Subnormal Peak Research Articles

Preterm birth and risk of bone fractures during childhood and early adulthood.

People born preterm have reduced bone mineral density, subnormal peak bone mass, and an increased risk of osteoporosis. Whether this translates to increased risk of bone fractures is uncertain. We assessed fracture risk from childhood to early adulthood in relation to gestational age and sex by conducting a nationwide register-linkage cohort study comprising all 223 615 liveborn (1/1987- 9/1990) singletons (9161, 4.1%, preterm) in Finland. Cox regression models provided hazard ratios (HR) for fracture diagnosis in public specialty healthcare in both first and recurrent event settings during the whole follow-up (0-29yr), and during different age periods (0-4/5-9/10-29yr). Gestational age was considered categorical (full-term, 39-41weeks, reference). A total of 39 223 (17.5%) children or young adults had at least one fracture. In analyses not stratified by sex, only extremely preterm birth (<28 completed weeks' gestation) was associated with risk of bone fracture at 0-29yr; adjusted HR (aHR) 0.46 (95% CI 0.28-0.74) compared with those born full-term. Among females, gestational age was unrelated to fracture risk at 0-29yr. Among males, extremely and very preterm (28-31weeks) birth was associated with lower risk of fracture at 0-29yr compared with those born full-term: aHR 0.38 (CI 0.21-0.71) and 0.75 (CI 0.59-0.95) respectively. Restricting the analyses to the individuals without severe medical condition(s) attenuated the associations. However, the fracture risk varied according age and sex: at 10-29yr moderately preterm (32-33wk) females, and extremely- and very preterm males had a lower risk: aHR 0.63 (0.43-0.94), 0.35 (0.17-0.69), and 0.74 (0.57-0.95) respectively, while late preterm birth (34-36wk) was associated to 1.6-fold higher risk among females at 0-5yr, and 1.4-fold risk among males at 5-10yr. Analyses on recurrent fractures showed similar pattern. Children and young adults, in particular males, born extremely or very preterm may have less bone fractures, this is partly explained by severe medical conditions in this group.

Comparison of Total Cortisol, Free Cortisol, and Surrogate Markers of Free Cortisol in Diagnosis of Adrenal Insufficiency in Patients With Stable Cirrhosis

Measurements of serum levels of total cortisol can overestimate the prevalence of adrenal dysfunction in patients with cirrhosis because they have low concentrations of corticosteroid-binding globulin and albumin. We used measurements of serum total cortisol and serum free cortisol after the low-dose short Synacthen test (LDSST) to assess adrenal dysfunction. We studied 79 patients with stable cirrhosis; adrenal dysfunction was defined by peak concentrations of total cortisol ≤494 mmol/L and/or peak concentrations of free cortisol ≤33 nmol/L after the LDSST. We determined free cortisol index (FCI) scores and calculated free cortisol levels by using Coolens' equation. The Cox regression model was used to assess the relationship between adrenal dysfunction and outcomes (death or liver transplant). On the basis of measurement of total cortisol, 34% of patients had adrenal dysfunction, and on the basis of measurement of free cortisol, 29% had adrenal dysfunction. There was agreement between total cortisol and free cortisol levels in 22% of patients; in 13%, adrenal dysfunction was diagnosed only on the basis of total cortisol and in 6% only on the basis of free cortisol (κ coefficient, 0.56; P < .01). Low concentrations of corticosteroid-binding globulin (21 vs 54 μg/mL, P < .01) led to an overestimation of adrenal dysfunction that was based on measurement of total cortisol. Measurements of calculated free cortisol constantly overestimated free cortisol concentrations, with variations as large as 87% for baseline values and up to 84% after stimulation. Adrenal insufficiency, defined by FCI scores <12, was detected in 30% of patients; among them, 23% also had subnormal peak levels of free cortisol (κ coefficient, 0.70; P < .001). Adrenal dysfunction was not significantly associated with patient outcomes, on the basis of Cox model analysis. Adrenal insufficiency, defined by LDSST, is frequent in patients with stable cirrhosis, on the basis of measurements of total and free cortisol. FCI scores are better than measurement of total cortisol in assessing adrenal function in patients with cirrhosis. We did not associate adrenal dysfunction with outcome, but further studies are needed.

Predicting the onset of Addison’s disease: ACTH, renin, cortisol and 21‐hydroxylase autoantibodies

Autoantibodies to 21-hydroxylase (21OH-AA) precede onset of autoimmune Addison's disease (AD). Progression to AD can take months to years, and early detection of metabolic decompensation may prevent morbidity and mortality. To define optimal methods of predicting progression to overt AD (defined by subnormal peak cortisol response to Cosyntropin) in 21OH-AA+ individuals. Individuals were screened for 21OH-AA at the Barbara Davis Center from 1993 to 2011. Subjects positive for 21OH-AA (n = 87) were tested, and the majority prospectively followed for the development of Addison's disease, including seven diagnosed with AD upon 21OH-AA discovery (discovered), seven who progressed to AD (progressors) and 73 nonprogressors. Plasma renin activity (PRA), ACTH, baseline cortisol, peak cortisol and 21OH-AA were measured at various time points relative to diagnosis of AD or last AD-free follow-up. Compared with nonprogressors, in the time period 2 months-2 years prior to the onset of AD, progressors were significantly more likely to have elevated ACTH (11-22 pM, P < 1E-4), with no significant differences in mean PRA (P = 0·07) or baseline cortisol (P = 0·08), and significant but less distinct differences seen with 21OH-AA levels (P < 1E-4) and poststimulation cortisol levels (P = 6E-3). Moderately elevated ACTH is a more useful early indicator of impending AD than 21OH-AA, PRA or peak cortisol, in the 2 months-2 years preceding the onset of AD.

A subnormal peak cortisol response to stimulation testing does not predict a subnormal cortisol production rate

A subnormal peak cortisol response to stimulation testing does not predict a subnormal cortisol production rate

Decreased Bone Mineral Density in Adults Born with Very Low Birth Weight: A Cohort Study

Very-low-birth-weight (VLBW, <1,500 g) infants have compromised bone mass accrual during childhood, but it is unclear whether this results in subnormal peak bone mass and increased risk of impaired skeletal health in adulthood. We hypothesized that VLBW is associated with reduced bone mineral density (BMD) in adulthood. The Helsinki Study of Very Low Birth Weight Adults is a multidisciplinary cohort study representative of all VLBW births within the larger Helsinki area from 1978 to 1985. This study evaluated skeletal health in 144 such participants (all born preterm, mean gestational age 29.3 wk, birth weight 1,127 g, birth weight Z score 1.3), and in 139 comparison participants born at term, matched for sex, age, and birth hospital. BMD was measured by dual energy X-ray absorptiometry at age 18.5 to 27.1 y. Adults born with VLBW had, in comparison to participants born at term, a 0.51-unit (95% confidence interval [CI] 0.28-0.75) lower lumbar spine Z score and a 0.56-unit (95% CI 0.34-0.78) lower femoral neck Z score for areal BMD. These differences remained statistically significant after adjustment for the VLBW adults' shorter height and lower self-reported exercise intensity. Young adults born with VLBW, when studied close to the age of peak bone mass, have significantly lower BMD than do their term-born peers. This suggests that compromised childhood bone mass accrual in preterm VLBW children translates into increased risk for osteoporosis in adulthood, warranting vigilance in osteoporosis prevention.

Cranially irradiated adult cancer survivors may have normal spontaneous GH secretion in the presence of discordant peak GH responses to stimulation tests (compensated GH deficiency)

We have previously demonstrated that spontaneous (physiological) GH secretion was entirely normal in cranially irradiated patients who had normal individual peak GH responses to the insulin tolerance test (ITT) but reduced maximal somatotroph reserve as indicated by substantially reduced group GH responses to the GHRH + arginine stimulation test (AST). The normality of spontaneous GH secretion was attributed to a compensatory increase in hypothalamic stimulatory input within a partially damaged hypothalamic-pituitary (h-p) axis. It is unknown, however, if such compensatory stimulation can also maintain normality of GH secretion in those who fail the ITT but pass the GHRH + AST. STUDY SUBJECTS AND DESIGN: We studied 24-h spontaneous GH secretion by 20-min sampling both in the fed state (n = 11) and in the last 24 h of a 33-h fast (n = 9) in adult cancer survivors with subnormal peak GH responses to the ITT but either normal or relatively less attenuated peak GH responses to the GHRH + AST. The study was conducted 8.3 +/- 1.8 (range 2-23) years after cranial irradiation for nonpituitary brain tumours (n = 9) or leukaemia/lymphoma (n = 2) in comparison with 30 normal controls (fasting, 14). Previously published diagnostic thresholds for the ITT, GHRH + AST and spontaneous GH secretion were used to characterize GH secretion. Four of the 11 patients with impaired stimulated responses to both tests showed only minor discordancies between stimulated and spontaneous GH secretion. Two of the remaining seven patients had subnormal spontaneous GH secretion. However, spontaneous GH secretion, both individually and as a group, was entirely normal in the remaining five patients who had impaired GH responses to the ITT but normal individual responses to the GHRH + AST; in these five patients, IGF-I standard deviation scores (SDS; -2.7 to -0.8) were significantly reduced to a moderate degree compared with normals. In cranially irradiated adult cancer survivors, it cannot be assumed that failure to pass the ITT in isolation reflects severe GH deficiency (GHD). It appears that in some patients near-maximal compensatory overdrive of the partially damaged somatotroph axis may result in near-normal quantitative restoration of spontaneous GH secretion, thus limiting further stimulation with the ITT to the extent that impaired GH responses can be seen even before spontaneous GH secretion starts to decline in adults. However, IGF-I status continues to provide useful information about the adequacy of the compensatory process and therefore the degree of normality of GH secretion.

Plasma Adrenocorticotropin (ACTH) Values and Cortisol Response to 250 and 1 μg ACTH Stimulation in Patients with Hyperthyroidism before and after Carbimazole Therapy: Case-Control Comparative Study

Although the production and metabolic clearance rate of cortisol is increased during thyrotoxic state, the net effect on adrenocortical reserves is not clear. We assessed circulating ACTH levels, cortisol binding globulin (CBG), and adrenocortical reserves in hyperthyroid patients (before and after carbimazole therapy) and healthy controls. This was a case-control investigative study in a tertiary care setting. Plasma ACTH and free cortisol index (FCI; serum cortisol/CBG) were measured in 49 consecutive patients with hyperthyroidism and 50 controls. ACTH(1-24) stimulation tests (250 and 1 microg) were carried out in the first 29 patients and 15 controls. Peak FCI less than the mean -3 sd of healthy controls was considered subnormal. ACTH(1-24) stimulation tests were repeated in 24 patients in the euthyroid state. The mean basal plasma ACTH and FCI were higher and CBG was lower in thyrotoxic patients in comparison with controls. The peak cortisol was less than 18 microg/dl in 10 of 29 and 14 of 29 on 250 and 1 microg ACTH(1-24) stimulation. Peak FCI was subnormal only in three of 27 (11.1%) and two of 21 (7.4%) on 250 and 1 microg ACTH(1-24) stimulation, respectively. The mean plasma ACTH, basal FCI, and subnormal peak FCI (two of the three) normalized after euthyroidism. Plasma ACTH and FCI did not correlate with severity of thyrotoxicosis. Up to 11% of thyrotoxics have subnormal peak FCI on ACTH(1-24) stimulation. Such changes occur despite high basal plasma ACTH and FCI. Use of FCI, rather than total cortisol, is required for the interpretation of cortisol values in thyrotoxicosis due to the variation in CBG.

Adrenal Function in Children with Severe Asthma Treated with High-Dose Inhaled Glucocorticoids: Recommended Screening Tests in Outpatient Conditions

A number of previous studies have suggested that adrenal suppression occurs in asthmatic children treated with high-doses of inhaled glucocorticoids (IGC). This study was designed to determine the frequency of adrenal suppression in children with severe asthma treated with recommended doses of IGC: namely 500-1,000 microg/day of fluticasone propionate or the equivalent of budesonide (1,000-2,000 microg/day) for a period of at least 12 months. Early morning cortisol (F) and ACTH serum levels were measured in 27 severe asthmatics aged 6-16 years old. The children underwent a low dose ACTH test (1 microg/1.73 m2) with a parallel glucose measurement. Twenty-four hour urine collection was performed before examination for free F (UfF) and creatinine levels. There were no clinical manifestations of adrenal hypofunction in the analyzed children. Of the 27 patients, 22 had normal basal and post-stimulatory levels of F and normal UfF, and the other five (18.5%) had basal serum F levels of <400 nmol/l. Four of the five also had normal post-stimulatory levels of F and normal UfF. One child had a subnormal peak F value of 484 nmol/l during the ACTH test. None of the patients had a suppressed serum ACTH level, but an elevated ACTH level was found in four children. This study provided biochemical evidence of suboptimal adrenal function in one child in the examined group (3.7%) and a good response to stimulation in all the others, even in those with slightly reduced basal cortisol levels. This study showed that the use of fluticasone in doses of up to 1,000 microg/day (or the equivalent of budesonide) as long-term treatment of children with severe asthma did not substantially affect their adrenal function.

Determinants of Exercise Function Following Univentricular Versus Biventricular Repair for Pulmonary Atresia/Intact Ventricular Septum

This study aimed to determine whether the exercise capacity of patients with pulmonary atresia/intact ventricular septum (PA/IVS) who have undergone biventricular repair is superior to that of patients with single ventricle repairs and to account for any differences. PA/IVS is generally treated with either biventricular (outflow tract reconstruction) or univentricular (Fontan) palliation. Although biventricular repair is believed to result in superior exercise function, this theory is untested. Symptom-limited programmed bicycle ergonometry with expiratory gas analysis was prospectively performed on all patients with PA/IVS >7 years old seen over 18 months. Nineteen biventricular and 10 Fontan patients (mean age 16.5 +/- 6.5 vs 12.7 +/- 5.0 years, p = 0.12) were enrolled. The exercise capacity of biventricular patients was not statistically superior to that of Fontan patients (predicted peak VO2 83.5 +/- 21% vs 76.0 +/- 17.5%, p = 0.34), although chronotropic function and ventilatory efficiency were significantly better in the former. The peak exercise capacity varied widely within each group, and there was considerable overlap between biventricular and Fontan patients. Within groups, imaging studies did not reliably predict exercise capacity. Most patients in each group had subnormal peak VO2, and there was a trend toward impaired performance with increasing age regardless of type of repair. In conclusion, biventricular repair may not guarantee superior exercise performance over single-ventricle palliation in PA/IVS. Regardless of repair type, aerobic capacity may deteriorate with age and is not reliably predicted by noninvasive imaging. These findings underscore the need for a quantitative, proactive approach to the assessment and preservation of exercise function.

The hypothalamic–pituitary–adrenal axis in critical illness: responses to the low-dose corticotropin (ACTH) stimulation test and human corticotropin-releasing hormone (hCRH)

The objective of this study was to investigate the functional integrity of the hypothalamic–pituitary–adrenal axis in critical illness by stimulating with the low-dose ACTH stimulation test (LDST) and hCRH. The study included 16 (15 male) mechanically ventilated patients, having a mean age of 52 ± 19 years. Underlying diagnoses included major operation (n = 7), multiple trauma (n = 5), stroke (n = 3), and pancreatitis (n = 1). Patients were enrolled in the study 3–14 days after initiation of mechanical ventilation. Median APACHE II and SOFA scores at the study day were 13 (range: 8–23) and 5.5 (range: 4–12), respectively. All patients underwent stimulation first with the LDST (1 μg) and then on the following day with 100 μg hCRH. ACTH and cortisol concentrations were determined from -15 to 120 min after hCRH. Normal cortisol responses to the LDST and hCRH were defined as peak plasma concentrations above 18 μg/dl and 20 μg/dl, respectively. An appropriate ACTH response to hCRH was considered if a twofold increase in ACTH was observed. In the entire patient population, baseline cortisol (mean ± SD) was 15.1 ± 7.1 μg/dl and stimulated cortisol (median) was 21.4 μg/dl following the LDST. Four (25%) of the 16 patients had subnormal stimulated cortisol levels after the LDST. These four patients also had subnormal peak cortisol concentrations following hCRH. Analysis of the individual ACTH responses in the four patients revealed two patterns: in three patients a twofold to eightfold increase in ACTH was noted, whereas one patient failed to augment appropriately ACTH levels (peak ACTH was 1.60 times the baseline value). In conclusion, a significant (25%) subset of critically ill patients has evidence of diminished cortisol production following dynamic stimulation with the LDST. This disorder is mostly due to primary adrenal dysfunction, but also to hypothalamic–pituitary failure.

The effect of thyrotoxicosis on adrenocortical reserve.

Variations in thyroid function are known to be associated with changes in adrenocortical activity. Previous studies in animals have suggested that long-standing hyperthyroidism may be associated with diminished adrenal functional reserve despite a continuing hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. In humans, there has been no direct assessment of adrenal secretory reserve in clinical thyrotoxicosis. This study aimed to assess adrenocortical reserve in response to low-dose ACTH, following dexamethasone suppression, in patients with severe thyrotoxicosis. Ten patients (four men and six women, 30-45 years) with severe long-standing thyrotoxicosis due to Graves' disease (n=6) or toxic nodular goitre (n=4) were studied at diagnosis and again when in a stable euthyroid state following drug therapy for 8-12 months. All patients underwent ACTH stimulation tests at 0800h with ACTH(1-24) (Cortrosyn; 0.1microg/kg body weight, i.v.) following overnight suppression of the HPA axis with dexamethasone (1mg per os at 2300h). Serum cortisol was assayed at -15, 0, 15, 30, 60 and 90min after the administration of ACTH. The mean (+/-s.d.) peak and delta cortisol responses to ACTH (634.5+/-164nmol/l and 618+/- 196nmol/l respectively), as well as the net area under the response curve (36769+/-12188nmol/lx min) in the hyperthyroid patients were significantly lower compared with the values when the same patients were euthyroid (911+/-157nmol/l, 905+/-160nmol/l and 57652+/-10128nmol/lxmin respectively; P<0.005). Subnormal peak cortisol responses (<500nmol/l) were observed in two severely toxic patients. The findings were independent of the cause of thyrotoxicosis. In patients with severe thyrotoxicosis, cortisol secretion in response to low-dose ACTH stimulation, following dexamethasone suppression, is lower in the hyperthyroid than in the euthyroid state. It appears that thyrotoxicosis is associated with subtle impairment of adrenocortical reserve.

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

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. 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. 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. 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.

Disturbed pubertal growth in girls treated for acute lymphoblastic leukemia.

Pubertal growth was studied in 10 girls previously treated for acute lymphoblastic leukemia. The average age at menarche was 12.2 years, which is significantly lower (p less than 0.01) than the expected 13.1 years. Compared with normal girls, these girls showed a subnormal (p less than 0.05) peak height velocity during the second year before menarche. The remaining growth before menarche as well as the total postmenarchal growth was close to the normal average. The average final standing height was 1 SD less than what would be expected from their height 1 year after the cessation of therapy. A relative growth hormone deficiency in combination with early onset of puberty could account for this loss in final height.

GnRH and HCG Tests are Both Necessary in Differential Diagnosis of Male Delayed Puberty

• The discriminative power of the gonadotropin releasing hormone test and the human chorionic gonadotropin (HCG) test in the diagnosis of gonadotropin deficiency was studied in 73 boys referred because of delayed pubertal development or suspicion of gonadotropin deficiency. Hypogonadotropic hypogonadism was confirmed by clinical follow-up in 21 of the boys and excluded in the others because of normal pubertal development. Those latter boys served as a reference group. The post-HCG serum testosterone level was subnormal in hypogonadotropic hypogonadism on 12 of 19 occasions (in the reference group on two of 46 occasions) and the post–gonadotropin releasing hormone serum luteinizing hormone level was subnormal on fourteen of 22 occasions (zero of 65). Four of the seven boys with hypogonadotropic hypogonadism who had normal post-HCG testosterone levels had subnormal peak luteinizing hormone levels. Of the remaining three boys, two had low basal testosterone levels. Combining the two tests therefore improved the diagnostic accuracy. ( AJDC 1985;139:494-498)

GnRH and HCG tests are both necessary in differential diagnosis of male delayed puberty.

The discriminative power of the gonadotropin releasing hormone test and the human chorionic gonadotropin (HCG) test in the diagnosis of gonadotropin deficiency was studied in 73 boys referred because of delayed pubertal development or suspicion of gonadotropin deficiency. Hypogonadotropic hypogonadism was confirmed by clinical follow-up in 21 of the boys and excluded in the others because of normal pubertal development. Those latter boys served as a reference group. The post-HCG serum testosterone level was subnormal in hypogonadotropic hypogonadism on 12 of 19 occasions (in the reference group on two of 46 occasions) and the post-gonadotropin releasing hormone serum luteinizing hormone level was subnormal on fourteen of 22 occasions (zero of 65). Four of the seven boys with hypogonadotropic hypogonadism who had normal post-HCG testosterone levels had subnormal peak luteinizing hormone levels. Of the remaining three boys, two had low basal testosterone levels. Combining the two tests therefore improved the diagnostic accuracy.

Does 1,25-dihydroxyvitamin D participate in the regulation of hormone release from endocrine glands?

The presence of receptors for 1,25-dihydroxyvitamin D3 in the pituitary, pancreas, testis, and ovary has raised the question of a possible direct role for 1,25-dihydroxyvitamin D (1,25(OH)2D) in the regulation of hormone synthesis and secretion. To evaluate this problem, six children with the syndrome of resistance to 1,25(OH)2D with rickets and alopecia underwent dynamic tests of insulin, TSH, PRL, GH, and testosterone secretion. Oral glucose loading resulted in normal glucose curves, subnormal peak insulin responses of 12-20 microU/ml in three hypocalcemic patients, and normal peak serum insulin values of 30-40 microU/ml in two normocalcemic patients. Basal serum, TSH, PRL, T4, and T3 concentrations were normal in all patients. Peak serum TSH values after TRH were 11-17 and 16-32 microU/ml in the hypo- and normocalcemic patients, respectively. The PRL response to TRH stimulation in either hypocalcemic or normocalcemic patients was normal [mean 26.2 +/- 5.1 (SD) ng/ml]. Peak serum GH levels were greater than 8 ng/ml in all five patients studied after one or more of the various stimuli. Serum testosterone concentrations after hCG stimulation were normal in the three patients studied (4.1-8.0 ng/ml). Thus, in children with resistance to 1,25(OH)2D, we could find no significant abnormalities in hormone secretion from the pituitary, pancreas, and testis apart from those presumably due to the hypocalcemia itself.

EFFECT OF THYROTROPHIN RELEASING HORMONE (TRH) IN PATIENTS WITH PITUITARY DISORDERS

The secretion and biological activity of thyroid stimulating hormone (TSH) were studied in 22 patients with a pituitary tumour (17 acromegalics and 5 patients with a chromophobe adenoma) and in 36 hypophysectomized patients (16 acromegalics and 20 with a chromophobe adenoma). Thyroid function was assessed by serum thyroxine (T4), serum triiodothyronine (T3), and thyroxine-binding globulin (TBG) concentration. Serum TSH was measured before and after injection of TSH releasing hormone (TRH), and in 19 hypophysectomized patients the T3 response after TRH was measured. In addition a TRH test was performed 1-2 weeks after surgery in 11 patients. The basal serum TSH did not differ from euthyroid control values in any of the groups and no late effect of hypophysectomy was observed. Subnormal peak TSH values were seen in 10 out of 37 euthyroid patients, whereas 9 out of 11 hypothyroid patients responded normally. Hypophysectomy caused an immediate but transient decrease in peak TSH in patients with a chromophobe adenoma only. The rise in serum T3 after TRH was significantly lower in hypophysectomized patients than in controls. An increase in TSH was followed by a T3 response in all patients except in 4 out of 8 euthyroid acromegalics. In patients operated on for a chromophobe adenoma the T3 response was correlated with serum T4, whereas this was not the case in acromegalics.

EFFECT OF CYPROHEPTADINE (CPU), A SEROTONIN ANTAGONIST ON ADRENOCORTICAL FUNCTION IN HYPOPITUITARY CHILDREN

We have previously demonstrated a significantly increased rate of growth in hypopituitary children treated chronically with CPH and growth hormone (GH) compared to those treated with GH alone. To determine the effect of chronic CPH in adrenocortical function, the cortisol (F) response to insulin hypoglycemia was determined in 10 hypopituitary children (8 idiopathic, 2 organic) treated for at least 4 months with GH and CPH (12-16 mg/day). All had previously normal oral metyrapone tests. While receiving CPH, five of the ten patients had a normal peak F response (> 15 μg/dl) to insulin hypoglycemia while five of the ten had subnormal peak F concentrations (6.4 ± 2.7 μg/dl). All patients were retested two or more months after cessation of CPH therapy. The five patients with a normal peak F response during CPH therapy did not have an increased peak response after cessation of CPH. Four of the 5 patients with an abnormal response subsequently had a normal peak F response significantly greater than that while receiving CPH (16.3 ± 1.3 μg/dl; p < .01). The patient who had persistent subnormal peak F response to hypoglycemia had received radiation therapy for craniopharyngioma. None of the ten patients experienced any symptoms of glucocorticoid insufficiency. We conclude that in some cases, long-term administration of CPH to hypopituitary children may be associated with decreased F response to insulin hypoglycemia.

Retinal studies in patients with hyperglycaemia, hypoinsulinaemia and hyperlipidaemia associated with hypopituitarism.

ABSTRACT Twenty-four patients who had a 10-year history of hypopituitarism resulting from treated chromophobe adenoma, without known family history of diabetes, were studied during oral glucose tolerance (GTT), arginine infusion, and insulin tolerance (ITT) tests. All patients were receiving thyroid and cortisone replacement. Serum immunoreactive growth hormone (HGH) was subnormal in all patients compared with normal subjects during both arginine infusion and ITT tests (P &lt; 0.001). Although 9 of this hypopituitary group were diabetic, all patients showed a subnormal peak immunoreactive insulin rise during an arginine infusion test and subnormal insulinogenic index during an oral glucose tolerance test, when compared with normal subjects in the same age range. Fasting plasma triglycerides were elevated in the majority of patients, serum cholesterol in 8 while free fatty acids were high in all patients. Hyperglycaemia, hypoinsulinaemia, hyperlipidaemia and low growth hormone levels were not associated with any of the clinical signs of vascular disease frequently seen in diabetic patients.

The absorption of folic acid in megaloblastic anaemia associated with pregnancy

The absorption of folic acid was studied in 29 patients with megaloblastic anaemia following pregnancy, and in control subjects. When compared with control subjects, the serum S. faecalis folic acid levels after an oral dose of pteroylglutamic acid (PGA) were within normal limits in 22 of 24 patients tested, and the urinary radioactivity after oral administration of tritiated pteroylglutamic acid ( 3H PGA) was normal in all nine patients tested. In one patient with a subnormal peak serum S. faecalis folic acid level, the urinary excretion of radioactivity after 3H PGA was normal. Haematological remission was induced with 0.4 mg. PGA daily by mouth in all nine patients so treated. It is concluded that there is no consistent defect in folic acid absorption in the patients studied.