hormone. Discovery of this peptide and studies in human adults and children resulted in unraveling the complex nature of the regulation of GH secretion. Discovery of regulatory mechanisms has permitted a greater understanding of normal and abnormal growth hormone physiology. The use of growth hormone therapeutically as replacement in GH deficient adults is in its medical infancy, but preliminary studies indicate a beneficial effect on body composition, serum lipid concentrations, bone mineral density, muscle strength, and exercise endurance. These studies over the past decade resulted in Food and Drug Administration approval of GH for replacement in adults with hypothalamic or pituitary disease. It remains to be determined whether or not chronic GH replacement will have beneficial effects on morbidity and mortality. The use of growth hormone in other areas such as aging, catabolic illness, obesity, diabetes, and muscular disorders is under active investigation and risks and benefits remain to be determined.

An effective systematic approach for the management of prolactin-secreting pituitary adenomas is described. This methodology has stood the test of time and has been modified in accordance with experience. The primary goals are to obtain satisfactory control of the tumor and to avoid undesirable side effects related to dopamine agonist-based therapeutic agents.

Determinants of GH secretion in adults are multifactorial. Of all of the influences on GH secretion, it is highly probable that the two more influential factors are age and body composition: older age and increased adiposity are negative influences on GH release. Although aging per se is immutable, body composition can be modified by appropriate diet and exercise.

The metabolic state influences GH secretion and, in turn, GH secretion influences overall body metabolism. While these are distinct physiological entities, separation of these interrelated phenomena should be considered artificial since the overall result is an organism which retains functional capacity in the setting of a variety of circumstances.

A prospective study of growth hormone, insulin-like growth factor (IGF-1), and cortisol secretion was undertaken in six adults with burn injury. Serum concentrations of growth hormone and IGF-1 were low in all patients during the first 2 weeks of hospitalization. The mean growth hormone level was 4.35 +/- 0.83 micrograms/L on day 1 and 1.70 +/- 0.50 micrograms/L on day 13. The mean serum concentration of IGF-1, which reflects overall growth hormone secretion, was 0.43 +/- 0.09 U/ml on day 1 and 0.61 +/- 0.11 U/ml on day 13; these values are distinctly low. After 3 to 4 weeks, IGF-1 concentrations increased to the mid-normal range, whereas growth hormone values did not change. Morning plasma cortisol concentrations were modestly elevated; however, urine free cortisol concentrations, which reflect total cortisol secretion, were elevated 2 to 28 times above normal values at the time of admission (mean, 443.5 +/- 323.7 nmol/L). Urinary free cortisol concentrations remained elevated after 2 weeks (mean, 230.5 +/- 94.5 nmol/L). Patients with burn injury have inappropriately low growth hormone secretion and IGF-1 production in spite of the stress of the injury and more than adequate nutritional therapy.

The regulation of growth hormone (GH) secretion in humans is a complex process which comprises more than stimulation by GH-releasing hormone and suppression by somatostatin. Although these two hypothalamic hormones are the primary regulators of GH secretion, they most likely function as the final pathway through which numerous factors influence GH synthesis and secretion. Some of the modulators of GH secretion include neurotransmitters, circulating glucose, insulin-like growth factor I and gonadal steroid concentrations. Age, nutrition and body composition are also related to the amount and pattern of GH secretion in humans. The influence of nutritional status on GH secretion is becoming more clearly defined.

Growth hormone (GH) secretion in man is pulsatile and this pattern is regulated by both GH-releasing hormone (GHRH) and somatostatin. A large body of experimental evidence in both man and animals supports the model that bursts of GH secretion are mediated by a reduction of tonic hypothalamic somatostatin secretion. Our studies have been performed in normal subjects with frequent blood sampling for GH measurements (from 20-minute to 30-second intervals); the data have been analyzed by computer algorithms to objectively determine pulse characteristics and, in some studies, to estimate both pituitary secretion and clearance rates using deconvolution analysis. The studies include profiles of GH secretion in normal men and women in fed and fasted states; analysis of GH secretion during sleep; and administration of GHRH during different stages of sleep and after sleep deprivation. The variable GH response to exogenous GHRH and the attenuated response after 6 hours of GHRH infusion to GHRH, while not to hypoglycemia, as well as the pulsatile profile of GH secretion in response to continuous GHRH infusions (24 hours to 14 days), all support the thesis that it is hypothalamic somatostatin that determines the timing of bursts of GH secretion. This is further confirmed by the profile of GH secretion in a patient with ectopic GHRH secretion. Recently, we have initiated studies with the novel synthetic GH releasing hexapeptide, HisDTrpAlaTrpDPheLysNH2 (GHRP). Our studies show that it acts synergistically with GHRH. Several lines of evidence suggest that GHRP stimulates GH secretion independently of GHRH receptors and acts at both the hypothalamic and pituitary levels. It may act to functionally antagonize somatostatin.

We have previously shown that a substantial part of human GH is complexed with GH-binding proteins (BPs) when GH is incubated with plasma in vitro. The proportion of GH bound in vivo, however, is unknown and may differ because of factors that cannot be assessed in vitro, such as binding to tissue receptors, distribution of GH outside the vascular compartment, and fluctuating GH and possibly BP levels. Accordingly, we studied the plasma transport characteristics of GH in vivo in six normal men. Monomeric, natural sequence human GH (Humatrope, Eli Lilly Co.) was injected iv in a dose designed to yield physiological plasma levels. Endogenous GH was suppressed before injection with oral glucose administration. Fifteen minutes after injection, plasma was obtained and immediately analyzed by zonal and frontal analysis in gel chromatography, followed by GH measurement in the fractions by RIA. The results obtained were very similar to those derived from in vitro studies, regardless of which analytical method was used. Frontal analysis at 37 C, which most directly reflects the true bound fraction, showed that 38.8 +/- 4.7% (mean +/- SD) of GH was bound to BPs at plasma GH levels ranging from 32-59 micrograms/L, indistinguishable from in vitro results. [When allowance was made for partial BP saturation, the fraction bound at low GH levels (greater than 7 micrograms/L) was calculated as 45.5 +/- 7.5%.] There was evidence for binding to both high and low affinity BPs in the expected proportions. In contrast to complex formation between GH and BPs, no evidence was obtained for conversion of the monomeric GH to oligomeric forms. We conclude that in vitro predictions about binding of GH to BPs in human plasma are representative of in vivo conditions. Shortly after a GH pulse, almost half of plasma GH circulates in complexed form, primarily bound to the high affinity (receptor-related) BP. Aggregation of GH in plasma does not occur (at least within a 15-min period), suggesting that the pituitary is the predominant, if not sole, source of circulating GH oligomers.

Alterations in pulsatile GH release in 13 acromegalic patients (7 men and 6 women) were studied by measuring serum GH concentrations in blood sampled every 5 min over 24 h. Specific properties of pulsatile GH release were quantitated by Cluster analysis, and Fourier expansion time series analysis was used to resolve fixed periodicities underlying GH secretion. Compared with sex-matched controls, 24-h integrated GH concentrations (IGHC; min.mg/L) were elevated 15-fold in the acromegalic men (40 +/- 27 vs. 2.6 +/- 0.35; P = 0.02) and 10-fold in the acromegalic women (43 +/- 19 vs. 4.1 +/- 0.35; P = 0.01). The increase in integrated GH concentrations was accounted for by an increase in the nonpulsatile fraction [men, 31 +/- 20 vs. 0.65 +/- 0.10 (P = 0.001); women, 35 +/- 14 vs. 1.2 +/- 0.10 (P = 0.0008)]; the pulsatile component was not different from that in normal subjects. Acromegalics had an increased number of pulses per 24 h [men, 17 +/- 1.5 vs. 6.7 +/- 1.4 (P = 0.0001); women, 19 +/- 1.6 vs. 11 +/- 1.0 (P = 0.002)] and increased basal GH concentrations [men, interpulse valley mean, 22 +/- 14 vs. 1.4 +/- 0.30 micrograms/L (P = 0.0006); women, 27 +/- 12 vs. 1.3 +/- 0.20 micrograms/L (P = 0.0001)]. The proportion of the mean GH concentration attributable to 24-h rhythmicity was decreased in the acromegalic patients. Five patients studied during biochemical remission (4 after transsphenoidal surgery and 1 during bromocriptine therapy) had GH profiles that resembled those of normal subjects. Pulsatile GH secretion in acromegaly is characterized by augmented basal GH concentrations, increased GH pulse frequency, and an attenuation of the underlying 24-h rhythm. Such a pattern may be secondary to the intrinsic pathology of adenomatous somatotrophs and/or the effects of altered hypothalamic regulation.

The half-life (t1/2) of disappearance of endogenous GH from serum was studied using physiological effectors to stimulate and then suppress GH release. GH secretion was stimulated by a single iv injection of GHRH, followed 45 min later by an iv bolus dose and then a 2.5-h infusion of somatostatin (SRIH) to suppress further release. The in vivo t1/2 of GH in seven men was calculated from serum GH concentrations measured at frequent intervals after beginning the SRIH infusion. The mean t1/2 of endogenous GH was 18.9 +/- 0.8 (+/- SE) min by monoexponential analysis and 3.5 +/- 0.7 and 20.7 +/- 0.7 min by biexponential fitting. In these normal men, the decline in GH concentrations after GHRH and SRIH administration was similar to that after the administration of GHRH alone, which yielded a t1/2 of 20.3 +/- 1.9 min. We conclude that the physiological kinetics of endogenous GH removal/disappearance can be estimated in vivo in man using GHRH with or without SRIH infusion.

Human GH (hGH) in the circulation of acromegalic patients and pharmacologically stimulated normal subjects consists of several monomeric and oligomeric molecular forms. However, little is known about the nature of plasma hGH under physiological conditions. We examined the molecular composition of plasma hGH secreted in response to synthetic human pancreatic tumor GRF-(1-40) (hpGRF-40), a peptide closely resembling or identical to hypothalamic GRF. The peptide (10 micrograms/kg) was injected iv into six normal men, and blood was obtained 30 min later. Plasma hGH was characterized by gel filtration and by polyacrylamide gel electrophoresis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and isoelectric focusing after extraction from plasma by immunoadsorbent chromatography. At least 53% of hGH eluted as little (monomeric) hGH, 27% as big (dimeric) hGH, and 20% or less as big-big (oligomeric and spurious) hGH during gel filtration. Among the monomeric forms, the 22,000-dalton form was predominant (83%), with smaller quantities of the 20,000-dalton variant (11%), and one or more unidentified acidic forms (N alpha-acetylated, deamidated, or cleaved hGH) (6%) also present. The molecular composition of plasma hGH secreted in response to hpGRF-40 is similar to that released after pharmacological stimuli or that circulating in acromegaly.

A growth-hormone-releasing factor has been characterised and sequenced from a pancreatic tumour removed from a patient with acromegaly. It is a 40-residue linear peptide. Synthetic human pancreatic growth-hormone-releasing factor (hpGRF-40), 1 microgram/kg bodyweight, was administered as an intravenous bolus to six healthy men. hpGRF-40 selectively stimulated growth-hormone secretion. Serum growth-hormone concentrations were increased within 5 min, reaching a peak between 30 and 60 min (20 . 4 +/- 6 . 5 ng/ml compared with 2 . 1 +/- 0 . 1 ng/ml after placebo). Serum levels of prolactin, thyrotropin, luteinising hormone, and corticotropin (measured indirectly through plasma cortisol) were not increased after administration of hpGRF-40. Similarly, the concentrations of blood glucose, plasma insulin, glucagon, pancreatic polypeptide, cholecystokinin, gastrin, gastric inhibitory peptide, motilin, and somatostatin were unaffected by hpGRF-40. There were no changes in blood pressure, pulse rate, or body temperature, and no side-effects were noted. The characteristics of this peptide fulfil many of the criteria required of the hypophysiotropic growth-hormone-releasing hormone. hpGRF holds promise for a new approach to the diagnosis and treatment of various disorders of growth-hormone secretion.

Human pancreatic GRF (hpGRF-40; 1 microgram/kg, iv) selectively stimulates GH release in normal men (9). We now report the effects of graded doses of hpGRF-40 on GH release in 12 normal men. Mean peak increments in serum GH after vehicle and the various doses of hpGRF-40 were 1.13, 11.40, 14.60, 17.01, 14.45, and 15.60 ng/ml after vehicle and 0.1, 0.33, 1.0, 3.3, and 10 micrograms/kg hpGRF-40 (iv bolus), respectively. Peak values were observed 30-60 min after hpGRF-40 treatment. There was considerable variability of responsiveness among individual subjects, and no dose-response relationship between the doses and maximal GH values was found. However, the higher doses of 3.3 and 10.0 micrograms/kg resulted in a more prolonged and biphasic pattern of GH release. A side effect of facial flushing of less than 5-min duration occurred in 4 or 6 subjects who received 3.3 micrograms/kg and in all 5 who received 10 micrograms/kg of hpGRF-40. No changes in serum glucose, LH, TSH, PRL, plasma cortisol, or 8 enteropancreatic hormones occurred after hpGRF-40 treatment. There were small increases in serum somatomedin C levels 24 h after the administration of various doses of hpGRF-40 in 11 of 13 studies. Plasma immunoreactive GRF levels measured 5 min after injection were 0.09, 2.0, 4.9, 23.9, and 66.6 ng/ml after 0.1, 0.33, 1.0, 3.3, and 10 micrograms/kg hpGRF-40, respectively. Serum GH responses after insulin-induced hypoglycemia were compared to GH responses after hpGRF-40. Comparable peak GH stimulation occurred with both provocative tests. Mean +/- SEM peak GH was 20.2 +/- 1.0 ng/ml after insulin and 20.9 +/- 3.2 after hpGRF-40 treatment. hpGRF-40 selectively stimulates GH release in normal men over a dose range of 0.1-10 micrograms/kg and is an effective probe to investigate the dynamics of GH release.

Human pancreatic tumor GH-releasing factor-40 (hpGRF-40) selectively stimulates GH secretion in normal men and in some adults with GH deficiency. To study its effects in women, we administered hpGRF-40 (3.33 micrograms/kg) or an equivalent volume of vehicle as an iv bolus at 0900 h to 10 normal women during the early follicular, late follicular, and midluteal phases of the menstrual cycle. Serum concentrations of GH, PRL, LH, and FSH were measured at intervals between 0800-1100 h. Serum somatomedin-C concentrations were measured before and 24 h after the administration of vehicle of hpGRF-40. Within 1-3 min after the injection of hpGRF-40 all women described warmth localized to the head and neck and exhibited facial flushing. No changes in pulse rate or blood pressure were noted. When expressed as change from baseline and compared to control values, peak levels of serum GH (nanograms per ml; mean +/- SEM) were higher after hpGRF-40 treatment during the early follicular (5.4 +/- 3.2 vs. 34.9 +/- 8.3; control vs. test day; P = 0.011), late follicular (5.6 +/- 1.5 vs. 25.2 +/- 6.8; P = 0.014), and luteal (0.8 +/- 1.0 vs. 32.7 +/- 12.8; P = 0.033) phases of the menstrual cycle. Similarly, integrated serum GH levels (nanograms per ml/h) were higher after hpGRF-40 administration during the early follicular (0.72 vs. 16.1; P = 0.011), late follicular (0.83 vs. 9.9; P = 0.037), and luteal (-1.54 vs. 17.0; P = 0.036) phases of the cycle. When the increases in serum GH after hpGRF-40 treatment were compared among the phases of the menstrual cycle, however, no differences were found. Serum somatomedin-C values 24 h after hpGRF-40 treatment were higher than those 24 h after vehicle at all stages of the menstrual cycle. hpGRF-40 did not stimulate the release of PRL, LH, or FSH. We conclude that hpGRF-40 stimulates the release of GH, but that in response to the dose used, hpGRF-40-stimulated GH release does not vary during the menstrual cycle.

Twenty-nine patients with acromegaly (8 untreated and 21 previously treated in various ways) and 16 normal men were given iv bolus doses of human pancreatic tumor GH-releasing factor (hpGRF-40). Twenty-five of the 29 patients responded to hpGRF-40 with elevations of plasma GH. The magnitude of the responses varied widely. Responses of untreated patients were generally similar to those of the normal subjects. Previously treated patients had a significantly lower response than normal individuals [change in GH, 7.5 +/- 1.8 vs. 42.0 +/- 11.0 ng/ml (mean +/- SEM); P less than 0.01], and 4 patients who had received radiation therapy failed to respond to hpGRF-40. There was no significant correlation between the magnitude of the response and patients' age, sex, baseline GH levels, GH responsiveness of TRH, or GH suppression after oral glucose administration. Patients studied both pre- and postoperatively were responsive to hpGRF-40 at all times tested, but the magnitude of the response decreased after successful surgical removal of the adenoma. Thus, most patients with treated or untreated acromegaly respond to hpGRF-40, but their responses do not clearly distinguish them from normal subjects. GH-releasing hormone testing is unlikely to replace other endocrine tests available for the diagnosis and evaluation of acromegaly.

Two patients with acromegaly secondary to ectopic GHRH secretion by metastatic carcinoid tumors were studied before and during therapy with the somatostatin analog octreotide (SMS 201-995). GH and GHRH secretory patterns were assessed during intermittent sc administration, continuous sc infusion (CSI), and continuous iv infusion of octreotide. Octreotide reduced serum GH and plasma GHRH levels in the two patients, although there was differential sensitivity of GH and GHRH. Intermittent sc therapy transiently lowered serum GH in both patients. A higher iv dose was required to reduce plasma GHRH by 50% than to reduce serum GH by 50% (2.0 vs. 0.05 micrograms/kg.h, respectively; patient 1). A similar pattern was found during CSI octreotide administration in the same patient. Chronic therapy with intermittent sc and CSI octreotide was assessed by serial 24-h profiles of GH and GHRH secretion in patient 2. Mean hourly serum GH levels decreased from a pretreatment level of 31.5 +/- 3.5 (+/- SE) to 9.5 +/- 1.5 micrograms/L during CSI therapy (1000 micrograms/day or 0.40 micrograms/kg.h). In contrast, plasma GHRH levels were less effectively suppressed. The mean serum GH levels and the variation in hourly GH values were reduced to a greater extent with CSI than with intermittent sc therapy. Serum insulin-like growth factor I also declined from 5.9 x 10(3) to 2.5 x 10(3) U/L during chronic CSI therapy (patient 2). CSI therapy with octreotide can be more effective than intermittent sc therapy in controlling GH excess in the rare syndrome of ectopic GHRH secretion, although serum GH may not decline to normal.

Human pancreatic tumor GH releasing factor-40 (hpGRF-40) selectively stimulates GH secretion in normal men and in some adult patients with GH deficiency. As the latter finding suggests that some children with GH deficiency may benefit from therapy with hpGRF-40 or an analogue, we investigated the effect of hpGRF-40 administered intranasally on GH release. Six normal men were given hpGRF-40 (30 ug/kg; test day) or an equivalent volume of vehicle alone (control day) at 0900 h. Immunoreactive GH was measured in serum obtained at intervals between 0800-1200 h. Mean (+/- SEM) integrated serum levels of GH (ng/ml/h) prior to and following administration of vehicle were not different (1.27 +/- 0.57 vs 0.87 +/- 0.28; p = 0.54). However, following hpGRF-40 administration, GH levels increased significantly (0.53 +/- 0.03 vs 2.88 +/- 0.75; p = 0.022). Peak levels of serum GH were detected within 30 min following hpGRF-40. Except for mild burning of the nasal mucosa reported by one subject, no side effects were noted. We conclude that, if hpGRF-40 or an analogue is shown to be useful in the treatment of some children with GH deficiency, the intranasal route of administration may be utilized and will be more acceptable for chronic therapy than intravenous, intramuscular, or subcutaneous injection.

Human pancreatic tumour growth hormone releasing factor (hpGRF-40) 10 micrograms/kg was administered intravenously to 6 normal young men and 12 adult patients who had presented in childhood with growth hormone (GH) deficiency (7 patients had isolated GH deficiency, 4 had multiple anterior pituitary hormone deficiencies, and 1 had Hand-Schüller-Christian [HSC] disease). hpGRF-40 administration increased serum GH concentrations in all normal subjects and in 3 of 7 patients with isolated GH deficiency and in the 1 with HSC disease; however, the mean serum GH concentration in the patients who responded was less than that of the normal subjects. Somatomedin C concentrations were increased 24 h after a single dose of hpGRF-40 in 8 of 10 patients with GH deficiency. All subjects experienced flushing in response to hpGRF-40. A patient with isolated GH deficiency received 0.33 micrograms/kg hpGRF-40 every 3 h for 5 days. Despite the modest increase in GH in response to a subsequent dose of 10 micrograms/kg hpGRF-40, serum somatomedin C levels increased within 12 h from 0.06 to 0.1 U/ml and peaked at 0.36 U/ml at 72 h; in addition the patient with HSC disease, treated with hpGRF-40 daily for 5 days, demonstrated an increase in somatomedin C from 0.4 to 0.58 U/ml. The increase after hpGRF-40 in serum GH levels in this patient and the similar or greater responses in 3 of 7 patients suggest that at least some of these patients may have hypothalamic GH-releasing-hormone deficiency. hpGRF-40 may be useful in distinguishing pituitary disease from hypothalamic disease. After hpGRF-40 administration serum somatomedin C levels may increase without a change in serum immunoreactive GH concentrations. Further studies are needed to determine whether hpGRF-40 is useful in promoting linear growth in children with GH deficiency.

Prolactin-secreting pituitary tumors are not rare. The diagnosis of a patient with hyperprolactinemia and possible tumor should be carried out in an orderly fashion by first excluding secondary causes. If the patient has pathologic hyperprolactinemia, assessment of pituitary anatomy with a high resolution CT scan (or MRI) should be done. In patients who have a macroadenoma, quantitative visual field examination should be a part of the ophthalmologic examination. The choice of therapy is dependent on the clinical findings, the risks of therapy, and patient preference. Currently, the most effective therapy for a patient with a macroadenoma is medical therapy with a dopamine agonist, but this must be given chronically. Regardless of the therapy selected, these patients must be followed regularly. Once fertility is established, there is usually no contraindication to pregnancy in women who wish to become pregnant.

This case documents scintigraphically that gastric dysmotility associated with hypoadrenalism secondary to hypothalamic-pituitary dysfunction was reversed when the adrenal insufficiency was treated. The patient reported upon received almost immediate relief of symptoms after corticosteroid replacement therapy and improvement of gastric motility, as demonstrated by both liquid and solid phase 99mTc-labeled studies. This experience suggests that glucocorticoids are important permissive hormones for normal gastrointestinal motor function and may have a role in the pathophysiology of gastrointestinal tract disease.

Continuous infusion of human GH-releasing hormone (GHRH) stimulates GH secretion in normal subjects, but a single supramaximal iv dose of GHRH thereafter elicits a diminished serum GH response compared to that after a saline infusion; the response to the single dose challenge is inversely related to the dose of GHRH previously infused. To determine if this attenuated GH response is a result of depletion of available GH or desensitization of the somatotroph, a 6-h infusion of saline or GHRH (10 ng/kg . min) was administered to 10 normal men, and an iv bolus dose of either GHRH (3.3 micrograms/kg) or regular insulin (0.15 U/kg) was given after 5.5 h of infusion. On both days of GHRH infusion, there was significant stimulation of GH secretion compared to that after saline infusion. The GH response to the supramaximal dose of GHRH was greater after saline infusion than after GHRH infusion, and the GH response to insulin-induced hypoglycemia was significantly greater after GHRH infusion compared with the responses on the other 3 study days. The greatest GH secretion occurred during GHRH infusion followed by insulin administration; therefore, pituitary reserve was not decreased by prior exposure to GHRH. These studies suggest that somatotrophs become partially refractory to GHRH stimulation over time, but remain responsive to an alternate stimulus of GH secretion. We suggest that the hypoglycemia-induced GH response occurs via a reduction in hypothalamic somatostatin secretion, and the attenuated GH response to the supramaximal GHRH dose after GHRH infusion probably represents either partial desensitization or down-regulation of the GHRH receptor.

Glycoprotein-secreting pituitary tumors are uncommon. With increased awareness that pituitary tumors may secrete FSH, LH, TSH, and the alpha-subunit, either as a sole product or in any combination, these tumors are more likely to be recognized. The standard therapy is surgical resection and, possibly, postoperative radiotherapy for residual tumor mass or persistent hormonal secretion. We report a patient with a FSH- and alpha-subunit-secreting tumor who refused surgery and was treated with the dopamine agonist bromocriptine as primary therapy. Bromocriptine treatment resulted in reduction of serum FSH and alpha-subunit levels to normal, improvement of visual field defects, and improvement in hypogonadism despite lack of demonstrable change in tumor size, as assessed by computed tomographic scan. Chromatographic analysis of the serum revealed distinct peaks corresponding to those of labeled FSH and alpha-subunit. The clinical and biochemical responses in this patient suggest that some glycoprotein-secreting tumors may be responsive to dopamine agonist therapy.

The effect of a 5-day fast on integrated, pulsatile, and periodic cortisol release was studied in 10 normal men by measuring serum cortisol concentrations every 20 min for 24 h before (day 0) and during the fifth day of fasting (day 5). Serum concentration profiles were analyzed for integrated cortisol release (area under the curve), pulsatile hormone release by an objective, statistically based pulse detection algorithm (cluster analysis), and periodic hormone release (circadian and ultradian rhythms) by Fourier expansion time series analysis. Urinary cortisol excretion per 24 h was measured in 5 men. The mean 24-h integrated serum cortisol concentration increased 1.7-fold during fasting (P = 0.0006). This increase resulted from a 2-fold increase in the serum cortisol concentrations between pulses (valley mean; P = 0.0004), an increase in the pulse height (P = 0.001), and an increase in pulse increment above baseline (P = 0.01). There were no changes in the number of pulses per 24 h, the interval between pulses, the width of the pulses, or the area of the pulses during fasting. Twenty-four-hour urinary cortisol excretion increased in all men, and the mean urinary cortisol (nanomoles per L)/creatinine clearance (milliliters per s) ratio increased from 119 on day 0 to 187 on day 5 (n = 5; P = 0.05). The pattern of periodic hormone release also changed during fasting; the mean (+/- SE) circadian rhythm (24-h) amplitude decreased from 160 +/- 14 nmol/L on day 0 to 102 +/- 105 nmol/L on day 5 (P = 0.06), and the amplitude of the 12-h rhythm increased from 68 +/- 11 to 99 +/- 11 nmol/L. There also were significant increases in the amplitudes of rhythms with periodicities of 8.1, 4.1, 2.4, 1.6, and 1.3 h (P = 0.02-0.008). Fasting in normal men results in distinct changes in the amount and pattern of pulsatile, circadian, and ultradian cortisol release.

In addition to stimulating GH release in normal subjects, GH-releasing hormone-40 (GHRH-40) stimulates GH secretion in some adults and children with GH deficiency. Recognizing that GHRH-40 may have potential as a therapeutic agent for the treatment of GH deficiency, we examined the effects of iv, sc, and intranasal (in) GHRH-40 administration on GH secretion and measured the plasma levels of immunoreactive GHRH achieved after the administration of the peptide via these different routes. Normal men were given vehicle or GHRH-40 iv (0.003, 0.01, 0.03, and 0.1 micrograms/kg; n = 10), sc (1, 3.3, and 10 micrograms/kg; n = 8), or in (3, 10, 30, and 100 micrograms/kg; n = 5). No subject had any symptoms after administration of vehicle or GHRH-40. During the 2-h period after iv administration of GHRH-40, the maximal increment in serum GH levels above basal (nanograms per ml; mean +/- SD) after the 0.1 micrograms/kg dose was 15.5 +/- 10.4 compared to 2.4 +/- 4.1 after vehicle (P = 0.0017). During the 3-h period after sc administration, when compared to the maximal increment in serum GH above basal after vehicle alone (10.2 +/- 12.9), the maximal increments above basal in serum GH were increased after both the 3.3 micrograms/kg (26.2 +/- 23.1; P = 0.022) and 10 micrograms/kg (63.6 +/- 53.5; P = 0.0003) doses. During the 3-h period after in administration, when compared to the maximal increment in serum GH above basal after vehicle alone (2.8 +/- 6.4), the maximal increments above basal in GH were higher after both the 30 micrograms/kg (18.5 +/- 10.4; P = 0.0053) and 100 micrograms/kg (21.7 +/- 8.1; P = 0.0028) doses. In addition, significant dose-response relationships were documented between the maximal increments above basal in serum GH and GHRH-40 administered by all routes. The mean (+/- SEM) peak plasma level of IR-GHRH (nanograms per ml) achieved after administration of 10 micrograms/kg GHRH-40, iv, as reported previously (66.6 +/- 17.6), was approximately 60- and 500-fold higher than the mean levels in the current study after administration of the same dose sc (1.11 +/- 0.39) or in (0.14 +/- 0.02), respectively. In summary, although GHRH-40 stimulates GH release when administered iv, sc, or in, significantly higher doses were required using the sc and in routes to achieve responses comparable to those obtained with iv administration.

Diabetes insipidus during pregnancy is an uncommon medical problem. We present a woman who developed transient central diabetes insipidus during two successive pregnancies. A water deprivation study with plasma arginine vasopressin concentrations confirmed the diagnosis and established the efficacy of 1-desamino-8-d-arginine-vasopressin (dDAVP). The patient was then successfully and safely treated through the second pregnancy with dDAVP.

Hypogonadism, either primary or secondary, results in diminished libido and/or impotence. Conventional treatment consists of periodic intramuscular injections (usually bimonthly) of a depot testosterone preparation or daily oral ingestion of methyl testosterone. These conventional treatments may be associated with side effects, such as gynecomastia, liver function abnormalities and edema. A new method of administering testosterone is by daily application of a transdermal therapeutic system. We studied the efficacy and safety of the transdermal therapeutic system in 4 hypogonadal men. Three patients were treated for 12 weeks and 1 for 7 weeks, and they were evaluated weekly. Of 4 patients 3 had improvement in erectile and/or sexual function. Mean plasma testosterone levels increased significantly compared to pre-treatment values during 7 of 12 treatment weeks. There were no adverse effects of the transdermal therapeutic system as indicated by serial physical examinations, daily reports, blood chemistry studies, liver function tests, urinalysis and hematological profiles. This preliminary report of transdermal testosterone delivery indicates that it may provide an effective alternative method of gonadal steroid replacement.

A 29 amino acid analog of growth hormone releasing hormone (GH-RH)-40 was given intravenously, subcutaneously, and intranasally to normal men to determine its effectiveness in stimulating growth hormone (GH) release. The GH-RH analog, [Nle27]GH-RH(1-29)-NH2, is an amidated 29 amino acid peptide that has one amino acid substitution at position 27. This peptide stimulates GH secretion when given by the intravenous, subcutaneous, and intranasal routes without adverse effect. The degree of GH stimulation was variable among subjects and the greatest amount of stimulation occurred with the highest doses. GH stimulation occurred in a dose-responsive manner after all three routes of administration. A tenfold higher subcutaneous dose was required to stimulate a comparable amount of GH secretion as compared with intravenous administration, and a thirtyfold higher intranasal than intravenous dose was required to stimulate approximately one fifth the amount of GH release. For comparison, one dose of GH-RH-40, 1 microgram/kg, was administered intravenously. GH secretion after 1 microgram/kg GH-RH-40 and 1 microgram/kg Nle27 GH-RH was comparable between the two groups of subjects. Stimulation of GH secretion by Nle27 GH-RH occurred within 5 minutes of intravenous and within 10 minutes of subcutaneous and intranasal administration; peak GH levels were observed within 30 minutes. GH levels declined and returned to near baseline levels 2 hours after administration of the analog.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth hormone-releasing factor (GRF) is found in the highest concentration (albeit lower compared to other hypothalamic regulatory hormones) in the hypothalamus. There is mounting evidence that GRF-like immunoreactivity is found in other sites in the CNS and in the periphery. The role of GRF, other than to stimulate growth hormone secretion by the somatotroph, is unknown. In addition generation of IGF-1 in response to GRF appears to be dependent on an intact pituitary.