Isolated ACTH deficiency with transitory GH deficiency

A nine-year-old girl, who presented with a severe hypoglycemic coma, proved to have isolated ACTH deficiency, a finding previously reported in only two children. On the initial evaluation, before any treatment, GH did not respond to provocative stimuli. On replacement therapy with hydrocortisone, normal linear growth was observed. Repeated testing while on glucocorticoids replacement four years after the initial attack revealed normal GH response to stimulation test. It is suggested that cortisol deficiency was responsible for the severe hypoglycemic coma and subnormal GH response. A similar mechanism is speculated for the normal growth observed in some patients with apparent deficiency of anterior pituitary hormones, including GH. The possibility of permanent ACTH deficiency and transitory GH deficiency following hypophysitis is discussed.     

Epinephrine deficiency in hypocorticotropic hypopituitary children

In rats, adrenal medullary synthesis of epinephrine is impaired by ACTH deficiency and is not improved by replacement doses of glucocorticoid. We have evaluated plasma epinephrine and norepinephrine concentrations in 43 children, 8-15 yr old. These children were divided into 5 groups, with 6-10 per group: normals; children with isolated GH deficiency; hypopituitary children deficient in both GH and TSH; hypopituitary children deficient in GH, TSH, and ACTH; and short children without known organic disease. The deficiencies of ACTH and TSH were being treated with replacement doses of cortisol and T4. Plasma catecholamines were measured in the supine position at rest every other hour from 0800-1600 h, and after exercise in the standing position at 1000 h. Plasma norepinephrine levels, both at rest and after exercise, were normal in all four groups of short children. Resting and postexercise plasma epinephrine levels were reduced to 10-20% of normal in the hypocorticotropic hypopituitary patients, and were normal in the other three groups of short children.     

Pituitary function in a man with congenital aromatase deficiency: effect of different doses of transdermal E2 on basal and stimulated pituitary hormones

To clarify the role of estrogen on male pituitary function, the effects of different doses of transdermal E2 on pituitary secretion were evaluated in a man with aromatase deficiency. The study protocol was divided into the following three phases: no E2 treatment (phase 1); 25 microg transdermal E2 twice weekly for 9 months (phase 2);12.5 microg transdermal E2 twice weekly for 9 months (phase 3). Pituitary function was studied in detail during each phase of the study protocol by measuring hormone levels in basal conditions and after dynamic testing (GnRH, insulin tolerance test, GHRH plus arginine, TRH, and corticotropin-releasing factor; tests). Basal and GnRH-stimulated gonadotropin levels resulted inversely related to E2 serum levels, according to the dosage of estrogen administered. Basal and stimulated GH, PRL, and TSH serum levels did not change during the protocol study. The secretory pituitary reserve of GH was clearly impaired. Basal and stimulated ACTH and cortisol serum levels were not modified by estrogen administration. This study demonstrated that in the human male E2 is required at pituitary level for normal functioning of gonadotropin feedback both in basal and stimulated conditions. In this patient GH deficiency seems to be an adult-onset event since he reached a tall stature. However, the finding of a severe impairment in GH response to potent provocative stimuli together with the insensitivity of GH/IGF-I axis to circulating estrogens strongly suggest a possible involvement of estrogens on both the development and maturation of the somatotrophic axis. Finally, the congenital lack of estrogen activity seems to be associated with a slightly impaired secretion of PRL and TSH, suggesting a possible role of estrogens on the pituitary secretion of these hormones in the human male.     

Pituitary-adrenal responses to CRH and insulin hypoglycemia in patients with idiopathic GH deficiency

It is well known that the activation of the hypothalamus-pituitary-adrenal axis (HPA) by insulin-induced hypoglycemia (IIH) is more potent and multifactorial than that caused by CRH administration. In this study we compared the clinical value of both tests in assessing the integrity of the HPA system. Plasma ACTH and cortisol responses to oCRH (1 microgram/kg iv) and IIH (insulin 0.1 U/kg iv, glycemia less than 40 mg/dl) were compared in 15 patients with idiopathic GH deficiency. The CRH-induced mean ACTH response was lower, but not significantly, in patients than in controls (peak: 8.8 +/- 1.7 vs 13.4 +/- 2.2 pmol/l), while the mean cortisol response was significantly lower than in normals (peak: 585.7 +/- 49.5 vs 764.5 +/- 52.2 nmol/l, p less than 0.005). Plasma ACTH and cortisol responses to IIH were significantly lower than in normal subjects (peak: 22.3 +/- 5.3 vs 35.8 +/- 5.2 pmol/l, p less than 0.05 and peak: 566.5 +/- 55 vs 803 +/- 38.5 nmol/l, p less than 0.02, respectively). Both in controls and in patients the CRH-induced mean ACTH response was significantly lower (p less than 0.02) than that after insulin, while cortisol peaks were not different. In conclusion, in patients with GH deficiency the impairment of ACTH secretion is not evident in basal condition, but it is disclosed after appropriate dynamic tests. It is confirmed that insulin hypoglycemia is a more potent stimulus than CRH for ACTH release.     

A case of isolated ACTH deficiency who developed autoimmune-mediated hypothyroidism and impaired water diuresis during glucocorticoid replacement therapy

A case of isolated ACTH deficiency who developed autoimmune-mediated hypothyroidism and still showed impaired water diuresis during glucocorticoid replacement therapy is reported. A 45-year-old woman was initially admitted for nausea, vomiting, and general malaise. Her serum sodium and plasma osmolality, ACTH and cortisol values were low, but her urine osmolality was high. Other pituitary hormone levels, thyroid hormone levels, and a computed tomogram of the pituitary gland were normal. The patient was treated with hydrocortisone and followed in the outpatient clinic; however, she was lost to follow up 18 months after admission. Three years later she presented with hypoglycemia and hyponatremia. Her serum or plasma ACTH, FT3, FT4, cortisol levels were low and her serum TSH level was high. Pituitary stimulation tests revealed a blunted response of ACTH to CRH and an exaggerated response of TSH to TRH. Plasma ADH was inappropriately high, and a water-loading test revealed impaired water diuresis and poor suppression of ADH. Although ADH was suppressed, impaired water diuresis was observed in the water loading test after hydrocortisone supplementation. Thyroxine supplementation completely normalized the water diuresis. Her outpatient clinic medical records revealed a gradual increase in TSH levels during follow up, indicating that she had developed hypothyroidism during glucocorticoid replacement therapy. The hyponatremia on the first admission was due to glucocorticoid deficiency, whereas the hyponatremia on the second admission was due to combined deficiencies of glucocorticoid and thyroid hormones.     

A case of congenital hypopituitarism: difficulty in the diagnosis of ACTH deficiency due to high serum cortisol levels from a hypothyroid state.

A three-month-old boy presented congenital hypopituitarism in which the hypothyroid state masked ACTH deficiency. Multiple anterior pituitary hormone deficiencies, including ACTH, were finally confirmed. High basal serum cortisol levels (up to 45.1 microg/dl) were observed during a stressful episode before L-thyroxine replacement therapy was started. Decreased morning serum cortisol levels (5.0 microg/dl or below) were observed on the sixth day of L-thyroxine replacement therapy despite mild hypoglycemia (lowest serum glucose level of 50 mg/dl). ACTH deficiency was then confirmed by insulin-induced hypoglycemia test (peak serum cortisol level of 4.9 microg/dl). The present findings showed that serum cortisol levels can be high during a stressful episode in an infant with ACTH deficiency and a coexisting hypothyroid state. Thus, the diagnostic evaluation of adrenal function soon after L-thyroxine replacement therapy is important in order to verify a possible subclinical ACTH deficiency, even in the presence of high serum cortisol levels before L-thyroxine replacement therapy.     

Effect of growth hormone deficiency and recombinant hGH (rhGH) replacement on the hypothalamic-pituitary-adrenal axis in children with idiopathic isolated GH deficiency

Objective Recombinant hGH (rhGH) therapy may unmask central hypoadrenalism in adults with organic GH deficiency (GHD), likely by normalizing 11β‐hydroxysteroid dehydrogenase type 1 isoenzyme (11βHSD1) activity and reducing cortisone to cortisol conversion. The aim of the present study was to evaluate the hypothalamic–pituitary–adrenal (HPA) axis in children with idiopathic isolated GHD and normal pituitary magnetic resonance imaging (MRI) both before and during rhGH therapy. Design and patients This was a single‐centre study of 10 consecutive children [five males and five females, mean age: 12·2 ± 1·0 year]. Evaluation was performed at baseline and on rhGH (mean duration: 10·9 ± 2·9 months, mean dose: 0·030 ± 0·002 mg/kg bw/day). Measurements HPA function was assessed by serum cortisol levels before and after appropriate provocative stimuli, that is, 1 µg ACTH test (N = 5 patients) or insulin tolerance test (ITT, N = 5 patients), evaluating all children with the same stimulation test both before and during rhGH therapy. Central hypoadrenalism was excluded by the presence of either a peak of > 500 nmol/l or a rise in cortisol levels of > 200 nmol/l, after both tests. Results On rhGH therapy, serum IGF‐I levels normalized, while serum cortisol and ACTH levels did not significantly differ from those recorded at baseline. The mean serum cortisol peak after both provocative tests was not significantly different on rhGH therapy and at baseline (498 ± 41 vs. 580 ± 35 nmol/l, respectively, P = 0·06), the mean cortisol rise being 280 ± 45 and 270 ± 36 nmol/l on rhGH and at baseline, respectively. Conclusions According to the diagnostic criteria, no child became hypoadrenal on rhGH, contrary to what observed in patients with organic GHD, further supporting the view that only in patients with organic multiple pituitary hormone deficiency GHD masks the presence of a hidden central hypoadrenalism.     

Reproducibility of the insulin tolerance test (ITT) for assessment of growth hormone and cortisol secretion in normal and hypopituitary adult men

OBJECTIVE: The within subject variability of the insulin tolerance test (ITT) for assessment of growth hormone (GH) status and cortisol reserve has rarely been examined, particularly in patients with hypopituitarism. This becomes important when biochemical criteria are used to determine which adults with hypopituitarism should receive GH and/or cortisol replacement. In the present study we assessed the reproducibility of GH and cortisol responses in repeated ITTs. Baseline insulin-like growth factor 1 (IGF-1) levels were also assessed for reproducibility on each occasion. DESIGN AND PATIENTS: Three consecutive ITTs were performed in seven normal adult men (ages 22-27 years) and two ITTs in 11 men with hypopituitarism and suspected GH deficiency (ages 23-48 years). MEASUREMENTS: Serum GH and IGF-1 were measured by immunoradiometric and cortisol by immunofluorimetric assays. RESULTS: In normal men group peak GH responses did not differ between the three tests. There was no correlation between individual peak values. The within subject peak GH variability was between 4.6 and 59.3%, and the overall variability in 21 tests was 35%. The lowest peak GH concentration was 70 mU/l (27 microg/l). All hypopituitary men had severe GH deficiency (all peak GH concentrations < 4 mU/l (1.5 microg/l) in both tests). There was a highly significant correlation between individual peak GH values (r = 0.95, P < 0.0001). Basal IGF-1-values in normal and hypopituitary men were highly correlated between tests (r = 0.98, P < 0.0001). The overall within subject variability of IGF-1-values was 11.9% in normal and 22.7% in hypopituitary men. In normal men group peak cortisol responses were not different between the three tests. There was a good correlation between individual peak cortisol responses in the three ITTs. The within subject peak cortisol variability (median 8.3%; range 0.7-21.5%) was significantly less than that of GH (P < 0.03) in two of three test comparisons. In hypopituitary men the within subject peak cortisol variability (median 41.6%; range 3.5-92.7%) was significantly greater (P < 0.001) than in normal men. All patients were correctly classified as cortisol deficient or normal in both ITTs. CONCLUSION: The cortisol response to repeated hypoglycaemia is very reproducible in normal men but the GH response is less so. In hypopituitary men the reproducibility of the GH response is good while that of the cortisol response is poor. However, a single ITT did not misclassify hypopituitary patients who are severely GH and/or ACTH deficient and was therefore adequate for clinical decisions regarding GH and/or cortisol replacement. Nevertheless, it remains possible that a single ITT could misclassify some hypopituitary patients with partial GH or ACTH deficiency.     

The prevalence of severe growth hormone deficiency in adults who received growth hormone replacement in childhood

OBJECTIVE The few previous studies in which reassessment of GH status has been carried out in young adults treated with GH therapy for childhood GH deficiency concentrated on determining the incidence of ‘transient GH deficiency’. As the benefits of GH replacement therapy in adults become increasingly appreciated, it is likely that GH therapy started in childhood for GH deficiency will be continued into adult life in many of those with severe GH deficiency. The aim of this study is to determine how many patients who received GH replacement therapy in childhood until completion of growth have GH deficiency severe enough to be considered for GH replacement therapy in adult life. DESIGN Retrospective analysis of the peak GH responses to provocative stimuli performed at the time of diagnosis of GH deficiency in childhood and at the completion of growth after GH replacement therapy had been stopped. PATIENTS Eighty-eight adults (49 male, 39 female) who had received GH therapy in childhood for a diagnosis of GH deficiency. The aetiology of the GH deficiency included craniopharyngioma, radiation induced associated with either a cerebral tumour or acute lymphoblastic leukaemia, histiocytosis-X and idiopathic. MEASUREMENTS In childhood the original diagnosis of GH deficiency was based biochemically on the failure of the peak GH response to reach 20 mU/l during two provocative tests in 59 of the 88 patients and to a single test in the remaining 29. A total of 147 tests were performed, the most common being an insulin tolerance test (ITT, n= 72) and an arginine stimulation test (AST, n= 53). At reassessment in young adult life 146 tests were performed (74 ITT, 64 AST). Severe GH deficiency was defined arbitrarily as a peak GH response of less than 9 mU/l to a single (n = 33) or to two (n = 55) pharmacological stimuli. RESULTS By definition all patients were considered GH deficient at the time of initial diagnosis. A peak GH response of less than 9 mU/l was seen in 64.8% at initial assessment and 60.2% at reassessment. Analysis in aetiological terms, however, showed that between assessments the incidence of severe GH deficiency increased in the group of radiation induced (48.8 vs. 55.8%) but decreased in the idiopathic group (78.1 vs. 53.1%). Out of the 55 patients who underwent two tests at reassessment, 47.3% of those with a GH peak less than 9 mU/l at one test had a GH peak greater than 9 mU/l at the second test. Fifteen of the 55 patients had additional pituitary hormone deficiencies and all 15 had a GH peak below 9 mU/l in both tests. CONCLUSIONS Our study suggests that all children who have received GH replacement therapy in childhood should undergo reassessment of GH status in young adult life. Between 40 and 60% of such patients merit consideration for GH therapy in adult life depending on the definition of severe GH deficiency in use. Patients with isolated GH deficiency should undergo two provocative tests of GH secretion, but those with additional anterior pituitary hormone deficiencies require only one test at reassessment.     

Corticotroph deficiency

Corticotroph deficiency usually results from exogenous glucocorticoid therapy or, more rarely, from hypothalamopituitary damages. Its diagnostic may be difficult, especially when the deficit in ACTH secretion is partial. Stimulation tests are then necessary to investigate the integrity of the hypothalamopituitary-adrenal axis. The insulin tolerance test has become the gold standard, but its utilization is limited by several contra-indications. The metyrapone and cosyntropin tests represent currently used alternatives but their sensitivity is not optimal. Measurement of basal plasma dehydroepiandrosterone sulfate may allow excluding corticotroph deficiency when normal. Finally, cortisol replacement in patients with corticotropic deficiency is based on hydrocortisone administration. However, the dose regimens employed in clinical practice do not allow mimicking the nycthemeral rhythm of cortisol secretion and are still disputed.     

Central hypocortisolism as part of combined pituitary hormone deficiency due to mutations of PROP-1 gene

BACKGROUND: One of the causes of combined pituitary hormone deficiency (CPHD) is represented by Prophet of Pit-1 (PROP-1) gene inactivating mutations. This disorder is generally characterized by GH, TSH, prolactin (PRL), and gonadotropin deficiency, but recent papers have described a concomitant alteration of the corticotrope function. OBJECTIVE: To make a detailed investigation of the hypothalamic-pituitary-adrenal axis in two sisters with PROP-1 gene mutations. PATIENTS: Two female siblings (17 and 16 years old) with CPHD, belonging to a Brazilian family of consanguineous parents, presented with growth retardation and central hypothyroidism during childhood, and showed central hypogonadism at the age of puberty. No clear clinical symptoms and signs of hypocortisolism were present. METHODS: GH, TSH, free thyroxine, total tri-iodothyronine, PRL, LH, FSH, ACTH and cortisol were measured in basal condition and after appropriate testing. The molecular study was performed by PCR amplification and sequencing analysis of PROP-1 gene. RESULTS: Both patients showed GH, PRL, LH and FSH deficiencies, associated with absent responses to an insulin tolerance test (ITT), TRH and GnRH injection. Circulating concentrations of TSH were normal in basal conditions, but failed to respond to a TRH test. Plasma ACTH concentrations were normal, but serum cortisol concentrations were below the lower limit of the normal range, showing a trend to decrease during 6 years of follow-up. The serum ACTH response to ITT was impaired, whereas its response to CRH was normal and prolonged. The cortisol response to both tests, and to the ACTH test, was clearly impaired. In both sisters, the genetic analysis showed the presence of a homozygous 2-bp deletion (296delGA) of PROP-1 gene, which results in the synthesis of a protein with no residual functional activity. CONCLUSION: In addition to GH, TSH, PRL and gonadotropin deficiency, patients with PROP-1 gene mutations can present with late-onset central hypocortisolism, possibly beause of the lack of important paracrine factors normally produced by the cells surrounding the corticotropes and absent in the pituitary of these patients, or because of progressive corticotrope apoptosis. This finding indicates the need for life-long endocrine monitoring of PROP-1-deficient patients.     

Isolated glucocorticoid deficiency

A three-month-old boy with hypoglycemic episodes, feeding problems and hyperpigmentation is described. Hormone assays revealed elevated serum ACTH values and low levels of plasma cortisol that did not rise after exogenous ACTH administration; blood pressure, serum electrolytes and earlier plasma aldosterone and renin activity were in the normal range. These data suggest a diagnosis of an isolated glucocorticoid deficiency, secondary to unresponsiveness to ACTH. Replacement therapy with glucocorticoids was highly effective. Despite replacement therapy, during follow-up he had an increase in basal plasma renin activity with aldosterone concentration normal. In our patient, a mineralcorticoid deficiency might eventually develop; therefore, the selective glucocorticoid deficiency might also be part of a progressive defect involving the glomerulosa too.     

The effect of growth hormone replacement therapy on adrenal androgen secretion in adult onset hypopituitarism

OBJECTIVE: Growth hormone replacement therapy in GH-deficient children is associated with enhanced adrenal androgen production, raising the possibility that GH might stimulate adrenocortical hormone secretion. This has not been extensively investigated in adults to date. GH is a potent modulator of the activity of the 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme and by altering cortisol metabolism can affect the function of the hypothalamo-pituitary-adrenal (HPA) axis and therefore potentially of adrenal androgen secretion. This study examined the effects of GH replacement in GH-deficient adults on adrenal androgen secretion. DESIGN: Prospective study of the effect of GH replacement therapy on adrenal androgen production in patients with adult onset hypopituitarism over a 12-month period. PATIENTS AND METHODS: Thirty adult GH-deficient patients were classified into two groups according to their cortisol responses to an insulin-induced hypoglycaemia or a glucagon stimulation test: 13 patients were adrenocorticotropic hormone (ACTH)-sufficient (nine females, age 45.1 +/- 3 years), whereas 17 patients were ACTH-deficient (11 females, age 45.5 +/- 3 years). Serum samples were collected before patients were initiated on GH replacement therapy using a dose titration regimen, and after 6 and 12 months on GH therapy for measurement of serum IGF-I, dehydroepiand-rosterone sulphate (DHEAS), Delta4-Androstenedione (A4), testosterone, cortisol, sex hormone binding globulin (SHBG) and cortisol binding globulin (CBG). RESULTS: Six months after the initiation of GH replacement therapy, serum IGF-I levels were within the normal age-related reference range in both groups of patients and this was maintained at 12 months [in all patients 0 vs. 6 months: median (interquartile range): 92.5 ng/ml (73-116 ng/ml) vs. 191 ng/ml (159-224 ng/ml), P < 0.01]. In both ACTH-sufficient and -deficient groups of GH-deficient patients, pretreatment serum DHEAS levels were lower than the normal age-related reference range (P < 0.01); the ACTH-deficient patients had significantly lower DHEAS levels than the ACTH-sufficient patients [median (interquartile range): 0.5 micro mol/l (0.4-1.2 micro mol/l) vs. 1.5 micro mol/l (0.6-2.7 micro mol/l), P < 0.05]. Following GH replacement therapy, median levels of serum DHEAS levels rose from 1.5 micro mol/l (0.6-2.7 micro mol/l) to 1.9 micro mol/l (1.9-3.9 micro mol/l) in ACTH-sufficient patients, increasing in 11 of the 13 patients (P < 0.02). In this group, the median percentage increase from baseline was 32% at 6 months (P < 0.05). In contrast, baseline serum DHEAS levels [0.5 micro mol/l (0.4-1.2 micro mol/l)] declined in or from the measurable range in 47% of ACTH-deficient patients [median -16%; range -36-0] and only in one patient a + 0.2 micro mol/l increase was observed. GH dose requirements tended to be lower in ACTH-sufficient patients [1.2 U/day (0.8-1.4 U/day) vs. 1.6 U/day (1.0-2.0 U/day); P = 0.062]. There were no significant changes in serum testosterone, A4, SHBG and/or CBG levels, compared to the pretreatment levels, in either group of patients over the 12 months of GH replacement. CONCLUSIONS: This study shows that median serum DHEAS levels are significantly lower in GH-deficient patients, even those with intact ACTH reserve, than in aged-matched controls. GH replacement therapy is associated with a significant increase in mean serum DHEAS only in ACTH-sufficient patients. These findings are consistent with either (i) GH stimulation of adrenal androgen production in the permissive presence of ACTH or (ii) an inhibitory effect of GH on 11beta-HSD type 1 activity leading to enhanced cortisol clearance, subsequent activation of the HPA axis and ACTH-mediated androgen secretion.     

CORTICOTROPHIN RELEASING FACTOR: RESPONSES IN NORMAL SUBJECTS AND PATIENTS WITH DISORDERS OF THE HYPOTHALAMUS AND PITUITARY

Synthetic CRF-41 has been given to 43 patients with hypothalamic, pituitary or adrenal diseases and contrasted with the responses in 20 normal subjects. In the normal subjects the mean increment in serum cortisol (± SE) was 276 ± 38 nmol/l; the increments showed a significant negative correlation with the basal serum cortisol levels (r= -0·56; P<0·02). The mean peak serum cortisol was 662 ± 34 nmol/1 and the mean peak corticosterone was 28·6 ± 3·8 nmol/1. There was a significant positive correlation between the peak serum corticosterone and cortisol concentrations (r= 0·84; P<0·0001). Dexamethasone pretreatment abolished the rise in cortisol in response to CRF-41. The peak serum cortisol following CRF-41 was not significantly different between the normal subjects and those patients with pituitary disease who had normal cortisol responses to insulin-induced hypoglycaemia. However, in individual patients the peak cortisol levels induced by hypoglycaemia were greater than, but significantly correlated with, those induced by 100 μg of CRF-41. Seven patients were ACTH deficient in response to hypoglycaemia, and of these six responded normally to CRF-41. Only one of these patients had a lesion clearly originating in the hypothalamus; four had pituitary tumours with suprasellar extensions and the remaining patient had idiopathic GH and ACTH deficiency. Our data suggest that these patients have a functional defect of ACTH secretion due to the failure of CRF to reach the corticotroph. Of the four patients with pituitary-dependent Cushing's disease who were on no treatment at the time of testing, three showed an exaggerated and one a normal response to CRF-41. These normal or enhanced responses of hypercortisolaemic patients with Cushing's syndrome contrast with the complete inhibition of the responses to CRF-41 in normal subjects given dexamethasone. In the treated patients with Cushing's syndrome     

The effects of growth hormone deficiency and replacement on glucocorticoid exposure in hypopituitary patients on cortisone acetate and hydrocortisone replacement

OBJECTIVE: 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta HSD1) converts inactive cortisone to active cortisol. 11 beta HSD1 activity is increased in GH deficiency and inhibited by GH and IGF-I in acromegaly. However it is not known whether these changes in cortisol metabolism exert significant effects during hydrocortisone therapy, and the effect has not been studied in patients taking cortisone acetate. We have studied the effect of GH induced 11 beta HSD1 inhibition in hypopituitary adults with severe GH deficiency to determine whether this inhibition has a different magnitude of effect when patients are taking different forms of glucocorticoid replacement therapy. DESIGN, PATIENTS AND MEASUREMENTS: We have taken the ratio of 11-hydroxy/11-oxo cortisol metabolites (Fm/Em), an established measure of net 11 beta HSD activity to reflect the likely balance of cortisol to cortisone exposure in tissues expressing 11 beta HSD1, principally the liver and adipose tissue. We recruited 10 hypopituitary adults all on established glucocorticoid replacement therapy, but who were not receiving GH. Patients were treated with their standard hydrocortisone therapy for one week and an equivalent dose of cortisone acetate in its place for one week in random order. Serial serum cortisol assessments and urine steroid profiles were performed on each treatment. All patients were then established on GH therapy for at least three months before the two-week cycle was repeated. Fm/Em was also measured in a control population (20F, 20M). RESULTS: Prior to GH, the ratio Fm/Em was greater with hydrocortisone compared with cortisone acetate replacement (1.17 +/- 0.28 and 0.52 +/- 0.09 respectively, P < 0.001) or with normal subjects (normal males: 0.81 +/- 0.24, females 0.66 +/- 0.14). Following GH replacement Fm/Em fell in patients on hydrocortisone and cortisone acetate (Pre-GH: 0.84 +/- 0.40, Post-GH: 0.70 +/- 0.34, P < 0.05) confirming the inhibition of 11 beta HSD1 by GH/IGF-I. Conversely, the ratio of urinary free cortisol/cortisone did not change indicating unchanged 11 beta HSD2 activity. Mean circulating cortisol also fell in all subjects after GH. This effect was greater during cortisone acetate treatment (-18.7%, P < 0.0001), than during hydrocortisone replacement (-10.9%, P < 0.05). CONCLUSIONS: Our data suggest that tissue exposure to glucocorticoid is supra-physiological in hypopituitary patients with untreated GH deficiency taking hydrocortisone replacement therapy. This situation is ameliorated by GH replacement therapy. However, local and circulating cortisol concentrations are more vulnerable to the inhibitory effect of GH on 11 beta HSD1 in patients taking cortisone acetate, such that serum cortisol assessments should be made in patients taking cortisone acetate after GH therapy to ensure that glucocorticoid replacement remains adequate.     

Hexarelin as a test of pituitary reserve in patients with pituitary disease

BACKGROUND: The insulin tolerance test (ITT) is the reference standard for the diagnosis of cortisol and growth hormone (GH) deficiency, but problems have occurred in small children in inexperienced hands and it is contraindicated in patients with cardiac disease and epilepsy. Hexarelin is a growth hormone-releasing peptide with GH-, ACTH/cortisol- and prolactin-releasing effects which involve both hypothalamic and direct pituitary mechanisms. We therefore investigated whether it could be used to test GH and ACTH/cortisol reserve in patients with pituitary disease. METHODS AND SUBJECTS: The changes in GH and cortisol in response to insulin-induced hypoglycaemia (intravenous human Actrapid 0.15 IU/kg) and hexarelin (2 microg/kg) in 19 patients with possible pituitary disease (5 males, mean age 39 years, range 21-70) were compared. The patients' responses during the hexarelin test were also compared to normal ranges of GH and cortisol responses established in healthy volunteers following hexarelin administration. RESULTS AND DISCUSSION: GH peak levels were significantly higher after hexarelin than after hypoglycaemia (mean +/- SEM; 67.1 +/- 16 vs. 26.9 +/- 6.8 mU/l respectively; P < 0. 001), while cortisol levels were significantly lower (420 +/- 34 vs. 605 +/- 50 nmol/l; P < 0.001). The peak responses of both hormones correlated significantly between the hexarelin and insulin-induced hypoglycaemia tests (r = 0.80, P < 0.001 for cortisol). Peak GH levels after hexarelin and ITT showed a significant positive correlation with IGF-I levels (r = 0.84 and r = 0.77, P < 0.001 for both). All patients with a subnormal GH response to hexarelin (<41.4 mU/l) had a peak GH response to ITT of <9 mU/l, and only one patient had a normal (although borderline) response to hexarelin with a subnormal GH response to the ITT. Although 17 of the 19 patients had corresponding cortisol responses to hexarelin and the ITT test (either failing or passing both), two patients had normal cortisol responses to hexarelin but subnormal responses to the ITT. A peak serum cortisol level following hypoglycaemia of >580 nmol/l is indicative of normal cortisol reserve, as established in patients undergoing surgery; only five of the normal volunteers and one of the thirteen patients with a normal ACTH/cortisol reserve on ITT had a peak cortisol >580 nmol/l in response to hexarelin. CONCLUSION: Adult patients who have a subnormal peak GH response to hexarelin are likely to be GH deficient on an insulin tolerance test. However, our data suggest that the hexarelin test is not a useful test of ACTH/cortisol reserve. The hexarelin test could be a useful first/screening test to diagnose adult GH deficiency, particularly in patients in whom an insulin tolerance test is contraindicated or who are already ACTH deficient and in whom the GH reserve alone is of interest.     

Modulation of cortisol metabolism by low-dose growth hormone replacement in elderly hypopituitary patients

11 beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) functions as a net reductase converting cortisone to cortisol. GH inhibits 11beta-HSD1, resulting in a shift in cortisol metabolism favoring cortisone, an observation that may have significance in patients with ACTH deficiency who are unable to compensate for such changes. We have studied the effect of three doses of GH replacement (0.17, 0.33, and 0.5 mg each given for 12 weeks in ascending order) on cortisol metabolism in nine patients, aged 62-70 yr, with hypopituitarism who were receiving fixed doses of oral hydrocortisone. Serum insulin-like growth factor I levels rose in a dose-dependent manner over the course of the study. Fat mass decreased significantly at 24 weeks (P = 0.02), a change that was maintained at 36 weeks. Fasting serum insulin levels did not change significantly over the course of the study. The ratio of urine cortisol to cortisone metabolites (Fm/Em) fell significantly at 12 weeks (GH dose, 0.17 mg/day) from 1.32 (0.91-2.20) at baseline to 1.08 (0.89-2.11) (P < 0.05). Although it did not fall further as the dose of GH was increased, the reduction in the Fm/Em ratio persisted at 24 weeks (GH dose, 0.33 mg/day), 1.09 (0.8-2.11) (P < 0.05 vs. baseline), and 36 weeks (GH dose, 0.5 mg/day), 1.19 (0.82-2.31) (P < 0.05 vs. baseline). The Fm/Em ratio did not correlate with serum insulin-like growth factor I, fat mass, or fasting insulin levels at any time during the study. This study confirms the inhibitory effect of GH on 11beta-HSD1 but has shown that the effect occurs maximally at very low GH doses and is not mediated indirectly by change in circulating insulin. Patients with partial or total ACTH deficiency, in whom cortisol replacement is suboptimal, may be at risk of the clinical manifestations of cortisol deficiency when they are commenced on GH therapy.     

Isolated corticotrophin deficiency

Isolated ACTH deficiency (IAD) is a rare disorder, characterized by secondary adrenal insufficiency (AI) with low or absent cortisol production, normal secretion of pituitary hormones other than ACTH and the absence of structural pituitary defects. In adults, IAD may appear after a traumatic injury or a lymphocytic hypophysitis, the latter possibly due to autoimmune etiology. Conversely, a genetic origin may come into play in neonatal or childhood IAD. Patients with IAD usually fare relatively well during unstressed periods until intervening events spark off an acute adrenal crisis presenting with non specific symptoms, such as asthenia, anorexia, unintentional weight loss and tendency towards hypoglycemia. Blood chemistry may reveal mild hypoglycemia, hyponatremia and normal-high potassium levels, mild anemia, lymphocytosis and eosinophilia. Morning serum cortisol below 3 μg/dl are virtually diagnostic for adrenal insufficiency. whereas cortisol values comprised between 5–18 μg/dl require additional investigations: insulin tolerance test (ITT) is considered the gold standard but—when contraindicated—high or low dose-ACTH stimulation test with serum cortisol determination provides a viable alternative. Plasma ACTH concentration and prolonged ACTH infusion test are useful in differential diagnosis between primary and secondary adrenal insufficiency. For some patients with mild, near-to-asymptomatic disease, glucocorticoid replacement therapy may not be required except during stressful events; for symptomatic patients, replacement doses i.e., mean daily dose 20 mg (0.30 mg/kg) hydrocortisone or 25 mg (0.35 mg/kg) cortisone acetate, are usually sufficient. Administration of mineralocorticoids is generally not necessary as their production is maintained.     

Synergistic effects of growth hormone therapy on plasma levels of 11-deoxycortisol and cortisol in growth hormone-deficient children

We have studied the response of blood levels of progesterone, 17-hydroxyprogesterone, 11-deoxycortisol, and cortisol to acute ACTH stimulation in children with isolated GH deficiency. Patients with isolated GH deficiency had generally higher levels of 11-deoxycortisol and lower levels of cortisol than controls both before and after ACTH stimulation. The steroid levels were almost completely restored to control levels after 3 months of treatment with GH. The pre-ACTH treatment levels of 11-deoxycortisol and cortisol were low in patients with both GH and ACTH deficiencies before and during GH therapy. Therefore, GH alone did not appear to have any effect on the hydroxylation of 11-deoxycortisol to cortisol. Before GH therapy, ACTH increased the concentrations of the two steroids. After GH therapy was started, the increase in 11-deoxycortisol was much smaller, but the increase in cortisol was much larger than before therapy. These results suggest a synergistic effect of GH on ACTH action on the biosynthesis of cortisol in the adrenals. Variations in the levels of 11-deoxycortisol and cortisol during hormonal manipulations lead to the identification of the mitochondrial hydroxylation of 11-deoxycortisol as one of the possible sites of action of GH.     

Effect of recombinant human growth hormone (GH) replacement on the hypothalamic-pituitary-adrenal axis in adult GH-deficient patients

The aim of the study was to evaluate the hypothalamus-pituitary-adrenal (HPA) axis in patients (nine males, three females; mean age +/- sem 51 +/- 2 yr) with adult-onset GH deficiency (GHD) due to surgically treated pituitary tumors with preserved HPA function and without evidence of tumor recurrence before and during recombinant human (rh) GH replacement therapy (duration 31 +/- 6 months). HPA function was assessed by urinary free cortisol and morning serum cortisol levels as well as cortisol responses to 1 mug ACTH test (n = 7 patients) or insulin tolerance test (n = 5 patients) before and during rhGH therapy, the cut-off for the diagnosis of hypoadrenalism being a cortisol peak less than 18 microg/dl (<500 nmol/liter) after stimulatory tests. Serum cortisol and urinary free cortisol levels were significantly lower on therapy than before [7.6 +/- 0.8 vs. 11.5 +/- 0.9 microg/dl (208 +/- 22 vs. 317 +/- 24 nmol/liter), P < 0.01, and 19.6 +/- 2.5 vs. 32.2 +/- 3.2 microg per 24 h (54 +/- 7 vs. 89 +/- 9 nmol per 24 h), P < 0.05, respectively], whereas no change in cortisol-binding globulin levels was observed. Cortisol peak after either ACTH test or insulin tolerance test was lower on rhGH therapy than before [15.9 +/- 1.5 vs. 20.2 +/- 1.1 microg/dl (437 +/- 43 vs. 557 +/- 31), P = 0.01, and 13.1 +/- 2.6 vs. 20.4 +/- 1.4 microg/dl (362 +/- 71 vs. 564 +/- 37 nmol/liter), P = 0.03, respectively]. Accordingly, central hypoadrenalism was detected in nine of 11 patients. In conclusion, low GH and IGF-I levels, likely enhancing the conversion of cortisone to cortisol, may mask a condition of central hypoadrenalism. Therefore, the reassessment of HPA function in GHD patients during rhGH therapy is mandatory.