Dirami, Ghenima;
(1992)
Effects of a dopamine agonist (cu 32-085) on rat leydig cells: functional and morphological studies.
Doctoral thesis (Ph.D.), University College London.
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Abstract
The dopamine agonist, 8a-aminoergoline (CU 32-085) (DA) developed for use in the treatment of hyperprolactinaemia and Parkinson's disease induces Leydig cell tumours in rats treated for 21/2 years. The aim of the present study was to investigate the changes in Leydig cell function and growth at earlier stages of treatment with the DA which may contribute to the formation of the Leydig cell tumours. Sprague Dawley rats were treated with CU 32-085 (2mg/kg body weight/day) for 1, 5, 12 or 57 weeks. The Leydig cells from rats treated for 5 weeks produced lower levels of testosterone in response to luteinizing hormone (LH) compared with the controls. The defect in steroidogenesis was associated with a decrease in the numbers of LH receptors and cyclic AMP production, a lesion in steroidogenesis at the 17a-hydroxylase and 17-20 lyase, and an increase in aromatase activity. Histological examination of testis sections from controls and treated rats revealed the presence of atypical sites of Leydig cells surrounded by clusters of macrophages in the testes from the 57 but not the 5 week treated animals. There was 42% and 31% increase in the number of Leydig cells and macrophages respectively, compared with the controls. A method for separating Leydig cells from macrophages was developed and heterogeneity of the Leydig cells was demonstrated. Preliminary evidence indicates that CU 32-085 may selectively inhibit the function of the Leydig cells with lower sedimentation velocities. The effect(s) exerted by CU 32-085 on Leydig cells may result from the increase in circulating levels of LH, ACTH/ glucocorticoids and the decrease in prolactin. Evidence for this was obtained from in vivo studies with human chorionic gonadotrophin (hCG) and dexamethasone which showed an effect similar to that of CU 32-085. LH-stimulated testosterone production was inhibited in the hCG-treated rats and dexamethasone caused a further decrease. The development of Leydig cell tumours caused by treatment with CU 32-085 could be due to the changes in testicular levels of testosterone and oestradiol- 1713 which may result in changes in factors involved in the control of Leydig cell growth. It is concluded that the changes in the biochemical properties of the Leydig cells in vitro after treatment with CU 32-085 provide a sensitive system for detecting the early effects of this compound on Leydig cell function and growth.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D. |
| Title: | Effects of a dopamine agonist (cu 32-085) on rat leydig cells: functional and morphological studies. |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis Digitised by Proquest. |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10124295 |
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