Bioactive GH-like immunoglobulins G in active acromegaly: response to long-term treatment with bromocriptine*

In acromegaly, certain forms of circulating immuno reactlve hGH are not true 6H but IgGs which possess G H biological activity (bioactive G H-like IgGs). In this study, we tested the effect of bromocriptine on circulating bioactive G H-like IgGs In an acromegalic woman. Increasing doses of oral bromocriptine (2.5, 5.0 and 7.5mg/day) were administered (for 2, 8 and 6 months respectively). TRH tests were performed before treatment and at the end of treatment with each dose. The patient was without detectable pituitary or extra-pituitary tumour by magnetic resonance imaging. Her serum contained bioactive G H-like IgGs equivalent to 240mU/l of hGH and elevated insulin-like growth factor I (IGF-I; 9500 U/l). Basal hGH was 12.8 μ/l and Increased to 220mU/l 15 min after TRH (200 μg, l.v.). In addition, in the basal samples of each test we measured total IgGs (radial immunodiffusion), bioactive GH-like IgGs (isolated by Sephadex and protein A affinity chromatography and assayed using the Nb2 cell assay) and IGF-I(RIA). Bromocriptine treatment gradually reduced serum levels of bioactive GH-like IgGs and IGF-I, with significant falls observed first at 10 months of treatment. Bioactive GH-like IgGs were 240, 240, 36-0 and <0.124mU/l and IGF-I levels were 9500,8700,4000 and 3100 U/l at 0,2,10 and 16 months of treatment, respectively. In contrast, IR-hGH response to TRH decreased after 2 months of treatment to 89 mU/l and to 49.2 mU/l at the end of the study while basal IR-hGH remained between 13 and 8-4 mU/l. Basal PRL fell to almost undetectable levels. Bromocriptine treatment decreased the G H response to TRH and the serum concentration of bioactive G H-like IgGs and IGF-I. The striking similarity between the pattern of decrease of serum bioactive GH-like IgGs and IGF-I supports the presence of an immuno component in our patient's acromegaly     

Timing of onset of growth hormone deficiency is a major influence on insulin-like growth factor I status in adult life

OBJECTIVE: Several reports have suggested that IGF-I levels in patients with childhood-onset (CO) GH deficiency are lower than those observed in patients with adult-onset (AO) GH deficiency. However, these reports are unsatisfactory as there are several differences between the cohorts studied other than the timing of onset of GH deficiency; in particular, the patients were not matched for equal severity of GH deficiency. We have pursued this question further by examining the IGF-I standard deviation score (SDS) in patients with CO and AO GH deficiency, with equal degrees of severity of GH deficiency, as defined by the peak GH response to the insulin tolerance test (ITT). PATIENTS AND MEASUREMENTS: IGF-I SDS were compared in 146 non acromegalic patients (69 male), aged 15.7-76.6 years (median 33.4 years), bone mass index (BMI) 27.8 +/- 5.8 kg/m2, with severe GH deficiency (peak GH response < 9 mU/l to insulin-induced hypoglycaemia). Patients were subdivided by timing of onset of GH deficiency and the peak GH response to the ITT (GH response < or = 1 mU/l, group 1; > 1-3 mU/l, group 2; > 3-6 mU/l, group 3; > 6-8.9 mU/l, group 4). RESULTS: The IGF-I SDS (mean value +/- SD) in the CO group (n = 63) as a whole was significantly lower than that found in the AO group (n = 83) (-3.7 +/- 2.8 vs.-1.55 +/- 2.2, respectively; P < 0.0001). Despite this, there was no significant difference in the peak GH response to an ITT between the two cohorts (2.8 +/- 2.3 mU/l in the AO cohort and 2.6 +/- 2.2 mU/l in the CO cohort; P = 0.5). When the cohorts were subdivided by severity of GH deficiency, there remained a significant difference in IGF-I SDS in groups 1 (P < 0.0001), 2 (P = 0.05) and 3 (P < 0.05), but there was no significant difference between the AO and CO cohorts in group 4. The peak GH response to an ITT was similar in the AO and CO cohorts in all groups (P = 0.8, 0.8, 0.9 and 0.3 in groups 1-4, respectively). Although increasing severity of hypopituitarism was associated with a decline in IGF-I SDS in the CO cohort (P < 0.01), this was not the case in the AO cohort (P = 0.3). CONCLUSION: These data support the hypothesis that there is an innate difference between adult patients with either CO or AO GH deficiency that cannot be explained solely by variation in the severity of GH deficiency. A possible explanation is that childhood GH deficiency programmes the subsequent relationship between GH and IGF-I in adult life or that the body composition changes, which are more severe in AO GH deficiency, influence IGF-I status.     

Biochemical and hormonal changes induced by one week of administration of rIGF-I to patients with Laron type dwarfism

OBJECTIVE: The purpose of this investigation was to evaluate the effectiveness of short-term administration of recombinant biosynthetic IGF-I on patients with an hereditary inability to generate this hormone. DESIGN AND PATIENTS: Ten patients with Laron type dwarfism (LTD) (4 males, six females) aged 3 1/2 to 37 3/4 years were submitted to seven daily s.c. injections of recombinant IGF-I in doses of 120 or 150 micrograms/kg/day. MEASUREMENTS: Blood samples were drawn before, after three and seven injections, and one week after stopping the trial. RESULTS: The main biochemical and hormonal changes registered were (mean +/- SD): a marked rise in serum type III procollagen (PIIINP) from 4.2 +/- 0.9 to 7.3 +/- 2 micrograms/l (P less than 0.0003) and decrease in the following blood components: plasma hGH from 32.51 +/- 43.77 to 4.02 +/- 2.48 mU/l (P less than 0.001), serum cholesterol from 5.9 +/- 1 to 5.7 +/- 0.8 mmol/l (P less than 0.04), serum SGOT from 28.9 +/- 11.6 to 15.5 +/- 7.6 U/l (P less than 0.01) and serum LDH from 286 +/- 88 to 222 +/- 37 U/l (P less than 0.0005). The response of plasma insulin was variable, decreasing in seven of ten and increasing in three. Some of these effects were transitory, and were found after 3 days therapy but afterwards decreased (insulin, cholesterol and liver tests), others persisted throughout the whole treatment period (hGH, PIINP). CONCLUSIONS: IGF-I mimics the biochemical and hormonal changes described after administration of hGH. The administration of IGF-I in patients with Laron type dwarfism is devoid of side-effects and warrants assessment in long-term studies.     

Polysomnographic findings in five adult patients with pituitary insufficiency before and after cessation of human growth hormone replacement therapy

OBJECTIVE: We observed the new onset of severe obstructive sleep apnoea syndrome (OSAS) in an adult male patient during human growth hormone (hGH) replacement therapy. This prompted us to evaluate the potential influence of hGH substitution therapy on sleep in middle-aged men. DESIGN: A longitudinal study. SUBJECTS: Five male patients (aged 44-56 years, median age 54 years) with postoperative pituitary insufficiency given hGH replacement therapy for 1-2 years (median dose 2.0 U/day; median IGF-I serum concentration 351 microg/l) and 6 months after cessation of hGH treatment (median IGF-I level 77 microg/l - 1 microg/l = 0.131 nmol/l). MEASUREMENTS: Polysomnographic studies were performed, and the following parameters were determined: time in bed (TIB), sleep period time (SPT), total sleep time (TST), sleep efficiency (SE = TST/TIB), sleep stage 1 onset latency (SL), different sleep stages [W (wake), S1, S2, SWS (slow wave sleep = S3 + S4) and REM; % of SPT], stage shifts per hour of SPT (SS/h), stage shifts to W/h of SPT [A/h (awakening)], index of apnoea and hypopnoea events per hour of TST (AH/h), arousals from apnoea and hypopnoea per hour of TST (Ar/h), index of obstructive (OAH/h), central (CAH/h) and mixed (MAH/h) events of apnoea and hypopnoea per hour of TST and minimal desaturation (MD). RESULTS: Median baseline results were: TIB, 479 min; SPT, 465 min; TST, 405 min; SE, 77%; SL, 8.5 min; W, 18.9%; S1, 8.2%; S2, 52.7%; REM, 13.5%; SS/h, 17.7; A/h, 2.8; AH/h, 11.9; Ar/h, 4.4; MD, 80%. These parameters did not change significantly after cessation of hGH treatment. In contrast, median SWS decreased significantly from 33 min (7.1%) to 7.5 min (1.8%; P = 0.03). Median OAH/h decreased significantly from 4.4 to 0.1 (P = 0.03) whereas CAH/h increased from 6.3 to 14.6 (P = 0.03) after cessation of hGH. Correspondingly, one patient with OSAS improved markedly whereas another patient developed new and asymptomatic central SAS after cessation of hGH. CONCLUSION: This study showed that hGH replacement therapy influenced sleep reaction in a complex way in middle-aged men; cessation of treatment was associated with a significant decrease in slow wave sleep and a shift from obstructive to central apnoea and hypopnoea.     

Inverse relationship between cord blood adiponectin concentrations and the number of cigarettes smoked during pregnancy

BACKGROUND: Maternal smoking is linked with several neonatal metabolic disorders. Adiponectin is an adipose-specific hormone with anti-inflammatory and antiatherogenic properties. AIM: The aim of this study was to evaluate the effect of maternal smoking on cord blood adiponectin concentrations. METHODS: We evaluate the effect of maternal smoking on cord blood adiponectin concentrations comparing 14 full-term and seven preterm newborns born to mothers who smoked during pregnancy with 77 full-term and 10 preterm neonates born to non-smokers mothers. RESULTS: Maternal smoking during pregnancy was significantly associated with decreased adiponectin levels of preterm newborns (p < 0.05). CONCLUSIONS: Our findings also reveal a significant relationship between the reported number of cigarettes smoked during pregnancy and cord blood adiponectin concentrations (p = 0.01), suggesting that this association could have a causal relationship.     

Do the limits of serum prolactin in disconnection hyperprolactinaemia need re‐definition? A study of 226 patients with histologically verified non‐functioning pituitary macroadenoma

BACKGROUND: The differentiation of a pituitary non-functioning macroadenoma from a macroprolactinoma is important for planning appropriate therapy. Serum PRL levels have been suggested as a useful diagnostic indicator. However, values between 2500 and 8000 mU/l are a grey area and are currently associated with diagnostic uncertainty. OBJECTIVE: We wished therefore, to investigate the serum PRL values in a large series of patients presenting with apparently non-functioning pituitary macroadenomas. PATIENTS AND METHODS: All patients presenting to the Department of Endocrinology in Oxford with clinically non-functioning pituitary macroadenomas (later histologically verified) between 1990 and 2005 were studied. Information documented in the notes on the medications and on the presence of conditions capable of affecting the serum PRL levels at the time of blood sampling was also collected. RESULTS: Two hundred and twenty-six patients were identified (median age at diagnosis 55 years, range 18-88 years; 146 males/80 females; 143 gonadotroph, 46 null cell, 25 plurihormonal and 12 silent ACTH adenomas). All tumours had suprasellar extension. At the time of blood sampling 41 subjects were taking medications capable of increasing serum PRL. Hyperprolactinaemia was found in 38.5% (87/226) of the patients. The median serum PRL values in the total group were 386 mU/l (range 16-3257) (males: median 299 mU/l, range 16-1560; females: median 572 mU/l, range 20-3257) and in those not taking drugs capable of increasing serum PRL 363 mU/l (range 16-2565) (males: median 299 mU/l, range 16-1560; females: median 572 mU/l, range 20-2565). Serum PRL < 2000 mU/l was found in 98.7% (223/226) of the total group and in 99.5% (184/185) of those not taking drugs. Among the three subjects with serum PRL > 2000 mU/l, two were taking oestrogen preparations. CONCLUSIONS: Based on a large series of histologically confirmed cases, serum PRL > 2000 mU/l is almost never encountered in nonfunctioning pituitary macroadenomas. Values above this limit in the presence of a macroadenoma should not be surrounded by diagnostic uncertainty (after acromegaly or Cushing's disease have been excluded); a prolactinoma is the most likely diagnosis and a dopamine agonist should be considered as the treatment of choice.     

Relationships between placental GH concentration and maternal smoking, newborn gender, and maternal leptin: possible implications for birth weight

The control of fetal growth depends on multiple hormones, including both IGF-I and placental GH (PGH) in the mother, and IGF-I rather than pituitary GH (pitGH) in the fetus. Leptin, which is produced by adipocytes and syncitiotrophoblast cells, has also been thought to influence fetal growth by an as yet unknown mechanism. This study assessed the relationships between the GH-IGF-I axis in mothers and newborns, and maternal smoking, neonate gender, and maternal and fetal leptin. We collected blood in 87 mothers at the onset of labor and cord blood immediately after birth in their 87 healthy full-term newborns. GH concentrations were log(10) transformed, and data were expressed as the geometric mean (-1, +1 tolerance factor). PGH was lower in the 30 smoking mothers, as compared with the 57 nonsmoking mothers [18.2 (11.5; 28.6) vs. 27.0 (15.1; 48.2) microg/liter, P < 0.01]. Cord blood IGF-I was lower in neonates from smoking mothers (90 +/- 44 vs. 135 +/- 65 microg/liter, mean +/- SD, P < 0.01), consistent with their lower birth weight percentile (P < 0.01). A gender effect was observed for PGH, which was higher when the newborn was female, and for newborn pitGH and newborn leptin, which were, respectively, lower and higher in females, even after adjustment for birth weight and maternal smoking category (P < 0.05 for all comparisons). Multiple regression analyses identified maternal leptin as a negative predictor of PGH (P < 0.05) and newborn leptin as a positive predictor of newborn IGF-I (P < 0.05). Maternal smoking is associated to decreased maternal PGH and cord blood IGF-I concentrations. A sexual dimorphism for PGH, newborn pitGH, and newborn leptin exists at the time of birth, but its physiological significance remains to be studied. The relationships between maternal leptin and PGH and between cord blood leptin and IGF-I are consistent with the hypothesis that leptin could contribute to the control of fetal growth.     

Quantitation of urinary somatomedin-C and growth hormone in preterm and fullterm infants and normal children

Urinary GH and somatomedin-C/insulin-like growth factor I (Sm-C/IGF-I) excretion were measured in 12-h urine collections obtained from 43 infants (27 stable preterm infants and 16 healthy fullterm infants) and 31 normal children, aged 3-17 yr. Urinary Sm-C/IGF-I was excreted as the free hormone, since no binding of radiolabeled Sm-C/IGF-I to any urine protein with a mol wt similar to those described for plasma Sm-C/IGF-I-binding proteins was found. The preterm infants excreted significantly more urinary GH [13.5 +/- 2.1 (+/- SE) ng/kg.12 h] than either the fullterm infants (5.3 +/- 1.6 ng/kg.12h) or the children (0.27 +/- 0.02 ng/kg.12 h; P less than 0.01). The mean urinary Sm-C/IGF-I excretion in the preterm infants (98.9 +/- 7.5 mU/kg.12 h) was comparable to that in fullterm infants (87.6 +/- 9.7 mU/kg.12 h); both groups excreted significantly more urinary Sm-C/IGF-I than children (28.4 +/- 2.1 mU/kg.12 h; P less than 0.01). The group differences were similar when the results were expressed in terms of creatinine excretion. Urinary GH excretion correlated positively with urinary Sm-C/IGF-I excretion (r = 0.68). The higher output of these peptides in rapidly growing infants and their positive correlation in urine provide additional support for the Sm hypothesis.     

Spontaneous growth hormone secretory characteristics in children with partial growth hormone insensitivity

OBJECTIVE: To investigate the characteristics of spontaneous GH secretion in four male children with short stature due to partial GH insensitivity. Their molecular defect consists of inclusion of a mutant intronic pseudoexon in the region of the GH receptor involved in homodimerization. SUBJECTS: The subjects were two pairs of brothers who were first cousins, aged 10.4-14.2 years, heights -3.3 to -5.6 SDS, from a consanguineous Pakistani family. Basal serum IGF-I levels were extremely low (20-29 mg/l; NR > 50), with absent or minimal response to human recombinant GH (hGH) stimulation. Serum IGFBP-3 SDS levels were also low (-2.9 to -8.9). GH binding protein (GHBP) levels were normal (28.1-51.7%). METHODS: Spontaneous GH secretion was studied by intermittent (20 min) venous sampling from 2000 to 0800 h. The secretion profiles were analysed using the Pulsar programme and compared to data from a reference population of 76 prepubertal Swedish children [median age 10.7 years, median height -1.1 SDS (-2.0 to 1.4)] according to Swedish growth standards. RESULTS: Median (range) Pulsar-derived values in the four patients and controls were, respectively: GHmax (mU/l) 276.6 (178.7-325.8) and 27.2 (13.1-94.9), mean GH (mU/l) 64.5 (41.9-77.8) and 5.8 (3.2-20.6), baseline (mU/l) 12.3 (11.7-20.1) and 1.1 (0.2-6.1), AUCb (mU/l x 24 h) 1210 (684-1555) and 112.5 (60.6-316.4), i.e. all parameters of GH secretion in the four patients were markedly elevated compared with the control population. CONCLUSIONS: Spontaneous GH secretion is elevated in partial GH insensitivity. This investigation could be of diagnostic value in children with short stature.     

Critically ill patients have high basal growth hormone levels with attenuated oscillatory activity associated with low levels of insulin–like growth factor-I

OBJECTIVE: The aim was to study the relationship between growth hormone (GH) and insulin-like growth factor-I (IGF-I) in critically ill patients. DESIGN: Case-control study of critically ill patients admitted to the intensive care unit was carried out. PATIENTS: Six critically ill patients (51-78 years) who required ventilation and parenteral nutrition and six age, weight, height, and sex-matched healthy adults were studied. MEASUREMENTS: The patients and controls were studied for two 24-hour periods; the patients before and after starting parenteral feeding, and the controls during a 36-hour fast and when taking meals equivalent in calories and protein to the patients' parenteral feed. Serum GH was measured at 20-minute intervals and analysed by a pulse detection algorithm (Pulsar) and Fourier transformation. IGF-I was measured at 0, 12, and 24 hours. RESULTS: Patients had low serum IGF-I levels compared with controls, whether fasted or fed, despite having mean GH levels similar to fasted controls. For fasted patients vs fasted controls the mean (+/- 1 SD) GH levels were 4.5 +/- 2.0 vs 4.0 +/- 2.4 mU/l respectively, and IGF-I levels at the end of the fast were 0.17 +/- 0.11 vs 0.78 +/- 0.29 U/ml (P = 0.003). Patients showed elevated baseline GH levels compared with controls when fasted and during parenteral feeding (patients vs controls fasted 3.1 +/- 1.9 vs 0.8 +/- 0.5 mU/l, P = 0.01; patients vs controls fed 4.2 +/- 4.5 vs 0.5 +/- 0.04 mU/l, P = 0.028). Fourier transformation confirmed oscillatory GH levels in the controls, fasted or fed, but this activity was attenuated in the patients. Parenteral feeding had no effect on the GH profiles or IGF-I levels of patients, but controls showed greater mean GH levels during their fast than when fed. CONCLUSIONS: We have demonstrated that critically ill patients have low IGF-I levels associated with augmented baseline GH levels which show reduced oscillatory activity. The results would be compatible with the hypothesis that there is an adaptive change in critically ill patients away from the indirect effects of GH (stimulation of IGF-I production and anabolism) and toward the direct effects (lipolysis and insulin antagonism) which increase the availability of energy substrates. The pattern of GH levels seen in our patients may be important in this adaptation.     

HDL-cholesterol reductions associated with adult growth hormone replacement

OBJECTIVE: To study the effects of human growth hormone (hGH) replacement on serum lipids and lipoprotein (a) (Lp(a)) concentrations. DESIGN: A randomized double blind placebo controlled trial for 6 months followed by an open trial where all patients were treated with hGH for a further 6 months. Treatment was with recombinant hGH given in a dose of 0.125U/kg/wk increasing to 0.25U/Kg/wk. PATIENTS: Thirty two patients with growth hormone deficiency were recruited, but two withdrew because of side effects. Of the thirty patients (age 35.1 +/- 11.8 year; mean +/- SD) completing the study 13 of were assigned to the placebo group for six months and 17 to active treatment from the start. MEASUREMENTS: Fasting serum samples were analysed for total cholesterol, High density lipoprotein (HDL)-cholesterol, HDL-subfractions, triglycerides, lipoprotein (a) (Lp(a)) and IGF-1. LDL-cholesterol was calculated using the Friedewald formula. RESULTS: Compared to placebo, 6 months treatment with hGH therapy resulted in increased IGF-1 (37.6 +/- 4.1 vs. 14.0 +/- 2.2 nmol/l, P < 0.01), but there was no significant difference in any of the lipid parameters measured between placebo and active treatment groups at 6 months. hGH was associated with a decrease in HDL-cholesterol concentration from baseline to 6 months (0.97 +/- 0.08 to 0.76 +/- 0.10 mmol/l P < 0.01), especially within the HDL2 subfraction. This reduction was maintained at 12 months. There was no change in Lp(a) concentrations from 0 to 6 months (placebo -26 (-340 to 82), median and range, active -4 (-586 to 212) mg/l). There was no change in total cholesterol, LDL-cholesterol, triglycerides or proportion of HDL subfractions. CONCLUSIONS: Treatment with hGH can reduce serum HDL-cholesterol concentrations. Further investigation of this is required.     

Measurement of human growth hormone in urine: development and validation of a sensitive and specific assay

A specific solid-phase immunoradiometric assay (IRMA), optimized for maximum sensitivity, has been developed for measurement of human GH (hGH) in urine. The sensitivity varied with sample size, giving a range of 0.001 to 0.003 mU/l for a sample volume of 2 ml. Recovery and dilution experiments, together with chromatography of urine samples, indicate that the method is specific for hGH. Added exogenous hGH was measured with a mean recovery of 101 +/- 10% (S.D.) for 1 ml samples and 87 +/- 8% for 2 ml samples. Measurements of samples diluted at 1:2 and 1:4 gave values of 97.4 and 96.6% respectively of those expected. Cross-reactions of human placental lactogen and prolactin were less than 0.008 and 0.04% respectively on a mol/mol basis. The assay was insensitive to the presence of NaCl (50-500 mmol/l), urea (50-1000 mmol/l), creatinine (1-20 mmol/l), Ca2+ ions (1-20 mmol/l), SO4(2-) ions (1-1000 mmol/l), Mg2+ ions (0.05-50 mmol/l), 0.5-5% (w/v) glucose and a pH range of 6-9. Chromatography of unextracted samples showed that the immunoreactive material in urine eluted in a single homogenous peak with a similar position to monomeric pituitary hGH (22 kDa). Administered hGH (0.002%) was recovered in urine collected over a 2-h period following an intravenous injection. The urine output of hGH showed a good correlation with serum hGH in 18 patients following routine insulin tolerance tests and in 25 patients following an oral glucose tolerance test.(ABSTRACT TRUNCATED AT 250 WORDS)     

PROLACTIN LEVELS AND PITUITARY ENLARGEMENT IN HORMONE-TREATED MALE-TO-FEMALE TRANSSEXUALS

PRL levels were evaluated during long-term treatment with cyproterone acetate 100 mg and ethinyloestradiol 100 micrograms/day orally or depot-oestrogens in 214 male-to-female transsexuals. PRL levels increased above normal in all subjects (normal less than 300 mU/l). In 46 (21.4%) subjects PRL levels rose to greater than 1000 mU/l. The incidence of PRL levels greater than 1000 mU/l was 3.7-7.2% per treatment year. Grossly elevated PRL levels were associated with high doses of oestrogens (P less than 0.05) and advanced age at the start of treatment (P less than 0.05). In 23 subjects PRL levels greater than 1000 mU/l decreased by more than 50% spontaneously (n = 5) or after dose reduction (n = 18). In five of the subgroup of 15 subjects with persistent PRL levels greater than 1000 mU/l enlargement of the pituitary gland was shown by CT-scanning. These data suggest that the lowest possible oestrogen dose and lifelong follow-up of hormone-treated male-to-female transsexuals is essential.     

The effects of systemic insulin, insulin-like growth factor-I and growth hormone on bone growth and turnover in spontaneously diabetic BB rats.

Spontaneously diabetic BB rats have a markedly depressed longitudinal bone growth and bone formation/turnover. In this study, male diabetic BB rats were infused intraperitoneally or subcutaneously for 2 weeks with hormones that are believed to stimulate skeletal growth and/or trabecular bone formation: insulin (3 or 4 U/day), human GH (hGH; 400 mU/day), recombinant human insulin-like growth factor-I (rhIGF-I; 300 or 600 micrograms/day) and testosterone (80 micrograms/100 g body weight per day). Saline-treated diabetic BB rats had decreased plasma concentrations of IGF-I and osteocalcin (OC) (OC, 3.7 +/- 0.3 vs 13.1 +/- 0.8 (S.E.M.) nmol/l in controls); bone histomorphometry showed decreased epiphyseal width, osteoblast surface (0.04 +/- 0.04 vs 1.5 +/- 0.3%) and osteoid surface, and mineral apposition rate (MAR) (1.8 +/- 0.5 vs 7.9 +/- 0.6 microns/day). Testosterone and hGH infusions had no effect on weight loss or on decreased skeletal growth and bone formation of diabetic rats, nor did they increase plasma IGF-I concentrations. Insulin infusions into diabetic rats resulted in hyperinsulinaemia and accelerated weight gain. The epiphyseal width, osteoblast/osteoid surfaces and OC levels of insulin-treated rats were normalized or stimulated well above control values (osteoblast surface, 4.3 +/- 0.8%; plasma OC, 16.1 +/- 1.4 nmol/l); the MAR (4.0 +/- 0.9 microns/day) was only partly corrected after the 2-week infusion. Infusions of rhIGF-I into diabetic rats doubled but did not restore plasma IGF-I levels to normal; weight gain, however, was similar to that in control rats. IGF-I treatment had no effect on epiphyseal width, osteoblast/osteoid surfaces and OC concentrations, but improved the decreased MAR (4.6 +/- 1.2 microns/day).(ABSTRACT TRUNCATED AT 250 WORDS)     

Recovery of growth hormone secretion following cabergoline treatment of macroprolactinomas

OBJECTIVE: Cabergoline therapy normalizes prolactin levels and reduces the size of macroprolactinomas. However there are no data indicating whether cabergoline can normalize growth hormone secretion in patients who were growth hormone deficient at the time of diagnosis of a macroprolactinoma. SUBJECTS AND METHODS: We studied nine patients with biochemical and radiological evidence of a macroprolactinoma who were also growth hormone deficient (peak growth hormone response to insulin-induced hypoglycaemia < 10 mU/l). Patients were assessed before and after cabergoline therapy to assess their growth hormone secretory status, IGF-I levels, cortisol response and change in tumour size. RESULTS: Treatment with cabergoline was associated with a significant reduction in prolactin concentration (74341 +/- 31939 mU/l vs. 265.9 +/- 86.3, P = 0.009). The mean change in peak growth hormone response to insulin-induced hypoglycaemia was significantly greater following cabergoline therapy compared with pretreatment levels (33.5 +/- 11.8 mU/l vs. 4. 34 +/- 1.21 mU/l, P = 0.022). However IGF-I levels were not different after treatment when compared with baseline although a nonsignificant trend towards improvement was noted (24.2 +/- 3.97 nmol/l vs. 18.4 +/- 4.94 nmol/l, P = 0.058). The mean peak cortisol concentration was 407.7 +/- 64.1 nmol/l before treatment with a nonsignificant rise to 477.4 +/- 84.8 nmol/l, P = 0.813 after treatment. These changes were associated with a significant reduction in mean maximal tumour diameter (21.2 +/- 2.9 mm vs. 29.1 +/- 2.8 mm, P = 0.009). There was no significant difference in either prolactin concentration or tumour size pre- or post-treatment between those who recovered growth hormone secretion and those that did not. Six of the nine (67%) patients recovered a normal growth hormone response (> 10 mU/l) after cabergoline therapy. Those that remained growth hormone deficient after treatment were all panhypopituitary at baseline while those that recovered showed only partial anterior hypopituitarism. CONCLUSION: These data indicate that growth hormone secretion may recover following successful reduction of prolactin levels after cabergoline therapy for a mean of 22 months (range 6-28 months) in most but not all subjects with a macroprolactinoma. It is therefore advisable that individuals with a macroprolactinoma in whom growth hormone replacement therapy is being considered undergo repeat assessment of growth hormone secretion following medical treatment.     

Variation in GH and IGF-I assays limits the applicability of international consensus criteria to local practice

BACKGROUND: There is increasing reliance on consensus criteria for decision making. Recent criteria state that acromegaly is excluded by a nadir GH during an oral glucose tolerance test (OGTT) of < 1 microg/l and a normal level of IGF-I. OBJECTIVE: To study GH and IGF-I assay performance close to cut-off values for active acromegaly. DESIGN AND METHODS: Two serum samples known to give borderline results were sent to all centres participating in the UK National External Quality Assessment Service (NEQAS). Sample A was assigned to be a nadir during an OGTT and sent for GH assessment to 104 centres. Sample B, with a clinical scenario, was sent to 23 centres that measure IGF-I, and these centres were asked to measure IGF-I, interpret the result and provide the source of their reference ranges (RRs). RESULTS: For sample A, the median GH was 2.6 mU/l (range 1.04-3.5 mU/l). Applying a conversion factor (CF) of 2.0 (1 microg/l = 2 mU/l), the most negatively biased method classified 10% of the values consistent with acromegaly, while the most positively biased method classified all values as consistent with the diagnosis. Applying a CF of 3.0 (1 microg/l = 3 mU/l), only 11% of results were consistent with acromegaly. For sample B, the median IGF-I was 50.8 nmol/l (range 24.3-60.9 nmol/l). All centres used age-related RRs. There was a 50% variation in the upper limit of the RRs between centres. Overall, 30% of the IGF-I results were against the diagnosis. There was little agreement in the RRs quoted by centres using the same method. CONCLUSION: Variability in assay performance, coupled with use of inappropriate CFs and RRs, undermines the applicability of international consensus criteria to local practice.     

Sexual dimorphism in the growth hormone and insulin-like growth factor axis at birth

In rodents and humans there is a sexually dimorphic pattern of GH secretion that influences the serum concentration of IGF-I. Pattern differences can be identified in children, but it is not known how early this difference is established. We studied the plasma concentrations of IGF-I, IGF-II, IGF-binding protein-3 (BP-3), and GH in cord blood taken from the offspring of 1650 singleton Caucasian pregnancies born at term and related these values to birth weight, length, and head circumference. Pregnancies complicated by preterm delivery, antepartum hemorrhage, pregnancy-induced hypertension, preeclampsia, or gestational diabetes and where cigarette smoking continued were excluded, resulting in a cohort of 987. Cord plasma concentrations of IGF-I, IGF-II, and IGFBP-3 were influenced by factors influencing birth size: gestational age at delivery, mode of delivery, maternal height, and parity of the mother. Plasma GH concentrations were inversely related to the plasma concentrations of IGF-I and IGFBP-3; 10.2% of the variability in cord plasma IGF-I concentration and 2.7% for IGFBP-3 was explained by sex of the offspring and parity. None of the factors, apart from maternal height, influenced cord serum IGF-II concentrations (adjusted r(2) = 1%). Sex of the baby, mode of delivery, and parity influenced cord serum GH concentrations (adjusted r(2) = 2.6%). Birth weight, length, and head circumference measurements were greater in males than females (P < 0.001). Mean cord plasma concentrations of IGF-I (males, 66.4 +/- 1.2 micro g/liter; females, 74.5 +/- 1.3 micro g/liter; P < 0.001) and IGFBP-3 (males, 910 +/- 13 micro g/liter; females 978 +/- 13 micro g/liter; P < 0.001) were significantly lower in males than females. Cord plasma GH concentrations were higher in males than females (males, 30.0 +/- 1.2 mU/liter; females, 26.9 +/- 1.1 mU/liter; P = 0.05), but no difference was noted between the sexes for IGF-II (males, 508 +/- 6 micro g/liter; females, 519 +/- 6 micro g/liter; P = NS). After adjustment for gestational age, parity, and maternal height, cord plasma concentrations of IGF-I and IGFBP-3 along with sex explained 38.0% of the variability in birth weight, 25.0% in birth length, and 22.7% in head circumference. These data demonstrate that in a group of singleton Caucasian babies born at term, cord plasma IGF-I, IGFBP-3, and GH concentrations relate to birth size, with evidence for sexual dimorphism in the GH-IGF axis.     

Cabergoline addition to depot somatostatin analogues in resistant acromegalic patients: efficacy and lack of predictive value of prolactin status

BACKGROUND: Somatostatin analogues (SA) are currently the mainstay in the medical treatment of acromegaly. However, even high doses of depot SA for prolonged periods do not achieve GH-IGF-I normalization in some patients. Even though some data were reported about the addition of cabergoline, a long-acting dopamine agonist (DA), to SA in resistant patients, definite data are still lacking. DESIGN: Prospective open trial. PATIENTS: In 19 acromegalic patients with active disease (34-82 years old, seven males, 12 females) resistant to chronic (9-12 months) depot SA (octreotide-LAR, 30 mg/28 days in 13 patients, lanreotide, 60 mg/28 days intramuscularly in six patients) cabergoline was added (combined treatment). In these patients, SA treatment had partially relieved GH and IGF-I hypersecretion but no patient had achieved 'safe' GH and normal IGF-I-values. Eight patients had PRL levels greater than 15 micro g/l (range 16-60 micro g/l; 1 micro g = 21.2 mIU). Immunohistochemistry (IHC) was positive for PRL in four out of eight operated patients. RESULTS: The addition of cabergoline, using the minimal effective and the maximal tolerated dose (range 1-3.5 mg/week), decreased GH from 6.6 +/- 0.9 to 4.6 +/- 0.6 micro g/l (P = 0.018), and IGF-I from 552 +/- 44 to 428 +/- 54 micro g/l (P = 0.019) after 6 months (median, range 3-18 Months). Combined treatment decreased GH to < 2.5 micro g/l in four patients (21%) and normalized IGF-I for age in eight patients (42%). It obtained a decline of both GH and IGF-I (-49 +/- 7%, and -47 +/- 5%, respectively) in nine patients (47%), and a partial improvement in six (32%) patients (GH decreased by 43 +/- 8% in four, and IGF-I by 35-38% in two patients). No change was observed in two patients, and worsening in two other patients. Results were not dependent on PRL status (serum levels or IHC). Combined treatment was well tolerated. CONCLUSIONS: The addition of cabergoline to depot SA-resistant acromegalic patients is effective, not dependent on PRL values and normalizes IGF-I levels in 42% of patients. The association of long-acting DA and SA deserves a more relevant role in the therapeutical algorithm of acromegaly.     

Study of growth hormone secretion and action in growth-retarded children with juvenile chronic arthritis (JCA).

The stimulated and spontaneous growth hormone (GH) secretion and the response to GH action were assessed in growth-retarded children with juvenile chronic arthritis (JCA), in order to determine the underlying mechanisms of growth retardation in such children. Six children (4 boys and 2 girls aged 10.7-13.8 years) with active JCA of systemic onset were included in the study which involved: (1) anthropometric measurements; (2) assessment of GH responses to insulin-induced hypoglycaemia and clonidine stimulation; (3) assessment of the nocturnal pulsatile GH secretion by measuring GH in blood samples obtained every 20 min from 20.00 to 08.00 h; and (4) the IGF-I generation test. As a control, the latter test was also performed in eight aged-matched children with physiological delay in puberty. Biosynthetic hGH (0.1 IU/kg BW) was administered s. c. for 4 days and blood samples were taken at baseline and the morning after the last GH injection for measurement of IGF-I and IGFBP-3.All six children with JCA were prepubertal and their growth velocity was <3 cm/year. The GH responses to both stimulation tests were normal (peak GH >20 mU/l). Analysis of the pulsatile GH secretion during the night revealed three-to-four GH pulses of normal amplitude (>20 mU/l). IGF-I (26.7+/-4.6 nmol/l, mean+/-SD) and IGFBP-3 (2.1+/-0.2 mg/l) levels were lower in the patients compared with the controls (43.0+/-3.7 nmol/l and 2.8+/-0.2 mg/l, respectively, P<0.01). Following stimulation with exogenous hGH, there was a significant increase in IGF-I and IGFBP-3 levels in the control group (85 and 73%, respectively), but only a small increase in the patients (31 and 14%).It appears that stimulated and spontaneous GH secretion is normal in children with active systemic JCA, but the response to endogenous and exogenous GH with regard to IGF-I and IGFBP-3 production is impaired, indicating a degree of GH insensitivity in such children.     

Sex difference in human growth hormone (GH) response to intravenous human pancreatic GH-releasing hormone administration in young adults

Intravenous administration of a 100-micrograms dose of human pancreatic GH-releasing hormone (human pancreatic GHRH1-44, indicated by GHRH) disclosed a sex difference in GH responsiveness. The maximum GH increments [41 +/- 11 (SEM) vs. 15 +/- 4 ng/ml, P* less than 0.05] and the areas under the curves (419 +/- 105 vs. 148 +/- 53 area U, P* less than 0.05) were significantly higher in 12 men than in 10 women. No significant correlation was found in either group between the basal plasma estradiol or testosterone levels and the maximum or integrated GH response to GHRH. Serum PRL levels significantly increased in both groups within 5 min after GHRH injection (men, P less than 0.001 vs. t = 0; women, P less than 0.05 vs. t = 0). The areas under the curves of the PRL responses (355 +/- 184 vs. 189 +/- 73 area U) and the maximum PRL increments (58 +/- 18 vs. 36 +/- 6 mU/l, P* greater than 0.10) were similar. In conclusion, a sex difference in GH responsiveness to GHRH was found between young adult men and women. Recent in vivo and in vitro data reveal a similar sex difference in rodents and an enhancing effect of androgens, but not estrogens, on the GH response to GHRH. These findings support the theory that in humans testosterone also plays a key role in the genesis of this sex difference.