Prevalence of diabetes among children treated with growth hormone in Israel.

AIMS: To determine the long-term risk of diabetes in a cohort of children treated with recombinant human growth hormone in Israel, using data from the Israeli National Diabetes Register. METHODS: Between 1988 and 2009, 2513 children were approved for growth hormone treatment. They were assigned to one of two groups. The first group included children treated for isolated growth hormone deficiency and who were small for gestational age and the second included those treated for multiple pituitary hormone deficiency, chronic renal failure, Turner syndrome or Prader-Willi syndrome. The cohort was cross-linked with the Israeli National Diabetes Register for 2014 (mean follow-up duration 12.1±5.3 years), and prevalent cases of diabetes were identified. Standardized prevalence ratios for diabetes were calculated for people aged 10-29 years. RESULTS: In 2014, a total of 23 individuals were identified with diabetes (four with pre-existing diabetes, seven developed diabetes before age 17 years and 12 developed it at a later age). In the isolated growth hormone deficiency and small-for-gestational-age group there was no difference in the prevalence of diabetes compared with the general population (standardized prevalence ratio 2.05, 95% CI 0.94-3.89). In the group that included people with multiple pituitary hormone deficiency, chronic renal failure, Turner syndrome and Prader-Willi syndrome there was a significantly higher diabetes prevalence (standardized prevalence ratio 11.94, 95% CI 6.53-20.00) compared with the general population. CONCLUSIONS: No difference in diabetes prevalence was found in the isolated growth hormone deficiency and small-for-gestational-age group, compared with the general population. Children treated with growth hormone with pre-existing risk factors had an increased prevalence of diabetes. It is advisable to monitor blood glucose levels closely during and after growth hormone treatment, especially in such children.

Treatment of growth failure with growth hormone in children with chronic kidney disease: an open-label long-term study.

AIMS: To assess long-term efficacy and safety of recombinant human growth hormone (GH) in children with chronic kidney disease (CKD). METHODS: An open-label, international, multicenter study. Children with CKD and growth failure received GH (0.35 mg/kg/week). The primary efficacy endpoint was a significant change in height velocity (HV) and height standard deviation score (SDS) versus baseline after 12 months of treatment, extended to 24 months, then to 5 years. RESULTS: In total, 81 patients enrolled (CKD Stage 4 - 5 = 37, on dialysis = 27, post-transplant = 17). After 12 and 24 months of treatment, increases were seen in mean (SD) HV (4.6 (3.1) to 9.0 (3.6) cm/year and 4.5 (3.3) to 7.5 (2.9) cm/year, respectively; both p < 0.001), mean (SD) height SDS (-3.7 (1.7) to -3.0 (1.7) and -3.6 (1.5) to -2.5 (1.5), respectively; both p < 0.001) and mean (SD) HV SDS (-2.4 (2.5) to 3.8 (4.5) and -2.4 (2.2) to 1.1 (3.8), respectively; both p < 0.001). A normal height SDS was seen in 1% of children at baseline, 17% after 12 months and 43% after 24 months of treatment. Improvements were similar across CKD subgroups with the greatest improvements in CKD Stage 4 - 5. Among 31 patients who completed about 5 years of treatment, four reached final height. There was no undue bone age acceleration and no deterioration of kidney function. Ten adverse events were related to GH treatment. CONCLUSIONS: In this long-term study, GH treatment was associated with significant improvements in growth and height in children with CKD and growth failure, and was well tolerated.

"Functional food" for acceleration of growth in short children born small for gestational age.

OBJECTIVE: To assess the effect of nutritional supplementation on growth in short children born small for gestational age (SGA). PATIENTS: Fifty four short but otherwise healthy children (26 boys), 6.4 +/- 1.8 years of age, were referred for growth retardation. METHODS: Following a 6 month observation period the participants were randomly allocated to receive growth hormone therapy (GH) 1.26 IU/kg/day (0.042 mg/kg/day) or nutritional program (NUT) or passive observation (OBS). Patients in the nutritional program received 10 mg/day iron, 11 mg zinc-three times a week and 10000 IU/week of vitamin A. The following parameters were obtained 3 monthly: height, weight, dietary intake and serum IGF-1. RESULTS: Six months of nutritional supplement induced growth acceleration somewhat lower than that seen in the growth hormone treated children, but significantly greater than noted in the observation group (OBS 4.6 +/- 1.3, NUT 7.9 +/- 1.7, GH 9.1 +/- 1.8 cm/yr, P<0.001). CONCLUSIONS: Six months of vitamin A, iron and zinc supplementation induces growth acceleration in short children born SGA with subnormal nutrients intake similar to growth hormone therapy.

Cognitive impairment is prevalent in pseudohypoparathyroidism type Ia, but not in pseudopseudohypoparathyroidism: possible cerebral imprinting of Gsalpha.

OBJECTIVE: Pseudohypoparathyroidism type Ia (PHP-Ia) is a hereditary disorder characterized by resistance to multiple hormones that work via cAMP such as PTH and TSH, accompanied by typical skeletal features including short stature and brachydactyly, termed Albright hereditary osteodystrophy (AHO). In affected kindreds, some members may have AHO but not hormone resistance; they are termed as pseudopseudohypoparathyroidism (PPHP). The molecular basis for the disorder is heterozygous inactivating mutation of the Gsalpha gene. In affected families, subjects with both PHP-Ia and PPHP have the same Gsalpha mutations. The skeletal features common to PPHP and PHP-Ia are presumably caused by tissue-specific Gsalpha haploinsufficiency. Other features that distinguish between PPHP and PHP-Ia, such as the multihormone resistance, are presumably caused by tissue-specific paternal imprinting of Gsalpha. This suggests that major differences in phenotype between PHP-Ia and PPHP point to specific tissues with Gsalpha imprinting. One such major difference may be cognitive function in PHP-Ia and PPHP. DESIGN: Description of a large family with PHP-Ia and PPHP. PATIENTS: Eleven affected subjects with PHP-Ia or PPHP in one family. MEASUREMENTS: Cognitive impairment (CI) was defined by a history of developmental delay, learning disability and the Wechsler intelligence scale. RESULTS: CI occurred only in the five PHP-Ia but not in the six PPHP subjects. Hypothyroidism which occurred in all PHP-Ia subjects was apparently not the cause of CI as it was mild, and was treated promptly. Analysis of additional Israeli cases, and the published cases from the literature, all with documented Gsalpha mutations, revealed that CI is prevalent in PHP-Ia [60 of 77 subjects (79%)] but not in PPHP [3 of 30 subjects (10%)] (P < 1 x 10(-6)). CONCLUSION: We suggest that Gsalpha is imprinted in the brain.

Human growth hormone and insulin-like growth factor-1 enhance the proliferation of human leukemic blasts.

As the number of long-term survivors of childhood leukemia increases, growth retardation has emerged as a significant complication. Treatment of these children with growth hormone (GH) has been suggested and sporadically implemented. We, therefore, studied the effect of human GH (hGH) and its by-product insulin-like growth factor-1 (IGF-1) on the growth of leukemic cells in vitro. Under serum-free conditions hGH and IGF-1 induced a significant dose-dependent proliferative effect on promyelocytic leukemia (HL60) and Burkitt's lymphoma (Daudi) cell lines. Anti-hGH antibodies negated the stimulatory effect of hGH and anti-IGF-1 serum abrogated the growth-promoting effect enhanced by IGF-1. Similar statistically significant stimulatory properties were found when freshly obtained marrow cells from four of five acute lymphoblastic leukemia (ALL) of childhood and four acute myelogenous leukemia (AML) patients were studied in ALL and AML blast-cell clonogenic assays. ALL colonies increased numerically by 72% (P less than .025) and AML colonies by 92% (P less than .01) in the presence of hGH at concentrations of 2.5 x 10(2) and 3.0 x 10(2) ng/mL, respectively. IGF-1 stimulated ALL and AML blast-colony growth at concentrations ranging from 0.05 to 0.5 ng/mL by up to 105% (P less than .025) and 65% (P less than .03), respectively. Our in vitro data suggest that circulating hGH and IGF-1 may promote leukemic blast cell replication in vivo, and the supplemental administration of hGH to leukemia patients in remission must be carefully monitored for early relapse.

Increased integrated concentration of norepinephrine, epinephrine, aldosterone, and growth hormone in patients with uncontrolled juvenile diabetes mellitus.

The 24-h integrated plasma concentration of glucose (IC-glucose), norepinephrine (IC-NE), epinephrine (IC-E), cortisol (IC-F), growth hormone (IC-GH), aldosterone (IC-ALDO), and plasma renin activity (IC-PRA) were measured in 11 nonobese juvenile-onset nonketotic diabetic patients exhibiting hyperglycemia and glycosuria and 34 matched control subjects using a portable pump, drawing blood at a constant rate through a nonthrombogenic i.v. catheter. The diabetic patients had a noticeable rise of their IC-NE, IC-E, IC-GH, and IC-ALDO. There was no significant difference between the IC-F and IC-PRA of the patients and the control subjects.

Correlation of urinary excretion of C-peptide with the integrated concentration and secretion rate of insulin.

The secretion rate of insulin (SR-I) of 50 normal subjects was calculated from the 24-h integrated concentration of insulin (IC-I), the peripheral metabolic clearance of insulin (pMCR-I), and the mean fractional hepatic insulin extraction (fhMCR-I) that was derived from our data. fhMCR-I was determined as the difference in the molar secretory rate of C-peptide (SR-C) and the molar peripheral clearance of insulin (pMCR-I x IC-I) divided by SR-C. The IC-I in our 50 subjects was 1.19 +/- 0.38 ng/ml and the IC-C was 2.93 +/- 0.58 ng/ml. Based on these data, the fhMCR-I was 0.40 and the Sr-I was estimated to be 54.8 +/- 18.0 U/24 h. The 24-h urinary C-peptide excretion (U-C), 44.9 +/- 20.4 micrograms/24 h, had a statistically significant correlation with SR-I (r = 0.838, P less than 0.0001), while the IC-I correlated significantly with the 24-h urinary C-peptide/g of creatinine (r = 0.838, P less than 0.0001). The U-C may thus serve as a practical method for estimating the SR-I.

Twenty-four-hour profile of plasma growth hormone-binding protein.

In experimental animals each burst of GH pulse is followed by a wave of receptor turnover and an increase in serum GH-binding protein (GH-BP), which occurs 60 min after the GH peak. The present report describes the 24-h profile of plasma GH-BP and its correlation to GH pulsatility in normal individuals. Four normally growing children in early puberty were the subjects of this study. Blood was withdrawn continuously for 24 h in 30-min fractions. Pulse analysis of both GH and GH-BP was performed by the Pulsar program. The vast majority of the GH pulses were accompanied by GH-BP pulses within 30 min. Correlation of plasma GH levels to GH-BP levels on the residual series above the smoothed baseline of all 172 individual samples was r = 0.447 (P less than 0.001). Thus, plasma GH-BP levels fluctuate rapidly in relation to the pulsatility of plasma GH levels. This may influence the GH disappearance rate and brings into question some of the deconvolution calculations of GH secretory impulses.

Normal integrated concentration of aldosterone and plasma renin activity: effect of age.

The integrated concentration of aldosterone (IC-ALDO) and PRA (IC-PRA) was studied in 78 normal subjects ranging in age from 9--50 yr. Whereas the IC-ALDO to IC-PRA were found to decrease with age, the ratio of IC-ALDO to IC-PRA was not affected by age. A significant lowering of the normal range and variance was achieved by measuring the 24-h integrated concentration instead of the concentration in discrete samples.

Assessment of growth hormone secretion in normal stature children using 24-hour integrated concentration of GH and pharmacological stimulation.

The integrated concentration of serum GH (IC-GH) is used for the assessment of spontaneous GH secretion. In order to use the IC-GH as a diagnostic tool a normative reference range needs to be established. We determined the IC-GH by continuous blood withdrawal in 119 children of normal height, weight and growth rate. Although the mean IC-GH increased with pubertal status, 4.4 +/- 1.2 micrograms/L at Tanner I (n = 36), 5.5 +/- 2.1 micrograms/L at Tanner II-III (n = 43), and 5.8 +/- 1.6 at Tanner IV-V (n = 40) (P less than 0.03), there was a considerable overlap of individual IC-GH levels between the pubertal groups. Gender affected the mean IC-GH level slightly, but not the range. Although the mean IC-GH of girls tended to be higher than that of boys this difference was not statistically significant. Ninety five percent of the IC-GH values were above the 3.2 micrograms/L level. The response to pharmacological stimulation (clonidine, insulin, or arginine) was also evaluated in 68 of the subjects. The peak GH response to pharmacological stimulation (micrograms/L) with clonidine 21.0 +/- 10.7 (n = 66) was significantly higher than to either arginine 13.1 +/- 6.1 (n = 23) or insulin 14.2 +/- 6.3 (n = 19) (P less than 0.01). The peak response to clonidine increased significantly with pubertal status (P less than 0.001) and there was an interactive effect of gender and pubertal stage where the GH response of prepubertal boys exceeded that of prepubertal girls but the response of pubertal girls exceeded that of pubertal boys (P less than 0.02). The peak stimulated GH levels was correlated with IC-GH in this subgroup r = 0.52, P less than 0.0001). This study provides a large normative data base for IC-GH and the GH provocative tests in normally growing children of varying pubertal status.

The definition of a spontaneous growth hormone (GH) peak: studies in normally growing and GH-deficient children.

GH spontaneous peaks and their diagnostic utility have not been previously evaluated by means of a 24-h continuous withdrawal (CW) procedure in children with growth disorders. Using a CW pump, we studied the 24-h spontaneous secretion of GH in 129 prepubertal subjects grouped as follows. The control group (C) consisted of 20 children of normal height and growth rate. Group GHD consisted of 53 patients with classical GH deficiency (48 idiopathic and 5 organic). The NSD group consisted of 36 patients with a growth velocity below 4.5 cm/yr, normal GH response to provocative stimuli (PS), but a mean 24-h GH in the deficient range. Group NSS consisted of 20 short children with normal growth velocity, normal PS, and normal mean 24-h GH concentration. The mean GH levels for the 24-h period were 4.1 +/- 1.7, 1.4 +/- 0.5, 2.1 +/- 0.7, and 4.2 +/- 1.9, respectively, for the C, GHD, NSD, and NSS groups. For each subject, GH levels were determined in 48 0.5-h samples collected during the CW study, and the GH profile was analyzed by the Pulsar computer program. The mean number of peaks was 9.0 +/- 2.5 for C, 9.5 +/- 3.7 for GHD, 10.5 +/- 1.8 for NSD, and 9.5 +/- 3.2 for NSS. There was no statistical difference between groups. The mean amplitude of peaks was 9.8 +/- 8.9 for C, 1.6 +/- 1.0 for GHD, 2.9 +/- 1.3 for NSD, and 9.9 +/- 9.1 for NSS. Mean peak amplitudes in both GHD and NSD were significantly lower than in the C and NSS groups. The presence of peaks of more than 8 micrograms/L during the daytime (0800-2000 h) was a characteristic of children with normal integrated GH concentration (IC-GH) and was seen in 90% of normally growing children but in only 7% of poorly growing children with subnormal IC-GH. There was no significant difference in the number of pulses during the night between C and NSD groups. We conclude that differences in IC-GH between normally growing and poorly growing children are due to a lower amplitude of peaks during the daytime hours.

Evaluation of the 6-hour integrated concentration of cortisol as a diagnostic procedure for Cushing's syndrome.

The diagnostic value of the 24-h integrated concentration (IC) test of cortisol (IC-24-F) was found to be superior to the value of both urinary 17OHCS and urinary free-cortisol tests. The IC-24-F test is too cumbersome for widespread clinical use. The purpose of the present study was to evaluate the diagnostic value of an abbreviated and practical 6-h IC of cortisol (IC-6-F) test. The IC of cortisol (IC-F) was measured in 68 normal subjects and 13 patients with surgically proven Cushing's syndrome. A portable nonthrombogenic constant blood withdrawal system was used over a 24-h period. The IC-F was measured in plasma withdrawn during each 1/2-h period (IC-1/2-F). The mean of 12 consecutive measurements of IC-1/2-F yielded the IC-6-F. The mean of all the IC-1/2-F collected over a 24-h period constituted the IC-24-F. The IC-1/2-F of the patients and their IC-6-F from 0800-1400 h, 1400-2000 h, and 2000-0200 h overlapped the corresponding levels in the control subjects. There was no overlap between the IC-24-F and the IC-6-F (from 2000-0200 h) of the patients and the control subjects. It was concluded that the diagnostic value of a 6-h IC-F test conducted during the afternoon and early part of the might is equal to the diagnostic value of the 24-h IC-F test.

Requirement of mineralocorticoid in congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency.

Marginal salt loss occurs in patients with congenital adrenal hyperplasia due to 11 beta-hydroxylase (11-OHase) deficiency treated with dexamethasone and is accompanied by increased PRA. The present study was undertaken to evaluate the effect of the stimulated renin-angiotensin system on pituitary-adrenal suppression. Seven patients with 11-OHase deficiency were subjected to a series of treatments with dexamethasone, cortisol, and combined cortisol and 9 alpha-fluorohydrocortisone. The latter combination suppressed PRA and sodium excretion, and produced better control of the pituitary-adrenal axis, as measured by plasma ACTA and serum 11-deoxycortisol. We conclude that in children with 11-OHase deficiency, PRA needs to be monitored, and when it is elevated, mineralocorticoid replacement is indicated.

Growth of short children during and after discontinuation of growth hormone therapy.

We have attempted to evaluate the relationship between spontaneous growth hormone (GH) secretion and the response to GH therapy as well as the effect of discontinuation of GH therapy on further growth. The 24-h integrated concentration of GH (ICGH) was determined in 150 short children (< 2 SD for age) with a GH response to clonidine stimulation of more than 10 mcg/L. The patients were treated with GH for 4 yr and were observed for 1 yr following cessation of GH treatment. Twenty-two out of 52 patients who had an ICGH of less than 3.2 mcg/L (group LICGH) and 28 out of 60 patients who had an ICGH of more than 3.2 mcg/L (group NICGH) were followed without GH therapy. Only patients who remained prepubertal throughout the study were included in the analysis. The growth response of the LICGH to GH was better than that of the NICGH children. Patients regained normal growth velocity 6-12 months after discontinuation of GH therapy. Three children of the LICGH subsequently developed classic GH deficiency. These studies demonstrate that short-term GH therapy can improve the growth channel. Children with a low ICGH grow better on GH than children with a normal ICGH. Children with a low ICGH need continued observation and retesting when growth velocity is low.

Integrated concentration of epinephrine and norepinephrine in normal subjects and in patients with mild essential hypertension.

Since the level of plasma catecholamines fluctuates rapidly during the day, measurement in a single blood sample could be misleading. A portable nonthrombogenic blood withdrawal system, permitting normal activity and sleep, was used for obtaining the 24-h integrated concentration (IC) of epinephrine (E) and norepinephrine (NE) in 46 normal control subjects, 30 patients with mild essential hypertension, and 1 patient with pheochromocytoma. The mean IC of E (ICE) and the mean IC of NE (ICNE) of the control subjects were 31 +/- 15 and 194 +/- 106 pg/ml, respectively (mean +/- 1 SD). The mean ICE and ICNE of the essential hypertensive patients were 30 +/- 21 and 224 +/- 90 pg/ml, respectively. No significant difference could be found between the levels found in essential hypertensive and normal control subjects. The levels of ICE and ICNE in the patient with pheochromocytoma were 1350 and 882 pg/ml, respectively, which are 88 and 6.5 SD above the mean of the normal control subjects.

Salt loss in hypertensive form of congenital adrenal hyperplasia (11-beta-hydroxylase deficiency).

Studies in patients with congenital adrenal hyperplasia due to 11-hydroxylase deficiency (11-OHD) suggest a common defect in the adrenal zona fasciculate and zona glomerulosa. The hypertension in untreated 11-OHD patients is considered to be secondary to the accumulation of deoxycorticosterone as a consequence of inadequate 11-beta-hydroxylation in the biosynthesis of aldosterone, and is alleviated by glucocorticoid suppression. To investigate whether deoxycorticosterone suppression in these patients resulted in loss of salt, 11 patients with 11-OHD aged 4-26 yr were studied. Patients were evaluated during dexamethasone suppression (0.6 mg/m for 2 weeks) while receiving a normal diet and a low salt diet (10 meq Na/24 h). There was no significant change in serum electrolytes, cortisol, 11-deoxycortisol, and DOC during these two dietary regimens. PRA in the recumbent and upright positions on both diets was significantly higher in the patients than in normal subjects. Plasma or urinary aldosterone levels were significantly lower in the 11-OHD patients than in the normal controls. Moderate salt loss occurred during the low salt diet. It is concluded that sodium retention is incomplete in glucocorticoid-treated 11-OHD patients. Partial sodium retention is maintained by increased PRA and a subnormal aldosterone response. 11-OHD patients should be carefully monitored during acute disease states and, when electrolyte imbalance is suspected, treatment with mineralocorticoid should be considered.

Reproducibility of growth hormone testing procedures: a comparison between 24-hour integrated concentration and pharmacological stimulation.

The purpose of this study was to compare the reproducibility of two approaches to the evaluation of GH secretion: the integrated concentration of GH (IC-GH), a physiological test of GH secretion, and pharmacological stimulation tests. IC-GH was determined in 40 poorly growing children twice within 4 weeks. The first and second IC-GH were highly correlated r = 0.859, P less than 0.001. One hundred and thirteen poorly growing children underwent pharmacological GH stimulation tests twice within 6 weeks. A moderate correlation was found between the first and second pharmacological test r = 0.524, P less than 0.01. Among the three pharmacological stimuli studied, clonidine (n = 81) had the highest reproducibility followed by arginine (n = 20), and insulin (n = 12). We conclude that IC-GH is more consistently reproducible than the GH response to repeated pharmacological stimulation.

Hypocortisolemia in children undergoing evaluation for growth hormone deficiency.

The group of children who have clinical manifestations of GH deficiency may potentially contain a large number of patients with secretory defects of cortisol. We assessed physiological cortisol secretion by measuring the 24-h integrated concentration of cortisol (IC-F) in a series of 105 patients, aged 7-19 yr, undergoing endocrinological evaluation for growth impairment possibly due to GH deficiency. The reference value for IC-F, established from 30 normal stature, normal weight children (controls), aged 7-18 yr, was 157 +/- 41 nmol/L (mean +/- 1 SD). There was no effect of age, gender, or pubertal status on IC-F in controls. The IC-F of patients was 150 +/- 72 nmol/L. Twelve patients (11%) had IC-F values more than 2 SD below the mean (i.e. less than 75 nmol/L) of the controls (P less than 0.001). An IC-F below 75 nmol/L was associated with a blunted peak cortisol response to insulin-induced hypoglycemia (367 +/- 160 nmol/L compared to 464 +/- 155 nmol/L in the other patients; (P less than 0.05). None of the patients had obvious clinical symptoms of hypocortisolemia at the time of testing. In general, IC-F levels were not correlated with IC-GH. However, 10 patients who had subnormal IC-F values also had laboratory evidence of GH secretory defects; 7 had subnormal IC-GH levels but normal stimulated GH responses, and 3 had both subnormal responses to stimulation as well as subnormal IC-GH. The long term prognosis and management implications of hypocortisolemia diagnosed in this patient group require further evaluation.

11 beta-Hydroxydehydroepiandrosterone in a case of virilizing adrenal adenoma: isolation from urine and mitochondrial conversion from dehydroepiandrosterone.

11 beta-Hydroxydehydroepiandrosterone has been isolated from the urine of a 14-yr-old girl with a virilizing adrenal adenoma. Its excretion was estimated to be 0.4 mg/24 h by gas chromatography and the compound was further identified by mass spectrometry. When [7-3H]dehydroepiandrosterone was incubated with mitochondria prepared from the adenoma, approximately 10% was converted to 11 beta-hydroxydehydroepiandrosterone. The identity of the radioactive 11 beta-hydroxydehydroepiandrosterone was verified by reversed isotopic dilution, its conversion to 11 beta-hydroxyandrostenedione, and its mobility in several chromatographic systems. This is the first demonstration of an 11 beta-hydroxylase from a human source having an affinity for dehydroepiandrosterone.

Detection of primary aldosteronism by the 6-hour integrated aldosterone/renin ratio.

An outpatient diagnostic procedure measuring the 6-hour integrated plasma concentration of aldosterone and plasma renin activity was used to detect primary aldosteronism in 12 patients with low renin hypertension, including six with mild hypertension and normal urinary excretion and spot plasma levels of aldosterone. The ratio of integrated plasma concentration of aldosterone to plasma renin activity in the 12 patients (mean, 339; range, 116-700; p less than 0.0001) did not overlap with that measured in 105 normotensive controls (mean, 27.8; range, 5-97) or in 87 subjects with essential hypertension (mean, 29.2; range, 4-67). Eight patients had surgically proven adenomas (3 of which measured less than 5 mm) with normalization of blood pressure following adrenalectomy. The four remaining patients had bilateral hyperplasia. The 6-hour integrated plasma concentration of aldosterone to plasma renin activity ratio was found to be a useful new outpatient diagnostic tool for evaluation of primary hyperaldosteronism.