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Marco Losa, Jochen Schopohl, O. Albrecht Müller and Klaus von Werder

Abstract. The effect of an iv injection of growth hormone releasing factor (GRF) on Prl secretion in healthy volunteers and patients with active acromegaly was investigated. Thirteen normal subjects received 100 μg GRF 1-44, and 19 acromegalics received 100 μg GRF 1-44. Nine normals and 9 patients were given the diluent only and served as placebo control. In healthy volunteers GRF did not affect Prl secretion significantly when compared to placebo, whereas in acromegalics Prl levels after GRF were higher than after placebo.

We have divided acromegalics in Prl-responders to GRF (n = 11) and Prl-non-responders (n = 8) using the criterion of strict parallelism between GH and Prl secretion after GRF. In cases with no GH response to GRF a clear increase of Prl levels with the maximum 15–30 min after GRF was also regarded as a Prl response. Acromegalic Prl-responders and Prl-non-responders did not significantly differ in age, sex, previous therapy, and basal GH and Prl levels. However, Prl-non-responders had a significantly reduced response of both GH and Prl to TRH (GH: 147.3 ± 16.0 vs 590.1 ± 127.8%; mean ± se; Prl: 159.4 ± 32.6 vs 504.9 ± 109.3%). It is concluded that 50 or 100 μg GRF does not affect Prl secretion in normal subjects. In contrast, in acromegaly GRF leads to Prl secretion in more than half of all patients.

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Marco Losa, Lilian Bock, Jochen Schopohl, Günter K. Stalla, O. Albrecht Müller and Klaus von Werder

Abstract. To evaluate the dynamics of GH-secretion after infusion of growth hormone releasing factor, human pancreatic growth hormone releasing factor (hpGRF1-44) was infused over 2 and 5 h at a dosage of 100 μg hpGRF1-44/h into 11 healthy subjects. The infusion was started and terminated with a 50 μg hpGRF1-44 bolus injection. In 5 subjects 200 μg TRH was given 4 h after starting the infusion. In addition, 4 healthy subjects received 50 μg hpGRF1-44 bolus injection every 2 h. GRF, somatostatin, GH, Prl, and TSH were measured by radioimmunoassay.

The initial 50 μg GRF bolus increased GH-levels in all 11 subjects with a maximum at 30 min (24.1 ± 5.1 ng/ml ± se). However, though hpGRF1-44 was continuously infused and GFR-levels remained elevated, GH decreased to a minimum 270 min after start of infusion (2.6 ± 0.6 ng/ml). The GH-response to the second bolus at the end of the infusion was lower compared to the first response (14.6 ± 3.4 ng/ml after 2 h and 7.6 ± 2.5 ng/ml after 5 h). TRH did not lead to a GH-increase during hpGRF1-44 infusion though Prl and TSH rose normally. The intermittent bolus injection of 50 μg hpGRF1-44 led to continuously decreasing GH-responses to the same GRF-dosage (I. bolus: 16.5 ± 1.6 ng/ml; II. bolus: 4.2 ± 0.8 ng/ml; III. bolus: 3.4 ± 0.5 ng/ml). No change in somatostatin levels was observed.

These findings show that GRF infusion or bolus injection in short intervals does not sustain elevated GH-levels. Pituitary GH is either not readily available for continuous GRF-stimulation or GH-secretion may be antagonized by increasing portal somatostatin levels which are not reflected in the peripheral circulation.

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Bärbel Reichardt, Gerhard Mehltretter, Karin Lechner, Hans K Rjosk, Otto A Müller and Jochen Schopohl

The inhibin concentration in 131 samples of human follicular fluid obtained from 31 women undergoing ovarian hyperstimulation for in vitro fertilization was measured using specific double antibody radioimmunoassay. We used the synthetic 1-32-α-inhibin as standard and radioiodinated 1-32-Tyr-α-inhibin as tracer. Antibodies were raised in rabbits by immunization with the synthetic peptide. Estradiol and progesterone concentrations were measured using commercial radioimmunoassays. Results: The inhibin concentration correlated with the estradiol (r = 0.57, N = 88.p<0.0001) and progesterone (r=0.82, N=88. p<0.0001) concentrations in human follicular fluid. The dosage of human menopausal gonadotropin given to individual patients correlated with the average inhibin concentration measured in their follicles (r = 0.72, N = 23, p<0.0001). Similarly, the size of follicles correlated with their inhibin content (r = 0.75, N = 131, p<0.0001). Nineteen samples of human follicular fluid originating from follicles of different size and volume were examined using gel-chromatography. In each human follicular fluid the main form of inhibin (32 kDa) was recovered. In small follicles (3 ml) we found 12.8±9.1% (mean±sd) of the whole immunoreactive inhibin eluating in the area of V0 (≤80 kDa). In the larger follicles (4-7 ml), however, only 4.4±4.2% of this large inhibin form could be found. Conclusions: Our data confirm that human menopausal gonadotropin stimulates ovarian inhibin production. In addition to the estradiol and progesterone concentrations, the inhibin concentration may be an index of granulosa cell function and follicular maturation. The occurrence of large molecular weight forms of inhibin in small follicles remains unclear. They may represent large precursor molecules which are proteolytically cleaved in more mature follicles.

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Marco Losa, Julia Alba-Roth, Sylwester Sobieszczyk, Jochen Schopohl, O. Albrecht Müller and Klaus von Werder

Abstract. We investigated the pattern of GH secretion in response to repetitive TRH administration in patients with active acromegaly and in normal subjects. Nine acromegalic patients and 10 normal subjects received three doses of 200 μg of TRH iv at 90-min intervals. There was a marked serum GH rise in acromegalic patients after each TRH dose (net incremental area under the curve [nAUC]: first dose = 4448 ± 1635 μg · min · 1−1; second dose = 3647 ± 1645 μg · min · 1−1; third dose = 4497 ± 2416 μg · min · 1−1; NS), though individual GH responses were very variable. In normal subjects TRH did not elicit GH secretion even after repeated stimulation. Each TRH administration stimulated PRL release in acromegalic patients, though the nAUC of PRL was significantly higher after the first (1260 ± 249 μg · min · 1−1) than after the second and the third TRH administration (478 ± 195 and 615 ± 117 μg · min · 1−1, respectively; P < 0.01). In normal subjects too, PRL secretion was lower after repeated stimulation (first dose = 1712 ± 438 μg · min · 1−1; second dose = 797 ± 177 μg · min · 1−1; third dose = 903 ± 229 μg · min · 1−1 P < 0.01), though different kinetics of PRL secretion were evident, when compared with acromegalic patients. TSH secretion, assessed in only 4 patients, was stimulated after each TRH dose, though a minimal but significant reduction of nAUC of TSH after repeated TRH challenge occurred. Both T3 and T4 increased steadily in the 4 patients. The same pattern of TSH, T3, and T4 secretion occurred in normal subjects. Our study demonstrates that repetitive TRH administration in acromegalic patients leads to similar, but individually heterogeneous GH responses. A qualitative difference in PRL responsiveness occurred in acromegalic patients compared with normal subjects, whereas TSH, T3, and T4 secretion was qualitatively and quantitatively similar in both groups.

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Timo Deutschbein, Martin Bidlingmaier, Jochen Schopohl, Christian J Strasburger and Stephan Petersenn

Context

Adult growth hormone (GH) deficiency (GHD) is diagnosed by provocative testing of GH secretion.

Objective

To improve the diagnostic accuracy of GH-releasing hormone (GHRH) plus arginine (GARG) testing, we evaluated the influence of age, BMI and sex and established normative data for an automatic immunoassay specifically measuring 22 kDa human GH.

Design/setting

Prospective multicenter study.

Participants

Eighty-seven patients with hypothalamic–pituitary disease and 200 healthy controls. Patients were classified according to the number of pituitary hormone deficiencies (PHD). GHD was assumed when ≥2 PHD (in addition to GH) were present (n = 51); 36 patients with <2 PHD were considered GH sufficient (GHS). ROC analysis identified cutoffs with ≥95% specificity for GHD. Controls were prospectively stratified for sex, age and BMI.

Interventions

All participants received GHRH and l-arginine.

Main outcome measures

GH was measured by immunoassay (iSYS, IDS).

Results

In controls, multiple stepwise regression analysis showed that BMI (21%, P < 0.0001), sex (20%, P < 0.0001) and age (5%, P < 0.001), accounted for 46% of GH peak level variability during GARG. Comparison of peak GH during GARG (GHD vs GHS + controls) revealed an overall cutoff of 3.9 ng/mL (sensitivity 86%, specificity 95%). After adjustment for BMI and sex, optimal cutoffs (male vs female) were 6.5 vs 9.7 ng/mL in lean, 3.5 vs 8.5 ng/mL in overweight and 2.2 vs 4.4 ng/mL in obese subjects respectively.

Conclusion

BMI and sex account for most of the variability of peak GH levels during GARG. Consequently, diagnostic accuracy of the GARG test is significantly improved by use of adjusted cutoffs.

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Martin Reincke, Katrin Ritzel, Andrea Oßwald, Christina Berr, Günter Stalla, Klaus Hallfeldt, Nicole Reisch, Jochen Schopohl and Felix Beuschlein

Objective

Our aim was to review short- and long-term outcomes of patients treated with bilateral adrenalectomy (BADx) in ACTH-dependent Cushing's syndrome.

Methods

We reviewed the literature and analysed our experience with 53 patients treated with BADx since 1990 in our institution.

Results

BADx is considered if ACTH-dependent Cushing's syndrome is refractory to other treatment modalities. In Cushing's disease (CD), BADx is mainly used as an ultima ratio after transsphenoidal surgery and medical therapies have failed. In these cases, the time span between the first diagnosis of CD and treatment with BADx is relatively long (median 44 months). In ectopic Cushing's syndrome, the time from diagnosis to BADx is shorter (median 2 months), and BADx is often performed as an emergency procedure because of life-threatening complications of severe hypercortisolism. In both situations, BADx is relatively safe (median surgical morbidity 15%; median surgical mortality 3%) and provides excellent control of hypercortisolism; Cushing's-associated signs and symptoms are rapidly corrected, and co-morbidities are stabilised. In CD, the quality of life following BADx is rapidly improving, and long-term mortality is low. Specific long-term complications include the development of adrenal crisis and Nelson's syndrome. In ectopic Cushing's syndrome, long-term mortality is high but is mostly dependent on the prognosis of the underlying malignant neuroendocrine tumour.

Conclusion

BADx is a relatively safe and highly effective treatment, and it provides adequate control of long-term co-morbidities associated with hypercortisolism.

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Sylvère Störmann, Bodo Gutt, Josefine Roemmler-Zehrer, Martin Bidlingmaier, Rudolf M Huber, Jochen Schopohl and Matthias W Angstwurm

Objective

Acromegaly is associated with increased mortality due to respiratory disease. To date, lung function in patients with acromegaly has only been assessed in small studies, with contradicting results. We assessed lung function parameters in a large cohort of patients with acromegaly.

Design

Lung function of acromegaly patients was prospectively assessed using spirometry, blood gas analysis and body plethysmography. Biochemical indicators of acromegaly were assessed through measurement of growth hormone and IGF-I levels. This study was performed at the endocrinology outpatient clinic of a tertiary referral center in Germany.

Methods

We prospectively tested lung function of 109 acromegaly patients (53 male, 56 female; aged 24–82 years; 80 with active acromegaly) without severe acute or chronic pulmonary disease. We compared lung volume, air flow, airway resistance and blood gases to normative data.

Results

Acromegaly patients had greater lung volumes (maximal vital capacity, intra-thoracic gas volume and residual volume: P < 0.001, total lung capacity: P = 0.006) and showed signs of small airway obstruction (reduced maximum expiratory flow when 75% of the forced vital capacity (FVC) has been exhaled: P < 0.001, lesser peak expiratory flow: P = 0.01). There was no significant difference between active and inactive acromegaly. Female patients had significantly altered lung function in terms of subclinical airway obstruction.

Conclusions

In our cross-sectional analysis of lung function in 109 patients with acromegaly, lung volumes were increased compared to healthy controls. Additionally, female patients showed signs of subclinical airway obstruction. There was no difference between patients with active acromegaly compared with patients biochemically in remission.

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Katrin Ritzel, Felix Beuschlein, Christina Berr, Andrea Osswald, Nicole Reisch, Martin Bidlingmaier, Harald Schneider, Jürgen Honegger, Lucas L. Geyer, Jochen Schopohl and Martin Reincke

Objective

The aim of the present study was to validate criteria of corticotropin-releasing hormone (CRH) stimulation and 8 mg dexamethasone suppression (high-dose dexamethasone suppression, HDDS) to distinguish the etiology of ACTH-dependent Cushing's syndrome.

Subjects and methods

We retrospectively analyzed cortisol and ACTH after the injection of 100 μg human CRH in confirmed Cushing's disease (CD, n=78) and confirmed ectopic Cushing's syndrome (ECS, n=18). Cortisol and ACTH increase (in percentage above basal (%B)) at each time point, maximal increase (Δmax %B), and area under the curve (AUC %B) were analyzed using receiver operator characteristics (ROC) curve analyses. Cortisol suppression (%B) after 8 mg of dexamethasone was evaluated as a supplementary criterion.

Results

An increase in ACTH of ≥43%B at 15 min after CRH was the strongest predictor of CD, with a positive likelihood ratio of 14.0, a sensitivity of 83%, a specificity of 94%, a positive predictive value of 98% and a negative predictive value of 58%. All of the other criteria of stimulated ACTH and cortisol levels were not superior in predicting CD in response to CRH injection. The addition of cortisol suppression by dexamethasone did not increase the discriminatory power. However, the combination of a positive ACTH response at 15 min and a positive HDDS test excluded ECS in all cases.

Conclusion

The present findings support the use of plasma ACTH levels 15 min after the injection of human CRH as a response criterion for distinguishing between CD and ECS. The addition of the HDDS test is helpful for excluding ECS when both tests are positive.

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Andrea Osswald, Timo Deutschbein, Christina M Berr, Eva Plomer, Anne Mickisch, Katrin Ritzel, Jochen Schopohl, Felix Beuschlein, Martin Fassnacht, Stefanie Hahner and Martin Reincke

Objective

Aim of our study was to analyze long-term outcome of patients with the ectopic Cushing’s syndrome (ECS) compared to patients with Cushing’s disease (CD) regarding cardiovascular, metabolic, musculoskeletal and psychiatric comorbidities.

Design

Cross-sectional study in patients with ECS and CD in two German academic tertiary care centers.

Methods

Standardized clinical follow-up examination was performed including health-related quality of life (QoL) in 21 ECS patients in long-term remission (≥18 months since successful surgery). Fifty-nine patients with CD in remission served as controls.

Results

Time from first symptoms to diagnosis of Cushing’s syndrome (CS) was shorter in ECS than in CD (8.5 (IQR: 30.3) vs 25 (IQR: 39.0) months, P = 0.050). ECS patients had lower self-reported psychiatric morbidity compared to CD (19% vs 43%, P = 0.050) at follow-up. Moreover, female ECS patients reported favorable scores for QoL in the SF-36 questionnaire (mental health: 92 (IQR: 30) vs 64 (IQR: 32) in CD, P = 0.010) and a Cushing-specific QoL questionnaire (73 (IQR: 18) vs 59 (IQR: 36) in CD, P = 0.030). In a pooled analysis of ECS and CD patients, QoL correlated with time from first symptoms until diagnosis of CS, but not with urinary free cortisol levels or serum cortisol after dexamethasone at the time of diagnosis. Long-term outcomes regarding hypertension, metabolic parameters, bone mineral density and grip strength were comparable in ECS and CD.

Conclusions

Our data support the concept that time of exposure to glucocorticoid excess appears to be a better predictor than peak serum cortisol levels at the time of diagnosis regarding long-term psychiatric morbidity and QoL.

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Christof Schöfl, Holger Franz, Martin Grussendorf, Jürgen Honegger, Cornelia Jaursch-Hancke, Bernhard Mayr, Jochen Schopohl and the participants of the German Acromegaly Register

Background

Acromegaly is a rare disease with significant morbidity and increased mortality. Epidemiological data about therapeutic outcome under ‘real life’ conditions are scarce.

Objective

To describe biochemical long-term outcome of acromegaly patients in Germany.

Design and methods

Retrospective data analysis from 1344 patients followed in 42 centers of the German Acromegaly Register. Patients' data were collected 8.6 (range 0–52.6) years after diagnosis. Controlled disease was defined by an IGF1 within the center-specific reference range.

Results

Nine hundred and seventeen patients showed a normalized IGF1 (157 (range 25–443) ng/ml). In patients with a diagnosis dated back >2 years (n=1013), IGF1 was normalized in 76.9%. Of the patients, 19.5% had an elevated IGF1 and a random GH ≥1 ng/ml, 89% of the patients had at least one surgical intervention, 22% underwent radiotherapy, and 43% received medical treatment. After surgery 38.8% of the patients were controlled without any further therapy. The control rates were higher in surgical centers with a higher caseload (P=0.034). Of the patients with adjunctive radiotherapy 34.8% had a normal IGF1 8.86 (0–44.9) years post irradiation, 65.2% of the medically treated patients were controlled, and 47.2% of the patients with an elevated IGF1 received no medical therapy.

Conclusion

The majority of acromegaly patients were controlled according to their IGF1 status. Long-term outcome could be improved by exploiting medical treatment options especially in patients who are not controlled by surgery and/or radiotherapy.