Katharina Schilbach

Growth hormone binding protein – Physiological and analytical aspects

A significant proportion of total circulating growth hormone (GH) is bound to a high affinity growth hormone binding protein (GHBP). Several low affinity binding proteins have also been described. Significant differences between species exist with respect to origin and regulation of GHBP, but generally it resembles the extracellular domain of the GH receptor. Concentrations are associated with GH status, body composition and other factors. Although the clinical relevance of GHBP is not fully understood it is suggested that concentrations indirectly reflect GH receptor status. This is supported by cases of Larons syndrome where a molecular defect in the extracellular domain of the GH receptor is associated with low or unmeasurable GHBP concentrations. Methods to measure GHBP have evolved from chromatographic, activity based procedures to direct immunoassays. In clinical practice, measurement of GHBP can be helpful to differentiate between GH deficiency and GH insensitivity, particularly if GHBP is absent.

Biochemical investigations in diagnosis and follow up of acromegaly

Measurements of human growth hormone (GH) and insulin-like growth-factor I (IGF-I) are cornerstones in the diagnosis of acromegaly. Both hormones are also used as biochemical markers in the evaluation of disease activity during treatment. Management of acromegaly is particularly challenging in cases where discordant information is obtained from measurement of GH concentrations following oral glucose load and from measurement of IGF-I. While in some patients biological factors can explain the discrepancy, in many cases issues with the analytical methods seem to be responsible. Assays used by endocrine laboratories to determine concentrations of GH and IGF-I underwent significant changes during the last decades. While generally leading to more sensitive and reproducible methods, these changes also had considerable impact on absolute concentrations measured. This must be reflected by updated decision limits, cut-offs and reference intervals. Since different commercially available assays do not agree very well, method specific interpretation of GH and IGF-I concentrations is required. This complexity in the interpretation of hormone concentrations is not always appropriately reflected in laboratory reports, but also not in clinical guidelines reporting decision limits not related to a specific analytical method. The present review provides an overview about methodological and biological variables affecting the biochemical assessment of acromegaly in diagnosis and follow up.

De-masking oxytocin-deficiency in craniopharyngioma and assessing its link with affective function

Despite the high prevalence of panhypopituitarism and diabetes insipidus in patients with craniopharyngioma (CP), little is known about the functioning of the neuropeptide oxytocin in these patients. This is of special interest as tumor-associated lesions often impair sites critical for oxytocin production and release, and affective dysfunction in CP links with elsewhere reported prosocial, antidepressant and anxiolytic oxytocin effects. Using a prospective study-design, we tested whether oxytocin is reduced in CP-patients, and whether altered oxytocin levels account for affective and emotional dysfunction. 26 adult CP-patients and 26 healthy controls matched in sex and age underwent physical exercise, a stimulus previously shown to induce oxytocin release. Baseline and stimulated salivary oxytocin levels, as well as empathy, depression and anxiety scores were measured. Results showed that patients overall did not present with lower baseline oxytocin levels than controls (F[1,30]=0.21, p=0.649), but baseline oxytocin levels were indeed reduced in patients with hypothalamic damage, as assessed by MRI-based grading (F[2,9.79]=4.54, p=0.040). In response to exercise-induced stimulation, all CP-patients showed a blunted oxytocin-release compared to controls (F[1,30]=9.36, p=0.005). DI was not associated with oxytocin levels. Regarding affective function, unexpectedly, higher baseline oxytocin was related to higher trait anxiety (b=2.885, t(43)=2.421, p=0.020, CI[.478; 5.292]); the positive link with higher depression failed to reach statistical significance (b=1.928, t(43)=1.949, p=0.058, CI[-0.070; 3.927]). A blunted oxytocin-release was linked with higher state anxiety (b=-0.133, t(43)=-2.797, p=0.008, CI[-0.230; -0.037]). Empathy was not associated with oxytocin measures. In conclusion, we observed reduced baseline oxytocin levels only in CP-patients with hypothalamic damage. Exercise-induced stimulation de-masked an oxytocin-deficiency in all CP-patients. Baseline oxytocin levels and stimulated OT-responses might have different effects on affective function, which should be considered in future substitution paradigms.

Biomarkers of GH action in children and adults

Growth hormone (GH) and IGF-I levels in serum are used as biomarkers in the diagnosis and management of GH-related disorders but have not been subject to structured validation. Auxological parameters in children and changes in body composition in adults, as well as metabolic parameters and patient related outcomes are used as clinical and surrogate endpoints. New treatment options, such as long acting GH and GH antagonists, require reevaluation of the currently used biochemical biomarkers. This article will review biomarkers, surrogate endpoints and clinical endpoints related to GH treatment in children and adults as well as in acromegaly.

Aldosterone to Renin Ratio as Screening Tool in Primary Aldosteronism

Primary aldosteronism (PA) is a severe and often underdiagnosed form of secondary hypertension. Determining the aldosterone to renin ratio (ARR) in hypertensive patients has been shown to be a valuable screening test for identification of patients suffering from PA. Since the introduction of a more widespread ARR screening the number of PA patients significantly increased worldwide. Interpretation of ARR might be challenging: Several factors from posture to interfering drugs affect the ARR and need to be taken into account when collecting samples. In addition, the wide variety of available assay methods and lack of well-established cut-offs present a challenge to the clinician. This review discusses the usefulness and possible difficulties of ARR screening.

Long-acting FC-fusion rhGH (GX-H9) shows potential for up to twice-monthly administration in GH-deficient adults

OBJECTIVE Hybrid Fc-fused rhGH (GX-H9) is a long-acting recombinant human growth hormone (GH) under clinical development for both adults and children with GH deficiency (GHD). We compared the safety, pharmacokinetics and pharmacodynamics of weekly and every other week (EOW) dosages of GX-H9 with those of daily GH administration in adult GHD (AGHD) patients. DESIGN This was a randomized, open-label, active-controlled and dose-escalation study conducted in 16 endocrinology centers in Europe and Korea. METHODS Forty-five AGHD patients with or without prior GH treatment were enrolled. Patients with prior GH treatments were required to have received the last GH administration at least 1 month prior to randomization. Subjects were sequentially assigned to treatment groups. Fifteen subjects were enrolled to each treatment group and randomly assigned to receive either GX-H9 or Genotropin (4:1 ratio). GX-H9 dosage regimens for Groups 1, 2 and 3 were 0.1 mg/kg weekly, 0.3 mg/kg EOW and 0.2 mg/kg EOW, respectively. All Genotropin-assigned subjects received 6 µg/kg Genotropin, regardless of treatment group. Main outcome analyses included measurements of serum insulin-like growth factor 1 (IGF-I), safety, pharmacokinetics, pharmacodynamics and immunogenicity. RESULTS Mean GX-H9 peak and total exposure increased with an increase in dose after a single-dose administration. The mean IGF-I response was sustained above baseline over the intended dose interval of 168 h for the weekly and 336 h for the EOW GX-H9 groups. Safety profiles and immunogenicity were not different across the treatment groups and with Genotropin. CONCLUSIONS GX-H9 has the potential for up to twice-monthly administration.

Update on the use of oral octreotide therapy for acromegaly

ABSTRACT Introduction: Somatostatin analogs are most commonly used in pharmacological treatment of acromegaly. Pegvisomant and dopamine agonists are alternatives, which are used to a lesser extent. Dopamine agonists are the only orally applicable medication but are less effective than the other options. For a large number of patients, life-long pharmacotherapy has to be applied and frequent injections represent a reduction of quality of life for many of them. Areas covered: Recently published evidence for the use of oral octreotide therapy for acromegaly. Expert commentary: Oral octreotide is a novel and effective treatment for acromegaly and the side effects have been shown to be comparable to the injectable SSAs. The combination with a transient permeability enhancer allows intestinal permeation but also enables molecules with a size <70 kDa to pass transiently. This does not seem to have an acute or subacute consequence, but the long-term effect is still elusive. Therefore, more long-term trials are desirable.