Synthetic GH secretagogues (GHSs; GH-releasing peptides and their nonpeptide mimetics) stimulate GH release, activate the hypothalamo-pituitary-adrenal axis, and release PRL in vivo. Patients with acromegaly show an exuberant GH response to GHSs, whereas patients with pituitary-dependent ACTH-secreting tumors show an exaggerated rise in ACTH and cortisol. We, therefore, studied the presence of GHS receptor (GHS-R) messenger ribonucleic acid (RNA) in 38 human pituitary tumors of different cell types, 3 ectopic ACTH-secreting tumors, a pancreatic gastrinoma, 3 insulinomas, and a non-secreting thymic carcinoid as well as in 7 normal pituitary glands. Certain pituitary tumors were also studied by in vitro cell culture with measurement of secreted GH, ACTH, PRL, FSH, LH, alpha-subunit, and TSH. RNA was extracted from tissue samples and, after RT, a duplex PCR reaction with primers for the GHS-R gene and for the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase was performed, allowing semiquantitation of GHS-R expression. All the somatotroph adenomas (n = 8) showed a 2-10 times higher expression of the GHS-R gene compared to normal pituitaries. Higher than normal expression was shown in 5 of 18 tumors from patients with ACTH-secreting pituitary adenomas and in 1 of 3 ectopic ACTH-secreting carcinoid tumors. Two of the pituitary ACTH-secreting adenoma samples showed completely absent expression of the GHS-R, 8 showed expression similar to that of normal pituitary tissue, and 3 of the corticotroph adenoma tissue samples and 2 ectopic ACTH-secreting tumors showed a very low level of expression. One of 4 prolactinoma samples showed a high level of expression, 1 showed expression similar to that of normal pituitary, and 2 samples showed a very low level of expression. Nonfunctioning pituitary adenoma samples showed either absent or very low level expression of the GHS-R. The pancreatic gastrinoma sample showed expression similar to that of normal pituitary tissue, whereas 3 insulinomas showed low level expression of the GHS-R gene; a nonsecreting thymic carcinoid tumor showed no detectable expression. In summary, although GHS-R messenger RNA is abundant in human somatotroph adenomas, it is also present in other pituitary adenomas, particularly ACTH-secreting tumors. These findings may explain the in vivo responses to GHSs in patients harboring such tumors. It also appears from our study that GHS-R may be expressed in other neuroendocrine tumors.

Acromegaly↗

PubMed1998

Optimizing growth hormone replacement therapy by dose titration in hypopituitary adults.

Although growth hormone (GH) replacement therapy is increasingly utilized in the management of adult hypopituitary patients, optimum dosing schedules are poorly defined. The use of weight-based or surface area-based dosing may result in overtreatment, and individual variation in susceptibility on the basis of gender and other factors is now being recognized. To optimize GH replacement and to explore further gender differences in susceptibility, we used a dose titration regimen, starting at the initiation of GH replacement therapy, in 50 consecutive adult-onset hypopituitary patients, and compared the results with those in 21 patients previously treated using a weight-based regimen. Titrated patients commenced GH 0.8 IU/day subcutaneously (0.4 IU/day if hypertensive or glucose tolerance impaired). Serum insulin-like growth factor I (IGF-I) was measured at 0, 2, 4, 6, 8, 10, and 12 weeks in all patients. Serum IGF binding protein 3 and acid labile subunit were measured at the same time points in 17 patients (8 male, 9 female). Patients were reviewed every 4 weeks and the dose of GH increased, if necessary, to achieve a serum IGF-I level between the median and the upper end of the age-related reference range. There was no significant difference between mean serum IGF-I at 2 and 4 weeks, or between 6 and 8 weeks, indicating that the full effects of a change in dose are evident within 2 weeks of that change. Maintenance doses were significantly higher in females than males [1.2 (0.8-2.0) vs. 0.8 (0.4-1.6) IU/day; median (range); P < 0.0001], and the median time to achieve maintenance dose was significantly shorter in males [4 (2-12) vs. 9 (2-26) weeks; P < 0.0001]. Median maintenance dose was lower overall than in a group of 21 patients initially commenced on GH using a weight-based dosing schedule, with subsequent adjustment of dose during clinical follow-up [1.5 (0.4-3.2) IU/day; P = 0.02]. Reduction in waist measurement and waist to hip ratio at 6 and 12 months was similar in females (P < 0.001) and males (P < 0.01). Well-being improved significantly after 3 months of GH therapy (14.2 +/- 5.9 vs. 7.4 +/- 4.5 SD; P < 0.0001), and there were no gender differences. Adult Growth Hormone Deficiency Assessment (AGHDA) scores at 6 months were similar to maintenance scores in patients commenced on weight-based regimens. Measurements of ALS and IGFBP-3 added no useful extra information to IGF-I in managing the dose titration. The practical scheme outlined for dose titration of GH replacement resulted in rapid achievement of lower maintenance doses than those achieved using conventional weight-based regimens without loss of efficacy. It was particularly important in female patients who demonstrated decreased overall sensitivity to GH and required higher doses to achieve the same effects as males. This constitutes the first report of a uniform titration regimen based on a defined target range of serum IGF-I in a large patient cohort.

Adolescent↗

PubMed1998

The pathophysiology of circulating corticotropin-releasing hormone-binding protein levels in the human.

To establish the factors that modulate circulating CRH-binding protein (CRH-BP) levels, we measured plasma CRH-BP in patients with a variety of endocrine and systemic disorders. CRH-BP was measured by RIA. Young women have higher plasma levels of CRH-BP than young men [females (n = 18), mean +/- SEM, 145 +/- 7; males (n = 20), 99 +/- 6 ng/mL; P < 0.0001], but levels do not fall with the menopause or vary during the menstrual cycle and are unaffected by estrogen replacement therapy. Levels were lower in patients with liver disease than in healthy men (26 +/- 3 vs. 99 +/- 6; P < 0.0001) and were elevated in chronic renal failure compared to those in healthy women (211 +/- 11.2 vs. 145 +/- 7; P < 0.01). Levels were unaffected by fasting in men or women (male fasted, 97 +/- 11; male fed, 97 +/- 8; female fasted, 136 +/- 9; female fed, 152 +/- 10). Dexamethasone treatment lowered CRH-BP in all subjects (129 +/- 8 vs. 111 +/- 9; P < 0.003). Similarly, CRH-BP levels were lower in patients with Cushing's syndrome (all female) than in healthy female controls (median, 82; range, 53-106; vs. median, 142; range, 101-190; P < 0.0001). In Cushing's patients, an i.v. bolus of 100 micrograms human CRH further lowered plasma CRH-BP at 15 min (81 +/- 5 vs. 50 +/- 4; P < 0.0003). Plasma levels of CRH-BP are higher in women than men, but this is unrelated to circulating estrogen levels. The low levels in liver disease and the high levels in renal failure support its hepatic origin and the kidneys as the route of clearance from plasma. The ability of glucocorticoids and exogenous CRH to lower plasma CRH-BP levels and of CRH-BP to modulate the bioactivity of circulating CRH suggest that the protein may be an important regulator of circulating CRH or related ligands.

Adult↗

PubMed1998

Menstrual abnormalities in women with Cushing's disease are correlated with hypercortisolemia rather than raised circulating androgen levels.

Menstrual irregularity is a common complaint at presentation in women with Cushing's syndrome, although the etiology has been little studied. We have assessed 45 female patients (median age, 32 yr; range, 16-41 yr) with newly diagnosed pituitary-dependent Cushing's syndrome. Patients were subdivided into 4 groups according to the duration of their menstrual cycle: normal cycles (NC; 26-30 days), oligomenorrhea (OL; 31-120 days), amenorrhea (AM; > 120 days), and polymenorrhea (PM; < 26 days). Blood was taken at 0900 h for measurement of LH, FSH, PRL, testosterone, androstenedione, dehydroepiandrosterone sulfate, estradiol (E2), sex hormone-binding globulin (SHBG), and ACTH; cortisol was sampled at 0900, 1800, and 2400 h. The LH and FSH responses to 100 micrograms GnRH were analyzed in 23 patients. Statistical analysis was performed using the nonparametric Mann-Whitney U and Spearman tests. Only 9 patients had NC (20%), 14 had OL (31.1%), 15 had AM (33.3%), and 4 had PM (8.8%), whereas 3 had variable cycles (6.7%). By group, AM patients had lower serum E2 levels (median, 110 pmol/L) than OL patients (225 pmol/L; P < 0.05) or NC patients (279 pmol/L; P < 0.05), and higher serum cortisol levels at 0900 h (800 vs. 602 and 580 nmol/L, respectively; P < 0.05) and 1800 h (816 vs. 557 and 523 nmol/L, respectively; P < 0.05) and higher mean values from 6 samples obtained through the day (753 vs. 491 and 459 nmol/L, respectively; P < 0.05). For the whole group of patients there was a negative correlation between serum E2 and cortisol at 0900 h (r = -0.50; P < 0.01) and 1800 h (r = -0.56; P < 0.01) and with mean cortisol (r = -0.46; P < 0.05). No significant correlation was found between any serum androgen and E2 or cortisol. The LH response to GnRH was normal in 43.5% of the patients, exaggerated in 52.1%, and decreased in 4.4%, but there were no significant differences among the menstrual groups. No differences were found in any other parameter. In summary, in our study 80% of patients with Cushing's syndrome had menstrual irregularity, and this was most closely related to serum cortisol rather than to circulating androgens. Patients with AM had higher levels of cortisol and lower levels of E2, while the GnRH response was either normal or exaggerated. Our data suggest that the menstrual irregularity in Cushing's disease appears to be the result of hypercortisolemic inhibition of gonadotropin release acting at a hypothalamic level, rather than raised circulating androgen levels.

Adolescent↗

PubMed1997

Leptin levels do not change acutely with food administration in normal or obese subjects, but are negatively correlated with pituitary-adrenal activity.

BACKGROUND: Leptin is a peptide secreted by white adipose tissue which has been shown to have a major influence on body weight regulation, while animal studies have revealed widespread interconnections between leptin and other endocrine systems, especially with insulin. However, its acute regulation has been little studied in the human. We have therefore investigated the effect of a 1000 kcal meal and fasting on the levels of leptin, insulin and cortisol, in both normal and obese subjects. SUBJECTS AND DESIGN: We have studied the effect of food and fasting on circulating leptin levels in 20 subjects of normal body mass index (BMI range 18-25) and in a group of 12 moderately-severely obese subjects (BMI range 34-61). We also studied the effect of food and fasting in a patient both before and after the successful removal of a pancreatic insulinoma as a model of excess insulin secretion. RESULTS: Mean leptin levels were significantly higher in the obese than in the lean group (42.7 +/- 3.41 vs 5.35 +/- 1.55 micrograms/l, mean +/- SEM; P < 0.001), and showed a positive correlation with body mass index (r = +0.71; P < 0.001). Frequent (every 20 minutes) sampling for 3 hours after food did not show any acute changes in circulating leptin levels. On the fasting day we observed a small but significant fall in circulating leptin levels in the last 4 hours of a 20-hour fast in our subjects as a group (92 +/- 0.03% of basal, P = 0.03); however, in the lean subjects the fall was greater (86 +/- 0.04% of basal, P = 0.02) than in the obese, where it did not reach statistical significance (96 +/- 0.05% of basal). Pre-meal and peak insulin levels showed a positive correlation with circulating mean leptin levels (r = +0.65; P < 0.001 and r = +0.78; P < 0.001, respectively) in all subjects, while pre-meal and peak serum cortisol levels showed an inverse relation with leptin levels (r = -0.53; P = 0.002 and r = -0.41; P = 0.02, respectively); this effect was independent of BMI in the obese subjects. In the patient with the insulinoma the markedly elevated insulin and leptin levels measured before the operation returned to normal after removal of the tumour, in accord with reports of experimental animal data that long-term insulin excess per se is associated with increased circulating leptin concentrations. CONCLUSION: Leptin is a robust indicator of BMI and insulin levels, both basal and stimulated, but does not change acutely following food. Fasting causes a proportionately greater decline in leptin levels in lean subjects than in obese subjects. Circulating leptin is inversely correlated with the activity of the hypothalamo-pituitary-adrenal axis: whether this is a direct influence of leptin on hypothalamo-pituitary-adrenal activity, or whether both are indirect indicators of body fat stores, requires further investigation.

Adult↗

PubMed1997

Clinical, radiological and pathological features of patients with Rathke's cleft cysts: tumors that may recur.

Rathke's cleft cysts are cystic sellar and suprasellar lesions, characteristically lined by a single layer of ciliated cuboidal or columnar epithelium. In contrast, craniopharyngiomass, which are also cystic sellar and suprasellar lesions, are characteristically lined by stratified squamous epithelium with keratinization on a layer of connective tissue. The usual management recommended for Rathke's cleft cysts is simple surgical drainage with partial excision of the cyst wall. Recurrences of these cysts reportedly have been very rare. This retrospective study presents the details of 12 patients (6 females; median age 30 yr, range 21-58 yr) with Rathke's cleft cyst, referred to our department over a 15-yr period (1981-1996), an unusual feature being the recurrence of 4 (33%) of these lesions. Clinical, endocrine, radiological, surgical (10 transsphenoidal; 2 transcranial), and pathological details were recorded. Nine out of 12 patients (75%) were symptomatic; visual symptoms were the commonest, and 8 had visual field defects. The median duration of symptoms was 12 months (range 3-24 months). Three patients (25%) had panhypopituitarism, 2 of whom also had diabetes insipidus (17%). The cysts varied in size from 6 mm to 50 mm, 1 being entirely suprasellar. There were no pathognomonic clinical or radiological features to differentiate them from other pituitary lesions, although the presence of diabetes insipidus in 2 patients suggested that the lesion was not a pituitary adenoma. A definite histological diagnosis was possible in 8 patients; in 4, the diagnosis was presumptive. The median duration of follow-up was 30 months (1-168 months). Four patients (33%) showed reexpansion at 3, 6, 48, and 48 months after initial surgery, 3 of whom were symptomatic and required repeat surgery. Two of these patients were given postoperative external beam pituitary radiotherapy. Apparent recurrence of Rathke's cleft cysts after initially successful surgery in our series was higher than suggested by previous reports, and thus, long-term follow-up with pituitary imaging and neuroophthalmological assessment is essential. There are no specific characteristics of the cyst that predict recurrence. Ideal management of these cysts is unclear, but aspiration, followed by extensive excision of the cyst wall when possible, seems to be the best initial option. For recurrent symptomatic tumors, surgical resection is the treatment of choice. Considering the high recurrence rate with residual structural and functional dysfunction, the role of radiotherapy in preventing recurrence of these cysts needs careful evaluation with a larger study with a longer follow-up period.

Adult↗

PubMed1996

Differential stimulation of cortisol and dehydroepiandrosterone levels by food in obese and normal subjects: relation to body fat distribution.

BACKGROUND: It has been previously shown that food intake elevates circulating ACTH and cortisol levels, but no report has been published regarding the changes in circulating dehydroepiandrosterone (DHEA). DHEA was originally described as a weak androgen, but more recently it has been associated with a wide range of metabolic functions. In addition, previous studies have described a hyper-responsive hypothalamo-pituitary-adrenal axis in obese subjects in response to various stimuli, but the specific response to food has not been studied. SUBJECTS AND DESIGN: We studied the effect of food on the hypothalamo-pituitary-adrenal axis in 20 subjects of normal body mass index (BMI range 18-25) and also in a group of 12 obese subjects (BMI range 34-61). Levels of glucose, insulin, ACTH, cortisol and dehydroepiandrosterone were measured every 20 minutes. RESULTS: A small rise in DHEA accompanies the rise in circulating ACTH and cortisol in response to food in both lean and obese subjects, but DHEA rose independently of cortisol and ACTH on the fasting day. In the obese subjects, food induced a significantly greater change in serum cortisol (peak cortisol rise (mean +/- SEM); normal-weight group, 169 +/- 14%; obese group, 294 +/- 23%) and in the cortisol/DHEA ratio (area under the curve; normal-weight group, 202 +/- 15%; obese group, 292 +/- 29%) than in the normal-weight subjects. This difference was particularly notable in those with central-type obesity (waist/hip ratio > 0.80). A group of the normal, jean female subjects showed no cortisol rise after food intake. CONCLUSION: Our results suggest that DHEA may vary independently of circulating cortisol, and that the cortisol response to food is enhanced in obese subjects, particularly in those with central obesity. We speculate that there may be a caused connection between the cortisol response to food in normal subjects, and the subsequent distribution of fat if such subjects overeat sufficiently to become obese.

Adipose Tissue↗

PubMed1996

L-arginine is unlikely to exert neuroendocrine effects in humans via the generation of nitric oxide.

There is now considerable evidence that nitric oxide is an important neuroregulatory agent, but there has been very little investigation of its possible role in neuroendocrine mechanisms in humans. We have investigated the effects of two nitric oxide precursors, L-arginine and molsidomine, under basal conditions on the pituitary hormones growth hormone (GH), prolactin, luteinizing hormone, follicle-stimulating hormone, thyrotrophin, adrenocorticotrophin (ACTH) and vasopressin, and also on serum cortisol; we have also studied the effect of L-arginine on circulating prolactin, ACTH and cortisol in normal human subjects under hypoglycaemic stress. L-Arginine stimulated both GH and prolactin release under basal conditions but had no effect on the other hormones studied, while the nitric oxide donor molsidomine showed no effect on any hormone studied. L-Arginine potentiated the hypoglycaemia-stimulated release of ACTH but did not influence the rise in GH. The current studies suggest that the effects of L-arginine on the stimulation of GH and prolactin release are unlikely to be mediated via the generation of nitric oxide.

Adrenocorticotropic Hormone↗

PubMed1996

Insulin-like growth factor-I and- II in combination inhibit the release of growth hormone-releasing hormone from the rat hypothalamus in vitro.

This study was designed to investigate the feedback loop between insulin-like growth factor-I (IGF-I) and IGF-II and the hypothalamic hormones growth hormone-releasing hormone (GHRH) and somatostatin (SS) using an in vitro rat hypothalamic model. IGF-I and, to lesser extent, IGF-II, both activate type 1 IGF receptors, while type 2 receptors are activated by IGF-II alone. IGF-I, IGF-II, their various specific analogues (Des[1-3]IGF-I, [Arg54/Arg55]IGF-II and [Leu27]IGF-II), insulin and the type 2 receptor antagonist beta-galactosidase were used on their own or in combination to study their effect on GHRH and SS release. Our results suggest that the simultaneous activation of type 1 and type 2 IGF receptors is needed for the negative feedback effect of IGFs on GHRH release in this in vitro system, in agreement with earlier findings in vivo. Somatostatin was not altered by any combination of peptides.

Animals↗

PubMed1995

Investigation, management and therapeutic outcome in 12 cases of childhood and adolescent Cushing's syndrome.

OBJECTIVE: Cushing's syndrome in childhood and adolescence is rare. We analysed the clinical presentation, investigation, management and therapeutic outcome in 12 paediatric patients with Cushing's syndrome. DESIGN: Retrospective review of case notes. PATIENTS: Twelve patients, 7 males and 5 females, aged 7.6-17.8 years with Cushing's syndrome who were admitted to St Bartholomew's Hospital between 1978 and 1993, were studied. Aetiologies of the Cushing's syndrome patients were: Cushing's disease (9), adrenal adenoma (1), nodular adrenocortical dysplasia (1) and ectopic ACTH syndrome (1). One further male patient, aged 17.8 years who presented with Nelson's syndrome after bilateral adrenalectomy for Cushing's disease in 1978, is described. MEASUREMENTS: Presenting symptoms, endocrine tests for hypercortisolism, imaging studies, simultaneous bilateral inferior petrosal sinus sampling and therapeutic strategies are discussed. RESULTS: The dominant clinical features were obesity, short stature, virilization, headaches, fatigue and emotional lability. Investigations confirmed Cushing's syndrome by demonstrating absent cortisol circadian rhythm and impaired suppression on low dose dexamethasone test and differentiated Cushing's disease from other aetiologies by high dose dexamethasone and hCRH tests. In Cushing's disease, pituitary CT scan identified a microadenoma in 4 out of 9 subjects. In 5 of the 9 patients (3 with a normal pituitary CT, 2 with a suggested microadenoma), a pituitary MRI scan was performed and confirmed the CT findings. Inferior petrosal sinus catheterization for ACTH in 4 patients confirmed excess pituitary ACTH secretion, correctly lateralizing the tumour in all cases. Cushing's disease was treated by transsphenoidal surgery alone in 6 patients and combined with pituitary irradiation in 3 patients. Of these 9 patients, 7 are cured and 2 are in remission. The patient with Nelson's syndrome is cured after total hypophysectomy. CONCLUSIONS: This series describes the clinical features, aetiologies and management of juvenile Cushing's syndrome. Investigation with low and high-dose dexamethasone suppression tests and hCRH test identified the aetiology in each case. Collaboration between paediatric and adult endocrine units together with an experienced neurosurgeon and a radiotherapist contributed to the successful therapeutic outcome of these patients.

Adenoma↗

PubMed1995

Benzodiazepines attenuate the pituitary-adrenal responses to corticotrophin-releasing hormone in healthy volunteers, but not in patients with Cushing's syndrome.

OBJECTIVE: The corticotrophin-releasing hormone (CRH) stimulation test has become established as a powerful tool in differentiating the source of ACTH in patients with Cushing's syndrome. Psychiatric symptoms are common in patients with Cushing's syndrome, and many patients with psychiatric illnesses may show disturbances of function of the pituitary-adrenal axis; both of these groups of patients may be receiving benzodiazepine drugs when presenting for evaluation of their possible endocrine problems. Both animal and human studies suggest that interactions occur between benzodiazepines and the hypothalamo-pituitary-adrenal axis. We have therefore evaluated the effects of a benzodiazepine drug on the pituitary-adrenal response to CRH. DESIGN: We have investigated the effects of 20 mg oral temazepam or placebo on serum cortisol and plasma ACTH after the administration of 100 micrograms i.v. human CRH in 12 healthy volunteers and in 9 patients with Cushing's syndrome. RESULTS: Temazepam significantly inhibited the peak serum/plasma levels and area under the curve for circulating cortisol and ACTH in normal subjects after CRH, but there was no such difference after temazepam in patients with Cushing's syndrome. CONCLUSIONS: Our results have shown that temazepam inhibits the pituitary-adrenal responses to human CRH in normal subjects, but not in those with Cushing's syndrome. We believe that inhibition of endogenous AVP by temazepam is the most likely explanation for our findings in healthy volunteers: the hypercortisolaemia in Cushing's syndrome suppresses the release of both endogenous CRH and AVP in portal blood which then results in abolition of the temazepam induced reduction in the pituitary-adrenal response to exogenous CRH, as seen in our patients. These effects of benzodiazepines should clearly be taken into account in patients using these compounds while undergoing endocrine assessment.

Adrenocorticotropic Hormone↗

PubMed1995

The effect of an opiate antagonist on the hormonal changes induced by hexarelin.

OBJECTIVE: Growth hormone-releasing peptides (GHRPs) stimulate growth hormone (GH) release in vitro and in vivo in animals and in humans. GHRPs were developed by modification of the structure of met-enkephalin but GHRP-6 does not activate opiod receptors in animal studies. These agents may well have diagnostic and/or long-term therapeutic potential in the future so their effects on opiod receptors need to be clarified in humans as well. Hexarelin is a recently developed six amino acid residue GHRP. DESIGN: We have investigated the effects of 100 micrograms/kg i.v. dose of the opiate antagonist naloxone and 2 micrograms/kg i.v. hexarelin or placebo on serum GH, prolactin, TSH, cortisol and plasma ACTH in 12 healthy volunteers in a double-blind, randomized trial. RESULTS: Hexarelin significantly stimulated the peak serum levels and area under the curve for circulating GH and this effect was not modulated by naloxone. Hexarelin also caused significant elevation of circulating prolactin, cortisol and ACTH but did not influence circulating TSH levels. The effect of naloxone on cortisol and ACTH was stimulatory, while it did not influence prolactin, GH and TSH levels. The effect of the two drugs together on cortisol and ACTH was less than additive. CONCLUSIONS: This study confirms that the activation of opiate receptors does not play a role in the GH-releasing effect of growth hormone-releasing peptides in humans.

Adrenocorticotropic Hormone↗

PubMed1995

The long-term outcome after adrenalectomy and prophylactic pituitary radiotherapy in adrenocorticotropin-dependent Cushing's syndrome.

We have reviewed our experience of adrenalectomy performed as part of the management of 56 patients with ACTH-dependent Cushing's syndrome between 1946 and 1993. Forty-three patients were operated on at our institution. Surgery-related mortality did not occur, but complications developed in 14 (33%); these were minor in 12. Eleven patients (29%) of the 38 for whom long-term follow-up data were available and who did not have a proven ectopic source of ACTH subsequently developed Nelson's syndrome, diagnosed on the basis of clinical pigmentation and markedly elevated ACTH levels that were not normally suppressible with glucocorticoids. The effects of prophylactic pituitary radiotherapy were assessed in 38 patients who underwent adrenalectomy at our institution and 18 who underwent surgery elsewhere. Patients who had received prophylactic radiotherapy were less likely to develop Nelson's syndrome (5 of 20, 25%) compared to those who did not (18 of 36, 50%; P > 0.07), and there was a low incidence of radiotherapy-induced hypopituitarism. We conclude that total adrenalectomy has proved to be a safe and effective operation and still may be indicated in selected patients with ACTH-dependent Cushing's syndrome; because prophylactic pituitary radiotherapy reduces the incidence of subsequent Nelson's syndrome by 50%, it should always be considered in the management of these patients.

Adolescent↗

PubMed1995

A comparison of the effects of human and ovine corticotropin-releasing hormone on the pituitary-adrenal axis.

To compare the clinical efficacy of ovine and human sequence corticotropin-releasing hormone (CRH), we examined the effects of both peptides on ACTH and cortisol secretion in normal human volunteers, obese subjects, and patients with pituitary-dependent (Cushing's disease) and adrenal-dependent Cushing's syndrome. All subjects in each group were studied twice in random order. One hundred micrograms of CRH were administered as an iv bolus through an in-dwelling forearm cannula at 0930 h, and thereafter, blood was drawn every 15 min for 2 h for the measurement of ACTH and cortisol. In the normal subjects, the peak ACTH, peak incremental ACTH, and mean area under the curve after CRH treatment were greater with ovine CRH than human CRH, although there was no difference in the cortisol response, however it was analyzed. There was no difference in the ACTH or cortisol response to the two preparations in the obese subjects, and no significant difference was found, for either cortisol or ACTH, between obese subjects and normal volunteers. With both varieties of CRH, Cushing's disease resulted in greater responses for ACTH and cortisol than those seen in the other 2 groups (P < 0.001 for all comparisons), but there was no difference between the sequences. However, a significant cortisol response, defined as an increase of greater than 4 times the coefficient of variation of the assay (24%), was seen in all 10 Cushing's patients with human CRH, but in only 8 with ovine CRH. In 3 patients with adrenal tumors, serum cortisol did not change after the administration of either preparation, whereas plasma ACTH remained undetectable throughout the study. We suggest that although ovine sequence CRH causes more prolonged and greater ACTH, and possibly cortisol, secretion compared to human CRH, the discriminatory value of the CRH test, in terms of either the diagnosis or differential diagnosis of Cushing's syndrome, is comparable for the two peptide sequences.

Adrenocorticotropic Hormone↗