Immunoreactive plasma inhibin levels in men after polyvalent chemotherapy of germinal cell cancer.

In vitro studies have shown that the Sertoli cell is the primary source of inhibin in the male. We measured immunoreactive inhibin with a new two-site immunoenzymatic assay in the plasma of 92 men: 40 normal men, 7 patients with germinal cell cancer after unilateral orchidectomy and 45 patients with the same disease following unilateral orchidectomy and subsequent chemotherapy based on cisplatin. Normal men had inhibin levels of 1.77 +/- 0.09 U/l x 10(-3) (mean +/- SEM). Seven patients after unilateral orchidectomy had inhibin concentrations within the lower normal range (1.23 +/- 0.22 U/l x 10(-3)). Forty-five patients were investigated in a cross-sectional study up to 102 months after completion of chemotherapy. Inhibin levels were within the normal range in 25 patients (1.76 +/- 0.14 U/l x 10(-3)); 18 patients had significantly lower inhibin levels (0.48 +/- 0.05 U/l x 10(-3), p less than 0.005) when compared to patients after unilateral orchidectomy. Two patients had elevated inhibin levels (4.4 and 5.6 U/l x 10(-3)). The proportion of patients with normal and subnormal inhibin was not dependent on the time that elapsed after completion of chemotherapy or on the chemotherapy combination. There was no correlation between immunoreactive plasma inhibin and LH, FSH, testosterone or sperm count. The decrease in inhibin concentrations after chemotherapy may indicate long-term damage to Sertoli cells in some of the patients.     

Low incidence of antibody formation due to long-term interferon-α2c treatment of cancer patients

Summary In order to study the long-term immunogenicity of interferon-_2c (Berofor) in cancer patients, serum was collected starting in 1983 from study patients with various proliferative diseases who received interferon-_2c at different doses, according to different schedules, and via different routes. A total of 1992 samples were tested for the presence of anti-interferon-_2c antibodies. Due to long-term interferon-_2c treatment, 346 patients were eligible for induction of neutralizing anti-interferon antibodies over a treatment period of 252 months. Most patients were treated for longer than 6 months. Of the 346 patients, three patients (0.87%) exhibited measurable titers of neutralizing antibodies following therapy with interferon-_2c. One hundred and sixty-three patients suffered from non-Hodgkin lymphomas, leukemias, and preleukemias. One patient with chronic myeloid leukemia experienced antibody induction under therapy. The other 183 patients had solid tumors. Two of them reacted with antibody production. All titers were very low (1:12, 1:8, and 1:64). Compared with figures reported for other interferon- preparations, the propensity of interferon-_2c to induce neutralizing antibodies seems to be very low. This property might be related to arginines occurring as critical residues in positions 23 and 34 of the interferon-_2c molecule.Abbreviations ANB antiviral neutralization bioassay - CE competitive sandwich ELISA - EBI Ernst Boehringer Institut - IFN interferon     

Four-year follow-up of acromegalic patients treated with the new long-acting formulation of Lanreotide (Lanreotide Autogel).

Lanreotide Autogel (Ipsen) is a long-acting somatostatin analogue (SA) in a new galenic formulation suitable for subcutaneous (s.c.) injection. In our department, 11 patients with therapy-resistant acromegaly were treated with Lanreotide Autogel for 48 months. 10/11 patients had previously undergone transsphenoidal surgery. For a median duration of 1.4 years prior to Lanreotide Autogel, the patients received Lanreotide PR 30 mg every 7, 10, or 14 days. 60, 90, or 120 mg of Lanreotide Autogel was administered by deep s.c. injection every 28 days, with the higher dosage being given to those with the previously shortest injection interval under Lanreotide PR. Dose was adjusted on the basis of Growth Hormone (GH) level after 4, 8, and 12 months with a minimum dose of 60 mg and a maximum dose of 120 mg. The efficacy of Lanreotide Autogel treatment was evaluated by measuring GH concentrations (4 hour profiles) and IGF-I levels. Before switching to Lanreotide Autogel, the multiple of the upper limit of normal (xULN) of IGF-I levels was 1.2 (median) and the median GH level was 1.3 microg/l. 3 out of 11 patients had an IGF-I within the age- and sex-adjusted normal range. After 48 months of treatment with Lanreotide Autogel, six patients had an IGF-I within the normal range. Median GH levels were at 1.3 microg/l and xULN of IGF-I was at 1.0 compared to Lanreotide PR 30 mg treatment (p < 0.001). At the end of the study, 8 patients received 120 mg Lanreotide Autogel, 2 patients 90 mg and 1 patient 60 mg, respectively. There was slight but significant deterioration of glucose metabolism with an increase of HbA1c. In conclusion, the new galenic formulation of Lanreotide improves not only the control of biochemical markers of acromegaly compared to the conventional PR formulation, but is also easier to administer given its deep s.c. method of administration. Glucose metabolism has to be followed carefully in patients on high-dose Lanreotide Autogel.     

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.     

Basal inhibin B and the testosterone response to human chorionic gonadotropin correlate in prepubertal boys

During childhood, the quiescent phase of testicular activity, the hCG stimulation test is widely used to evaluate testicular function. Inhibin B, a gonadal peptide regulating FSH secretion, is an established marker of Sertoli cell function and spermatogenesis in adults. In contrast to the other hormones of the hypothalamo-pituitary-gonadal axis, inhibin B is also secreted in detectable amounts during childhood. The aim of this study was to determine whether basal inhibin B levels are able to predict prepubertal testicular function, so as to avoid a stimulation test. Inhibin B and testosterone before and after hCG stimulation were measured in 54 male children with various testicular disorders by an immunoassay specific for inhibin B. Basal inhibin B was compared to the testosterone increase after hCG. Inhibin B and the hCG-induced testosterone increment correlated strongly (r = 0.84; P<0.0001). Patients with anorchia were clearly distinguishable from those with abdominal testes, having undetectable (inhibin B, <15 pg/mL) respective normal inhibin B levels for age. Inhibin B and the testosterone response to hCG were low in boys with testicular damage (delayed diagnosis of cryptorchidism; after testicular torsion) and in patients with gonadal dysgenesis, but were normal or increased in children with androgen insensitivity syndrome. We conclude that basal inhibin B predicts the testosterone response to hCG in boys and therefore gives reliable information about both the presence and function of the testes. The diagnostic procedure in cryptorchidism may be reduced to a single inhibin B measurement. Furthermore, inhibin B levels show specific alterations in patients with sexual ambiguity, adding a valuable diagnostic tool to the complex differential diagnosis of male pseudohermaphroditism.     

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.