H. M. SCHULTE, K. WIESE and B. ALLOLIO
B. Allolio, W. Winkelmann and F. X. Hipp
In order to evaluate the possible role of endogenous histamine in ACTH secretion we investigated the effect of the H1 antagonist meclastine on plasma ACTH in patients with ACTH hypersecretion. Seven patients with primary adrenal insufficiency (group 1) and 5 patients with ACTH dependent Cushing's syndrome (group 2) were given an iv infusion of meclastine (4.8 mg/90 min). In patients of group 2 plasma ACTH was unaffected by meclastine infusion. However, in patients of group 1 with intact steroid feedback meclastine was followed by a significant drop in plasma ACTH as compared with ACTH levels after saline infusion (46.0 ± 4.6% vs 85.0 ± 7.0%, P < 0.01). These results suggest that histamine is involved in the control of ACTH secretion, possibly by stimulation of CRF release.
F Callies, W Arlt, HJ Scholz, M Reincke and B Allolio
There is no established therapeutic regimen for treatment of hypoparathyroidism during pregnancy. This is due particularly to uncertainty about the use of vitamin D or its analogues, as in animal experiments teratogenic side-effects have been reported. Nevertheless, vitamin D or its analogues are required to control tetany predisposing to abortion and preterm labour. We herein report the course of two pregnancies in a hypoparathyroid woman treated with calcitriol (1,25(OH)2D3). Additionally, we describe the outcome of pregnancy in ten women receiving calcitriol, reported to the Drug Safety Department (DSD), Hoffmann-La Roche AG. A 29-year-old hypoparathyroid woman receiving chronic treatment with calcitriol (0.25 microg/day) and calcium (1.5 g/day) was referred in the 6th week of her first pregnancy. Calcitriol was initially discontinued, but during the 20th week of pregnancy recurrent tetany occurred (serum calcium 1.74 mmol/l). Calcitriol (0.25 microg/day) was added, stabilizing serum calcium around 2.15 mmol/l with 1,25(OH)2D3 concentrations around 60 ng/l (normal range 35-80 ng/l). To maintain normocalcaemia the calcitriol dose was increased to 0.5 microg/day during the 33rd week and to 0.75 microg/day shortly before delivery of a healthy girl in the 3 7th week. During her second pregnancy calcitriol was given initially at a dose of 0.25 microg/day with further adaptation to 0.5 microg/day during the 20th and to 1.00 microg/day in the 31st week. Serum calcium and 1,25(OH)2D3 were continually within the lower normal range. She gave birth to another healthy girl during the 39th week. In eight of the ten pregnancies reported to the DSD no adverse effects of calcitriol (0.25-3.25 microg/day) were seen and healthy babies were delivered. In two retrospectively reported cases, serious adverse events were described: premature closure of the frontal fontanelle, and stillbirth in the 20th week due to complex fetal malformation respectively. However, in both cases the causative role of calcitriol administration remains highly questionable. We conclude that, during pregnancy, management of maternal hypoparathyroidism with calcitriol and calcium is feasible, if the 1,25(OH)2D3 concentrations are adapted to the physiological needs during pregnancy and serum calcium levels are kept in the lower normal range.
F Beuschlein, M Fassnacht, A Klink, B Allolio and M Reincke
The regulation of the ACTH-receptor gene is unique in that it is up-regulated by its own ligand, ACTH. Ligand-induced up-regulation of ACTH-receptor expression may be an important adaptive process directed towards optimizing adrenal responsiveness to ACTH in the context of physiological stress and the maintenance of metabolic homeostasis in which the adrenals play a pivotal role. Whereas enhancement by ligand-induced up-regulation permits a more efficient and rapid glucocorticoid response, negative feedback regulation of glucocorticoids in the hypothalamus and pituitary inhibits ACTH secretion and allows a balanced adrenal response to stress. Since the cloning of the promoter region of the ACTH receptor, considerable progress in the understanding of the regulatory processes has been made. The effects of ACTH on ACTH-receptor expression is dependent on cAMP, probably mediated through AP-1.The profound effect of three SF-1-binding sites in the ACTH-receptor promoter was demonstrated by deletion experiments. Conversely, ACTH-receptor expression can be suppressed by adrenal-specific transcription factors,like DAX-1.Despite an extensive search, no activating ACTH-receptor mutations have been found in adrenal tumors,excluding the ACTH receptor as a relevant oncogene in adrenal tumorigenesis. However, the ACTH receptor may act as a differentiation factor as suggested by LOH in adrenal carcinomas with an undifferentiated tumor type.In benign adrenal tumors, a strong correlation between ACTH-receptor expression and expression of P450 steroidogenic enzymes is evident. This close regulative relationship is lost in adrenal carcinoma, probably as a result of tumor dedifferentiation. Down-regulation of ACTH-receptor expression in normal and neoplastic tissue can be achieved by adrenostatic compounds such as aminoglutethimide and metyrapone.
B. Allolio, A. Hoeppener, U. Leonhardt, U. Deuβ and W. Winkelmann
Abstract. We investigated the chromatographic pattern of serum prolactin in 41 patients with prolactinoma and correlated the distribution of immunoreactive prolactin with the clinical variables sex, tumour size, age, and response to bromocriptine therapy. In addition, the effect of long-term storage and repeated freezing and thawing on the different molecular weight forms of prolactin was evaluated. Gel chromatography (column 100 cm × 1.5 cm) was performed in 0.1 mol/l phosphate buffer, pH 7.5, using Ultrogel ACA 54 (LKB).
No correlation of age or the response to drug therapy to the elution pattern of prolactin was found. Females showed a higher percentage of big prolactin than males (10.4 ± 1.2% vs 6.8 ± 0.7%, x̄ ± sem, P <0.05) and patients with microprolactinomas too had a higher percentage of big prolactin than those with macroprolactinomas (11.3 ± 1.8% vs 7.7 ± 0.7%, P <0.05).
Serum samples kept frozen for more than 2 years showed a higher percentage of bigbig prolactin (P < 0.01) than samples stored for less than 12 months suggesting formation in vitro. However, examination of fresh samples prior to freezing also demonstrated bigbig prolactin, indicating that bigbig prolactin circulates in vivo.
Repeated freezing and thawing of bigbig prolactin led to almost complete interconversion to little prolactin without any increase in immunoreactivity. This finding supports the concept that bigbig prolactin represents little prolactin loosely associated to a carrier molecule.