Total Amount Of Growth Hormone Research Articles

Implications of a Data-Driven Approach to Treatment with Growth Hormone in Children with Growth Hormone Deficiency and Turner Syndrome

BackgroundResponse to growth hormone (GH) therapy may vary between individual patients. Therefore the use of GH in children should be closely monitored to avoid over, under, or ineffective treatment regimens. The treatment response can be evaluated using growth prediction models. In an effort to improve the accuracy of these prediction models, Ranke et al. (J Clin Endocrinol Metab 95(3):1229–37) proposed a novel ‘data-driven’ approach based on a quantitative analysis of a large cohort of patients from the Pfizer International Growth Database (KIGS) treated with Genotropin (human growth hormone). This model allows physicians to predict and evaluate the level of growth response and responsiveness for their patients so they can adapt treatment accordingly. By comparing the actually observed and the predicted growth response the ability of an individual to respond to GH (responsiveness) can be estimated and further treatment can be adapted accordinglyObjectiveTo determine the potential population level reduction in the amount of GH used and impact on height outcome of using this data-driven approach to guide treatment decisions, compared to conventional, ‘experience-based’ GH treatment in prepubertal patients with growth hormone deficiency (GHD) or Turner syndrome (TS).MethodsA model was developed to study the height outcome and the total amount of GH used in the presence or absence of data-driven treatment decisions. The proportion of patients for whom height outcome could be improved or GH use could be reduced (i.e. for low compliance, high or low responder) was estimated using the KIGS cohort. The analysis assumed that this segmentation allows physicians to tailor dosage to the individual patient’s needs or even to discontinue therapy when it is not effective. The analysis used a 4-year time horizon, with Germany as an example country, but results are extendable to other countries. Only the total amount of GH used was included, and effects were defined as the height outcome after 4 years.ResultsThe analysis estimated that an evidence-driven approach may reduce the total amount of GH utilized by 7.0 % over 4 years for the treatment of short stature in prepubertal patients with GHD and TS in Germany. Despite the reduction in drug use the average growth outcomes remained unaffected with the new treatment approach. Univariate and probabilistic sensitivity analyses showed that the results are robust.ConclusionsOur analysis showed that using a data-driven approach to guide treatment decisions for children with GHD or TS is estimated to result in efficiencies in the amount of GH used, without reducing the average growth in the population.

Assessment of endogenous growth hormone pulsatility in gelded yearling horses using deconvolution analysis

Hypothesis/objectives: Defining normal Growth Hormone (GH) secretory dynamics in the horse is necessary to understand altered GH dynamics related to issues like welfare and disease. Animals and methods: Twelve healthy yearlings and two mature Standardbreds were used to quantify GH secretion. Endogenous GH half-life was determined after administration of 1.0 µg/kg BW GH releasing hormone (GHRH). Exogenous GH half-life was determined after administration of 20 µg/kg BW recombinant equine GH (reGH) with and without suppression of endogenous GH secretion by somatostatin infusion (50 µg/m2/h). Pulse detection algorithm (Cluster) as well as deconvolution analysis was used to quantify GH secretory dynamics based on GH concentration-time series sampled every 5 min from 22:00 till 06:00 h. In addition, reproducibility, impact of sampling frequency and influence of altering initial GH half-life on parameter estimates were studied. Results: Mean endogenous GH half-life of 17.7 ± 4.4 (SD) min and mean exogenous half-life of 26.0 ± 2.9 min were found. The mean number of GH secretion peaks in 8 h was 12 ± 3.2. Ninety-nine percent of the total amount of GH secreted occurred in pulses, basal secretion was 0.012 ± 0.014 µg/L/min and half-life was 8.9 ± 2.6 min. Compared with a 5-min sampling frequency, 20- and 30-min sampling underestimated the number of secretory events by 45% and 100%, respectively. Conclusions: The deconvolution model used was valid to GH time series in Standardbreds. As in man, the equine pituitary gland secretes GH in volleys consisting of multiple secretory bursts, without measurable intervening tonic secretion. The required GH sampling frequency for the horse should be around 3 min. Clinical relevance: Defining normal GH secretory dynamics in the horse will make it possible to detect alterations in the GH axis due to pathophysiologic mechanisms as well as abuse of reGH.

Growth Hormone (GH) Secretion during Continuous Infusion of GH-Releasing Peptide: Partial Response Attenuation*

The synthetic hexapeptide GH-releasing peptide (GHRP; SK&F 110679) specifically stimulates GH release in man. To determine the effect of a continuous GHRP infusion and whether response attenuation occurs in man, we administered to six healthy subjects a 6-h infusion of saline and three doses of GHRP, each followed by a 1.0 micrograms/kg bolus injection. GH was measured every 10 min using an immunoradiometric assay. During the saline infusion, spontaneous GH peaks occurred at variable times in four of the six subjects. During the continuous GHRP infusion, a single burst of GH release occurred with the two lower doses (0.1 and 0.3 micrograms/kg.h). With the highest dose of 1.0 micrograms/kg.h, a primary burst of GH release was followed by sporadic secretory episodes of lesser magnitude during the infusion; the GH concentrations remained above baseline before administration of the iv GHRP bolus in all six subjects. The mass of GH secreted was indirectly determined using waveform-independent deconvolution analysis. Mean GH secretion rates (micrograms per L distribution volume/h) were calculated by dividing the GH mass by the time interval. The GH secretion rates during the infusion period (0900-1430 h) were 2.40 +/- 0.68, 2.47 +/- 0.61, 7.67 +/- 1.86, and 14.75 +/- 2.32 on the saline and GHRP (0.1, 0.3, and 1.0 micrograms/kg.h) infusion days, respectively (P less than 0.05, 1.0 micrograms/kg.h vs. saline). The GH secretion rates after the iv GHRP bolus were 18.28 +/- 3.81, 19.01 +/- 2.03, 11.70 +/- 2.55, and 7.86 +/- 0.80 on the saline and GHRP (0.1, 0.3, and 1.0 micrograms/kg.h) infusion days, respectively (P less than 0.05, 1.0 micrograms/kg.h vs. saline). Compared with the saline infusion, the GH response to GHRP infusions was dose dependent (r = 0.81; P less than 0.001). The GH response to the iv bolus was inversely related to the dose of the preceding 5.5-h continuous GHRP infusion (r = -0.58; P = 0.003), and the total amount of GH secreted (constant infusion plus the bolus infusion periods) was not different among the GHRP doses. Constant GHRP infusion stimulates GH release in man, and partial response attenuation occurs with a subsequent 1.0 micrograms/kg GHRP bolus. We hypothesize that GHRP is active at multiple sites and may act as a functional somatostatin antagonist. Further studies are needed to better determine the site(s) of GHRP action and its potential use as a diagnostic and therapeutic agent.

Effects of the Short-Acting Benzodiazepine Triazolam, Taken at Bedtime, on Circadian and Sleep-Related Hormonal Profiles in Normal Men

Studies in rodents have shown that triazolam, a commonly used hypnotic, may shift circadian rhythms, with the direction and magnitude of the phase-shifts being dependent on the time of drug administration. To determine whether benzodiazepine, taken at standard bedtime, modifies the amount and/or temporal organization of hormonal secretion, six normal men were studied during basal conditions and on the first and third days of treatment with 0.5 mg triazolam. In each study, sleep was polygraphically monitored and plasma cortisol, growth hormone (GH), melatonin, and prolactin (PRL) (i.e., hormones influenced by circadian rhythmicity and/or sleep) were measured at 20-min intervals for 24 h. The sleep latency and the number and duration of awakenings were reduced during triazolam treatment as compared to baseline conditions. The only alteration of sleep architecture was a partial suppression of stages III + IV (SW) in late sleep. Triazolam did not affect the mean cortisol and melatonin levels or the total amount of GH secreted over the 24-h span. The circadian timings of the onsets of cortisol and melatonin secretions were essentially unaltered. The nocturnal rise of melatonin was prolonged by 45 to 60 minutes. Sleep-associated GH release was not modified by triazolam. Sleep-associated PRL secretion persisted, but in half of the nights studied was enhanced almost threefold. This effect of the drug on nocturnal PRL secretion was not specific to either the first or the third night of treatment, nor was it specific to certain subjects. Irrespective of the magnitude of the nocturnal elevation, morning PRL levels were slightly but consistently higher after triazolam treatment than under basal conditions. Normal PRL levels resumed around noon. In conclusion, administration of 0.5 mg triazolam at normal bedtime (2230) for three consecutive days may induce a transient hyperprolactinemia, but does not abolish sleep-related hormone secretion and does not affect the timing of endocrine events controlled by the circadian clock. These findings are consistent with studies in hamsters where treatment with triazolam in the early subjective night was also without effect on the rodent circadian clock.

Growth hormone secretion during longterm incubation of the pituitary of the Japanese eel, Anguilla japonica

Growth hormone (GH) secretion from organ-cultured pituitaries of the eel (Anguilla japonica) was studied during incubation in a defined medium for 2 weeks, using a homologous radioimmunoassay which does not distinguish between the two molecular forms of eel GH. The total amount of GH secreted increased gradually during the incubation period; so that the amount of GH released on day 14 was about 30 times greater than that on day 1. On day 14, the proportion of GH released relative to the total amount of GH present (the sum of GH released into the medium and residual content in the pituitary) was 96% and the amount produced on day 14 was 4 times greater than the content in the unincubated pituitary. Somatostatin (SRIF, 1.8 × 10(-7) M) inhibited the increase in GH release. On day 7, the proportion of GH released by pituitaries treated with SRIF (28%) was less than that released by the control pituitary (91%). There was no significant difference in GH release between the pituitaries incubated in isotonic medium (300 mOsm) and those in hypotonic medium (240 mOsm) for 2 weeks except for the first 3 days, when the pituitaries in hypotonic medium secreted significantly greater amounts of GH than those incubated under isotonic condition. Hypertonic medium (350 mOsm) had no effect on GH release except for significant inhibition on days 6 and 14. When secretion of the two forms of GH (GH I and II) was examined after separation by polyacrylamide gel electrophoresis followed by densitometry, slightly more GH I tended to be secreted than GH II during the culture period, although the effects of SRIF and osmolality of the media on GH I release were similar to those on GH II. It is concluded that GH secretion and production in the eel is mainly under the inhibitory control of hypothalamus, and that osmolality has a minimum influence on the GH release.

Heterogeneity of Growth Hormone (GH) Release by Individual Pituitary Adenoma Cells From Acromegalic Patients, as Determined by the Reverse Hemolytic Plaque Assay: Effects of SMS 201-995, GH-Releasing Hormone and Thyrotropin-Releasing Hormone*

We used the reverse hemolytic plaque assay to study the dynamics of GH secretion by individual pituitary adenoma cells from eight acromegalic patients. There was a considerable variation between the adenomas with respect to the percentages of GH-secreting cells (25-78.5%) and also with respect to the amount of GH released per individual pituitary adenoma cell (mean plaque areas varying from 901-3559 micron 2). The GH plaque area frequency distributions from the adenoma cells were not normally distributed, but revealed a preponderance of small plaques, defined as those with areas smaller than the mean plaque area. The large plaques, that is those with areas larger than the mean plaque area, constituted 24-38% of the total cell population from different tumors and accounted for a large fraction (63-80%) of the total plaque area (the total amount of GH released by the adenoma cells). The somatostatin analog SMS 201-995 caused a shift in the GH plaque area frequency distributions toward smaller plaques, but had no effect on the overall percentages of GH plaque-forming cells in three of the five adenomas in which it was studied. This finding suggests that the adenoma cells from these patients that formed large plaques were preferentially inhibited by SMS 201-995. GHRH (studied in two adenomas) and TRH (studied in one adenoma) had no preferential effect on any subpopulation of adenoma cells. We conclude that GH secretion by individual somatotroph adenoma cells is highly variable both within and between adenomas and that SMS 201-995 has a preferential inhibitory effect on a subpopulation of adenoma cells in some adenomas.

Growth hormone activity of the anterior pituitary lobe of the male rat at various ages.

WITHIN the past few years several reports have dealt with the relationship between the age of an animal and the pituitary content of growth hormone. Pigs1,2, ox3, and the rat4,5 have been examined. In general, it has been found that although the total amount of growth hormone in the pituitary gland increases greatly with age, the concentration of the hormone in the gland tends to remain fairly constant. The present work on the male rat supports this concept, but also indicates that relative to body-weight there may be a decreased amount of total growth hormone in the anterior lobe as the animal advances in age. This latter relationship has likewise been found in the larger species which have been examined, but previous evidence5 on the rat has indicated a lack of correlation between the total pituitary growth hormone/body-weight ratio and age.

Stilbestrol Feeding and Growth Hormone Stimulation in Immature Ruminants2

Nitrogen balance experiments with lambs and growth hormone assay experiments in cattle were carried out to study the physiological mechanism whereby stilbestrol in proper amounts brings about accelerated liveweight gains in immature ruminants. Nitrogen balance was favorably influenced by stilbestrol, growth hormone administration and higher ration energy and protein levels. The cattle growth hormone assay results revealed a positive relationship with the amount of stilbestrol fed. Stilbestrol feeding increased the size of the anterior pituitary, total amount of growth hormone in the anterior pituitary and the amount of growth hormone per unit of cattle weight. The results were discussed as evidence supporting the theory that the growth-stimulating influence of stilbestrol in immature ruminants is primarily mediated through growth hormone stimulation within the animal body.