Lowering total plasma insulin-like growth factor I concentrations by way of a novel, potent, and selective growth hormone (GH) receptor antagonist, pegvisomant (B2036-peg), augments the amplitude of GH secretory bursts and elevates basal/nonpulsatile GH release in healthy women and men.

The present clinical study implements a novel interventional strategy of short-term profound and selective blockade of GH receptors to reduce plasma insulin-like growth factor I (IGF-I) concentrations reversibly in healthy eumetabolic adults. Thereby, we examine the feedback role of systemic IGF-I on GH secretion without introducing the complex metabolic disarray that can otherwise accompany secondary IGF-I deprivation. To this end, we sampled blood at 10-min intervals for 10 h overnight in 8 men (aged 19-46 yr) and 4 women (aged 19-39 yr) to quantitate endogenous GH secretion and half-life 72 h after the prospective, randomly ordered, double blind, and within-subject cross-over administration of pegvisomant (1 mg/kg) or saline (0.5 mL) sc. Pegvisomant is an oligopegylated recombinant human GH peptide mutated to antagonize GH receptor-dependent signaling. Statistical analyses of paired plasma IGF-I concentrations and deconvolution-based quantitation of pulsatile GH secretion revealed that GH receptor blockade 1) suppressed fasting total IGF-I concentrations by 31%, viz. from (mean +/- SEM) 276 +/- 42 (placebo) to 190 +/- 20 microg/L (pegvisomant; P = 0.006) 84 h after drug injection; 2) increased the 10-h mean serum GH concentration by 71% from 1.4 +/- 0.33 (placebo) to 2.4 +/- 0.58 (pegvisomant; P = 0.024); 3) augmented the amplitude of underlying GH secretory bursts by 2.1-fold (i.e. from 0.13 +/- 0.032 to 0.27 +/- 0.076 microg/L.min; P = 0.0088); and 4) elevated the basal/nonpulsatile rate of GH secretion by 2.5-fold (from 2.3 +/- 0.77 to 5.07 +/- 1.8 microg/L.10 h; P = 0.022). The rise in the amplitude of GH secretory bursts correlated with the fall in plasma IGF-I concentrations (r = 0.603; P = 0.038). In contrast, IGF-I depletion did not alter GH secretory pulse frequency, half-duration, interpulse interval, percentage of pulsatile GH release, or half-life of endogenous GH. In summary, selective short-term reduction of systemic IGF-I concentrations in healthy eumetabolic adults drives GH secretion via the specific bipartite neuroregulatory mechanism of amplified GH secretory burst amplitude and elevated basal/nonpulsatile GH release. Endogenous GH half-life and frequency-related features of pulsatile GH secretion are not measurably affected, thus identifying a highly distinctive mode of IGF-I feedback-dependent control of GH output. As the increment in GH secretory burst amplitude correlated with the decrement in plasma IGF-I concentrations, we infer that variations in circulating IGF-I availability within the adult midphysiological range can influence pulsatile and basal GH production by way of negative feedback. Based on data in experimental animals, we speculate that the negative feedback actions of systemic IGF-I on GH secretion are mediated via increased hypothalamic somatostatin release, decreased GHRH (or GH-releasing peptide) secretion, and/or suppressed pituitary GH biosynthesis.     

Motivation for and adherence to growth hormone replacement therapy in adults with hypopituitarism: the patients‘ perspective

Pituitary - While reasons for non-adherence in children requiring growth hormone (GH) replacement (GH-Rx) are well researched, few studies have investigated adherence in adult GH deficient...     

Observational Study Mortality in Treated Primary Aldosteronism: The German Conn's Registry

In comparison with essential hypertension, primary aldosteronism (PA) is associated with an increased risk of cardiovascular morbidity. To date, no data on mortality have been published. We assessed mortality of patients treated for PA within the German Conn's registry and identified risk factors for adverse outcome in a case-control study. Patients with confirmed PA treated in 3 university centers in Germany since 1994 were included in the analysis. All of the patients were contacted in 2009 and 2010 to verify life status. Subjects from the population-based F3 survey of the Cooperative Health Research in the Region of Augsburg served as controls. Final analyses were based on 600 normotensive controls, 600 hypertensive controls, and 300 patients with PA. Kaplan-Meyer survival curves were calculated for both cohorts. Ten-year overall survival was 95% in normotensive controls, 90% in hypertensive controls, and 90% in patients with PA (P value not significant). In multivariate analysis, age (hazard ratio, 1.09 per year [95% CI, 1.03-1.14]), angina pectoris (hazard ratio, 3.6 [95% CI, 1.04-12.04]), and diabetes mellitus (hazard ratio, 2.55 [95% CI, 1.07-6.09]) were associated with an increase in all-cause mortality, whereas hypokalemia (hazard ratio, 0.41 per mmol/L [95% CI, 0.17-0.99]) was associated with reduced mortality. Cardiovascular mortality was the main cause of death in PA (50% versus 34% in hypertensive controls; P<0.05). These data indicate that cardiovascular mortality is increased in patients treated for PA, whereas all-cause mortality is not different from matched hypertensive controls.     

Failure of temozolomide and conventional doses of pegvisomant to attain biochemical control in a severe case of acromegaly

It has been suggested that treatment with adequate dose titration of pegvisomant, a GH antagonist, up to a maximum of 40 mg daily, can achieve IGF-1 normalisation in virtually all patients with acromegaly. On the other hand, temozolomide (TMZ), an alkylating cytostatic agent, has been reported to reduce pituitary tumour size and hormone hypersecretion in a small number of aggressive pituitary macroadenomas. In this paper we report the case of a patient resistant to very high doses of pegvisomant used in combination with somatostatin analogs (SSA) and to TMZ therapy. The patient, initially a 22 year-old man with an invasive GH-secreting pituitary macroadenoma (IGF-1, 371% upper limit of normal), had active acromegaly despite a repeat transsphenoidal surgery followed by radiotherapy and SSA (octreotide 800 μg sc daily) (IGF-1, 262% ULN). In combination with SSA, pegvisomant was started at 20 mg daily and doses were titrated up to 60 mg daily. IGF-1 was moderately reduced and stabilized at 200% ULN after 1 year of treatment. Serum pegvisomant level was 30,500 ng/l, the denaturalized GHBP concentration 1,120 pM and the endogenous GH level was 220 μg/l. Pegvisomant was stopped and TMZ therapy was given for 5 cycles. However, the patient reported an increase of acromegaly symptoms and the serum IGF-1 was raised to the same level prior to pegvisomant therapy. Consequently, pegvisomant was tried again with doses up to 100 mg daily finally resulting in normalisation of serum IGF-1 level and improvement of acromegaly symptoms and patient well-being. We conclude that in some patients with severe acromegaly refractory to multimodal therapy, biochemical control may be difficult to attain with conventional doses of pegvisomant or TMZ therapy.     

Allopregnanolone serum levels and expression of 5 alpha-reductase and 3 alpha-hydroxysteroid dehydrogenase isoforms in hippocampal and temporal cortex of patients with epilepsy

In the human central nervous system, progesterone is rapidly metabolised to 5 alpha-dihydroprogesterone which subsequently is further reduced to allopregnanolone (AP). These conversions are catalysed by 5 alpha-reductase and 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD). Although different isoforms of both enzymes have been identified in the brain, our knowledge of their expression in the human brain remains limited. The aim of the present study was to investigate the mRNA expression of 5 alpha-reductase 1 as well as 3 alpha-HSD 1, 2, 3 and 20 alpha-HSD in brain tissue from patients with pharmacoresistant temporal lobe epilepsy (TLE). Specimens were derived from either the hippocampus or the temporal lobe cortex and from the tumor-free approach corridor tissue of patients with brain tumors. Quantification of different mRNAs was achieved by real time PCR. In addition, we provide data on simultaneous evaluation of serum AP concentrations. We could demonstrate that 3 alpha-HSD 1 was not expressed in the hippocampus and temporal lobe of patients with TLE. In the hippocampus and temporal lobe, the expression levels of 3 alpha-HSD 2 were about 20% of that in liver tissue, those of 3 alpha-HSD 3 about 7% and those of 20 alpha-HSD about 2%, respectively. In patients with TLE, expression of 3 alpha-HSD 2 was significantly higher in the hippocampus than in temporal lobe cortex tissue (P<0.006). AP concentrations did not correlate significantly with the mRNA expression levels of 5 alpha-reductase 1, 3 alpha-HSD 2 and 3 and 20 alpha-HSD in any of the patient groups under investigation. In conclusion, the present study demonstrates mRNA expression of 5 alpha-reductase 1 and 3 alpha-HSD 2 and 3 and 20 alpha-HSD in the hippocampus and temporal lobe of epileptic patients. These findings provide further molecular biological evidence for the formation and metabolism of neuroactive steroids in the human brain.     

Measurement of human growth hormone by immunoassays: Current status,unsolved problems and clinical consequences

Measuring the concentration of growth hormone (GH) in blood samples taken during dynamic tests represents the basis for diagnosis of growth hormone related disorders, namely growth hormone deficiency and growth hormone excess. Today, a wide spectrum of immunoassays are in use, enabling rapid and sensitive determination of growth hormone concentrations in routine diagnostics. From a clinical point of view several difficulties exist with the use and interpretation of GH assay results in the assessment of GH related disorders: Many physiological factors such as fat mass, age and gender influence the outcome of dynamic tests, overall leading to significant inter-individual differences in GH responses. However, in addition to the physiological variability, considerable variability exists in GH assay results obtained by different immunoassays. Unfortunately, all the new technical advances in the field of GH measurement techniques have not reduced this methodological variability. To a large extent, the actual values reported for the GH concentration in a sample depend on the method used by the respective laboratory. Obviously, such discrepancies limit the applicability of consensus guidelines on diagnosis and treatment in clinical practice.This review summarizes current practices for GH measurement with respect to the methods used, their limitations and the clinical consequences of the existing heterogeneity in GH immunoassay results.