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Sverre O. Lie, Jakob Havnen and Ole Djøseland

ABSTRACT

A female infant has been described, who developed the typical clinical signs of Cushing's syndrome from the age of 41/2 months. The symptoms were caused by a benign tumour in the left adrenal gland. The tumour was removed surgically, and the patient recovered completely.

Tissue cultures of the tumour cells were established. Using explant techniques, there was no visible outgrowth of epithelial cells. However, the tumour cells secreted hormones into the growth medium for periods up to 4 weeks. The addition of ACTH was not required, suggesting an autonomous type of production. The explants were able to metabolize radioactively labelled testosterone for periods up to two months. The various metabolic products have been identified.

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Jens Bollerslev, Sian Thomas, Ellen Grodum, Kim Brixen and Ole Djøseland

Bollerslev J, Thomas S, Grodum E, Brixen K, Djøseland 0. Collagen metabolism in two types of autosomal dominant osteopetrosis during stimulation with thyroid hormones. Eur J Endocrinol 1995;133:557–63. ISSN 0804–4643

In order to investigate collagen metabolism in two different types of autosomal dominant osteopetrosis (ADO), eight patients with type I (aged 23–61 years, mean 40.4 years) and nine patients with type II ADO (aged 20–49 years, mean 32.8 years) were compared with ten normal controls (aged 22–54 years, mean 35.4 years). The subjects were treated with 100 μg of triiodothyronine (T3) daily for 7 days and followed for a total of 4 weeks. Serum T3 increased in all subjects and a corresponding suppression of thyroid-stimulating hormone (TSH) was observed. Serum carboxy-terminal propeptide of type I collagen (S-PICP) in the control and type I groups showed no difference at baseline, whereas type II was lower than controls (p < 0.01). No significant alterations following stimulation were observed in any of the groups. Serum BGP (osteocalcin) values in the two patient groups were insignificantly lower than controls both at baseline and throughout the study. Following stimulation, a significant response was seen in the three groups (p < 0.001). The increases during the treatment period (delta values) for controls, type I and type II were 47.6% (p < 0.01), 51.7% (p = 0.05) and 34.8% (NS), respectively, with no difference between the groups. Serum bone-specific alkaline phosphatase (S-ALP) was not different between the groups and no alterations were observed in relation to treatment. The serum N-terminal propeptide of type III collagen (S-PIIINP) showed no difference at baseline between type I and controls but was significantly higher (p < 0.003) in type II than in the controls. After stimulation, significant responses were observed in all three groups (p < 0.001). Serum PIIINP increased following 1 week of treatment by 64% (p < 0.01), 41% (p < 0.02) and 18% (NS), respectively. Serum carboxy-terminal telopeptide of type I collagen (SICTP) did not differ between type I and controls at baseline but was increased in type II (p < 0.04), as it was throughout the observation period (p < 0.12 and p < 0.02). A significant response was observed in the three groups following stimulation. The delta values were 69% (p = 0.005), 56% (p < 0.02) and 34% (p < 0.02), respectively. The urinary hydroxyproline (OHP)/creatinine ratio did not differ between the groups either at baseline or following stimulation. A significant response (p < 0.001) was observed, with delta values of 44.2% (p < 0.06), 35.9% (p < 0.04) and 34.3% (p < 0.01), respectively. The two bone resorptive markers (S-ICTP and OHP/creatinine ratio) were correlated significantly at baseline for all three groups. It is concluded that collagen metabolism is disturbed in type II ADO, which might reflect an increased turnover of extra-osseous collagen. Because ICTP levels are increased in disorders with increased extra-osseous collagen turnover, we question the suitability of this parameter as a sensitive marker of bone resorption.

Jens Bollerslev, Department of Medical Endocrinology, National University Hospital, N-0027 Oslo, Norway

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Vidar Hansson, Ole Djøseland, Ellen Reusch and Synnøve Aasvik

ABSTRACT

Following the administration of [3H] testosterone to castrated rats in vivo, most of the radioactivity in the epididymal cytosol fraction was bound to macromolecules. The molecular weight of the androgen-macromolecular complexes was determined to about 90 000, and the frictional ratio (f/fo) was 1.62. The sedimentation coefficient was shown to be 4.6 S (± 0.2) and the complex was slightly retarded on a column of Sephadex G-100 (Einstein-Stokes radius 47–48 Å). On polyacrylamide gel electrophoresis it moved as a sharp zone with RF: 0.41.

Almost all the radioactivity bound to these macromolecules was identified as 5α-dihydrotestosterone (5α-DHT) (95%) and only a minor part (3–4%) as testosterone.

The receptor for 5α-DHT in the epididymal cytosol fraction was in its physico-chemical properties shown to be different from the androgenbinding proteins of the rat ventral prostate, and could not be demonstrated in non-target organs like liver and kidney. The receptor for 5α-DHT in the epididymal cytosol fraction did not form aggregates in hypotonic solutions, and was roughly of the same molecular size both at high and low salt concentrations.

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Jens Bollerslev, Jens Møller, Sian Thomas, Ole Djøseland and Jens S Christiansen

Bollerslev J, Møller J, Thomas S, Djøseland O, Christiansen JS. Dose-dependent effects of recombinant human growth hormone on biochemical markers of bone and collagen metabolism in adult growth hormone deficiency. Eur J Endocrinol 1996:135:666–71. ISSN 0804–4643

Administration of growth hormone (GH) to patients with growth hormone deficiency (GHD) has beneficial effects, but so far has been employed only empirically. We have, therefore, investigated the dose-dependent effect of GH on target tissue by studying biochemical markers of bone and collagen turnover in GHD. Then patients with GHD (nine males and one female aged 21–43 years, mean age 28 years) participated in the study. Growth hormone deficiency was defined as a peak serum GH response of less than 15 mU/l in two provocation tests. After a 4-week run-in period, the study population received increasing doses of GH at 4-week intervals (1,2 and 4U/m2). Blood samples were collected in the fasting state at 7.00 h on the last day of each period and assayed for serum levels of osteocalcin (S-BGP), bone alkaline phosphatase (B-ALP), C-terminal propeptide of type I collagen (S-PICP), carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen (S-ICTP) and N-terminal propeptide of type III collagen (S-PIIINP). Following replacement therapy, serum insulin-like growth factor I and insulin-like growth factor binding protein 3 increased sequentially with time (p<0.001 and p<0.001, MANOVA) and the values were elevated significantly over baseline levels after treatment with 1 U/m2. Serum BGP values were below normal at the start of the study and increased gradually following GH treatment to levels in the low–normal range. Baseline values for serum bone alkaline phosphatase (B-ALP), PICP and PIIINP were within the normal range. The collagen parameters increased with GH replacement (p<0.001, MANOVA) to levels above normal, whereas B-ALP stayed within normal limits. Serum ICTP values were elevated above the normal range at baseline, indicating increased bone resorption in GHD. A linear increase in values was observed with GH treatment (p< 0.001, MANOVA). Serum ICTP did not correlate significantly with the bone formative parameters but was correlated positively to PIIINP. The sensitivity of S-ICTP as a bone resorptive marker is thus questioned. In conclusion, a dose-dependent increase in markers of growth hormone metabolism and in biochemical markers of both bone and non-bone collagen synthesis was seen following incremental doses of GH in GHD.

Jens Bollerslev, Department of Medical Endocrinology, National University Hospital, N-0027 Oslo, Norway

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Per Olav Dale, Tom Tanbo, Ole Djøseland, Jak Jervell and Thomas Åbyholm

To investigate the effect of long-term androgen suppression on insulin sensitivity, obese and non-obese women with the polycystic ovary syndrome and obese and non-obese ovulatory women were given an oral glucose tolerance test before and after treatment with a gonadotropin-releasing hormone agonist. The women with polycystic ovary syndrome showed higher basal luteinizing hormone and androgen levels than the ovulatory women. All women with the polycystic ovary syndrome responded non-diabetically to the glucose tolerance test. However, compared with controls, the obese women with the polycystic ovary syndrome showed a hyperinsulinemic response to the glucose tolerance test, indicating insulin resistance. During the 3-h glucose tolerance test there was no concomitant change in androgen levels in the hyperinsulinemic women with the polycystic ovary syndrome. The insulin response to an oral glucose tolerance test remained unchanged in all women, although a hypogonadotropic hypogonadal state was maintained for several weeks. This study therefore suggests that endogenous androgens do not play a role in sustaining insulin resistance in women with the polycystic ovary syndrome.

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Anette Kvistborg, Johan Halse, Soren Bakke, Trine Bjøro, Egill Hansen, Ole Djøseland, Judith Brownell and Jak Jervell

The long-term efficacy and tolerability of CV 205-502, a non-ergot dopamine agonist with D-2 receptor affinity, were studied for up to 36 months in 16 patients with macroprolactinomas. Prolactin values were reduced in all cases, becoming either normalized or suppressed in 12. The pituitary tumor size was reduced in the 13 patients with an obvious tumor and visual function normalized in all six patients with initial defects. Concomitantly we observed improvement in gonadal function, galactorrhea, headache, libido and general well-being. Adverse reactions were experienced by 1 5 patients during dosage increment and caused one patient to discontinue the medication. Seven patients had persistent adverse effects which prohibited a dosage increase of CV 205-502, sufficient to normalize PRL levels in three. Two patients experienced serious adverse events, causing the discontinuation of treatment in one case. In eight patients treatment with CV 205-502 and bromocriptine could be compared. Three patients responded better to CV 205-502 than to bromocriptine treatment. Only one patient preferred bromocriptine to CV 205-502 for long-term treatment. We conclude that CV 205-502 is an effective and in most cases well-tolerated treatment for patients with macroprolactinomas. CV 205-502 is preferable to bromocriptine as an initial treatment and should also be tried in patients where treatment with bromocriptine has failed.

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Ole Djøseland, Nicholas Bruchovsky, Paul S. Rennie, Navdeep Otal and Sian Høglo

Abstract. The 5α-reductase activity was assayed in homogenates of stroma and epithelium in the rat ventral prostate and epididymis. Samples consisting of 0.3 mg/ml tissue protein in TES buffer, pH 7.0 were incubated at 37°C for 30 min in the presence of 50 nm [1,2-3H]testosterone and a NADPH-generating system started with 5 × 10−4 m NADP. The yield of 5α-reduced metabolites, as established by using thin-layer chromatography, gave an estimate of enzyme activity. Whereas the specific activity of 5α-reductase was highest in prostatic stroma and epididymal epithelium, most of the total enzyme activity was associated with the epithelium in both the prostate and epididymis. The effect of dihydrotestosterone on specific activity of 5α-reductase was studied by administering the hormone to 7-day castrated rats. In prostate, the specific activity of both stromal and epithelium forms of the enzyme reached a maximum after 4 days of treatment. In epididymis only the epithelial form of 5α-reductase underwent a major change in specific activity, the latter peaking after 8–12 days of treatment. Furthermore, while the total activity of 5α-reductase in the prostatic tissue fractions could be induced by as much as 4-fold the normal control values, the epididymal enzyme could not be induced above the normal level either in the stroma or the epithelium. This may explain the relative resistance of epididymis to abnormal growth stimulation under the influence of hormones.