cyproterone and Hyperplasia

Cell proliferation and cell death appear in several systems as mutually exclusive, which raises the assumption that a same factor or secondary signal(s) might exert opposite control on the two processes. To test this assumption we investigated the time-course evolution of the S phase and apoptotic indices in rat liver during cyproterone acetate (CPA) induced hyperplasia and during the recovery of normal liver mass provoked, respectively, by cyproterone acetate (CPA) treatment and withdrawal. The levels of c-myc and c-ras transcripts were also followed in view of the indications of a positive role of these oncogenes in proliferation. The data showed that proliferation and cell death are not always mutually exclusive and that a high rate of cell death was indifferently associated with high or low c-ras expression. Our data are consistent with a role of this gene in proliferation but exclude that it plays an opposite role in controlling cell death.

Topics: Animals; Cell Death; Cyproterone; Cyproterone Acetate; Female; Gene Expression; Genes, ras; Hyperplasia; Liver; Microscopy, Electron; Organ Size; Rats; Rats, Inbred Strains; S Phase

Experiments were designed to investigate the expression of three cell-cycle-dependent proto-oncogenes in response to two different types of proliferative stimuli: compensatory cell proliferation after partial hepatectomy (PH) or CCl4 and liver hyperplasia induced by the mitogens ethylene dibromide (EDB) and cyproterone acetate (CPA). Steady-state levels of messenger RNAs for c-fos and c-myc were found to be elevated after PH or CCl4 with a maximum increase between 0.5 and 2 h for c-fos and at 2-3 h for c-myc and a rapid decline after 3 h. However, when liver cell proliferation was induced by mitogens, no increase in the expression of c-fos mRNA was observed with both EDB or CPA during the first 24 h. In addition, elevated expression of c-myc was found only in liver hyperplasia induced by EDB, but not with CPA. While the expression of c-myc mRNA and c-fos mRNA was different in the two types of proliferative stimuli, that of c-Ha-ras and c-Ki-ras was similar in all the experimental groups. Cell proliferation monitored by means of incorporation of labelled thymidine into DNA or mitotic index at 24 h following PH, EDB and CPA occurred at a similar extent in all the experimental groups. Our data indicate that the transient and sequential expression of cell-cycle-related genes may vary in response to proliferative stimuli of different nature and suggest that increased expression of cell-cycle-related genes may not be a necessary prerequisite for the entry of the cells into the cell cycle.

Topics: Animals; Carbon Tetrachloride; Cell Division; Cyproterone; Cyproterone Acetate; Ethylene Dibromide; Gene Expression; Genes, ras; Hepatectomy; Hyperplasia; Kinetics; Liver; Male; Proto-Oncogenes; Rats; Rats, Inbred Strains; RNA, Messenger

Previous studies have shown that "xenobiotic" compounds such as the environmental pollutant alpha-hexachlorocyclohexane (alpha-HCH) and the synthetic sex steroid cyproterone acetate (CPA) induce growth of rat liver by hypertrophy and hyperplasia. After withdrawal of the growth stimuli, liver hypertrophy was usually found to be readily reversible. Conflicting observations were made concerning the fate of liver hyperplasia: hepatic hyperplasia persisted when induced by alpha-HCH but was found to be partially reversible when induced by CPA. The present study confirms the reversibility of hepatic hyperplasia induced by CPA in rats: about 30% of liver DNA present at maximal liver enlargement disappeared within 6 days after cessation of CPA treatment. Simultaneously, a dramatic increase in the rate of cell elimination by apoptosis was found. Glutamate-pyruvate transaminase and alkaline phosphatase in serum did not show major increases, suggesting that cell death was not due to lytic membrane damage. Furthermore, if treatment with CPA was continued or resumed, the enhanced DNA content persisted and the number of apoptotic bodies was greatly reduced. These observations suggest that the occurrence of cell death is due to withdrawal of the growth stimulus CPA. It may reflect a regulatory phenomenon serving to maintain homeostasis of cell number. Further studies showed that CPA is rapidly eliminated from rat liver and serum: t 1/2 in the liver is about 11 h. In contrast, alpha-HCH was previously found to be eliminated more slowly: t 1/2 approximately 144 h. The present study revealed that alpha-HCH, CPA and nafenopin lower the number of apoptotic bodies. This suggests that inducers of liver growth can inhibit hepatocellular death by apoptosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Cell Survival; Cyproterone; Cyproterone Acetate; DNA; Female; Hexachlorocyclohexane; Hyperplasia; Kinetics; Liver; Nafenopin; Rats; Rats, Inbred Strains

Hyperplasia of the rat liver can be induced by cyproterone acetate (CPA). The fate of this hyperplasia after cessation of CPA treatment has been studied and the following findings were obtained: Liver DNA content decreased by about 25% within a few days after CPA withdrawal. In histological sections some hepatocytes showed degenerative changes. Among these, small membrane bounded bodies ("apoptotic bodies"; ABs) with or without chromatin were most numerous. Their incidence coincided with the phase of DNA elimination. Inflammatory reactions were not observed. Their small size and occurrence in clusters suggests that many of these ABs are formed by fragmentation of dying hepatocytes. Liver DNA was prelabelled with 3H-thymidine. Autoradiographic evaluation showed that many hepatocytes contained labelled nuclei, but unlabelled ABs. This finding strongly suggests that ABs, after the fragmentation stage, can be phagocytized by intact hepatocytes. About 80% of all ABs were found within hepatocytes. Extracellular ABs (early stage) contained no or very few active lysosomes. Intracellular ABs were sometimes surrounded by lysosomes, while others were in various stages of digestion. These observations suggest that the lysosomes of the phagocytizing hepatocytes degrade intracellular ABs, whereas intraapoptotic lysosomes seem to be inactive until the late stages of this degradation. Hepatocytes that did not replicate during CPA-induced liver growth appear to die off preferentially after CPA withdrawal. Retreatment with CPA greatly reduced the number of ABs within 4 h. Phenobarbital, another stimulus of liver growth, had the same effect. These findings suggest that the present type of cell death can be inhibited by growth stimuli and is therefore a controlled event serving to eliminate an excess of cells, rather than a manifestation of toxic injury to hepatocytes. The findings also suggest that this type of cell death and elimination is a rapid process completed within a few hours. It is concluded that cell death under the present experimental conditions probably occurs through apoptosis.

Topics: Animals; Cell Survival; Cyproterone; Cyproterone Acetate; Deoxyribonucleases; DNA; Female; Hyperplasia; Liver; Lysosomes; Necrosis; Phagocytosis; Phenobarbital; Rats; Rats, Inbred Strains; Ribonucleases

Treatment of female Wistar rats with cyproterone acetate (CPA) leads to considerable enlargement of the liver. The organ content of water, dry mass, protein, RNA, and DNA increased in parallel with the enlargement; only lipid accumulation showed a slight excess. The changes were maximal after treatment for 3 days and increased in a dose-dependent manner, the threshold dose being 5--10 mg CPA/kg DNA synthesis was strongly enhanced after a lag phase of 12--14 h; a maximal rate of synthesis was attained after 18--24 h. The number of parenchymal cells involved in DNA synthesis and mitosis were increased up to 20-fold. Sinusoidal cells participated only slightly in the growth process, and their number decreased relative to the number of parenchymal cells. These results indicate that CPA induces (presumably adaptive) liver growth essentially by parenchymal hyperplasia; of the model inducers used for comparison only pregenolone-16 alpha-carbonitrile (PCN) produced a similarly strong hyperplastic response while liver enlargement elicited by a alpha-hexachlorocyclohexane (alpha-HCH), phenobarbital (PB) and 3-methylcholanthrene (3-MC) was partly or exclusively due to hypertrophy. Liver growth was also observed in male rats treated with CPA, but was less pronounced in this sex. After discontinuation of treatment, liver enlargement and the increase of DNA regressed partially within 1--3 weeks; this regression seemed to be due to sequestration of old cells which were not involved in replication after CPA treatment. The relationship between induction of liver growth by CPA and hepatoma formation in rats is discussed.

Topics: Adaptation, Physiological; Animals; Cyproterone; DNA; Female; Hyperplasia; Liver; Organ Size; Rats; Time Factors

Effects of cyproterone acetate, a synthetic steroidal compound, on the reproductive organs of female rats have been investigated. This agent caused reduction of ovarian weights indicative of suppression of pituitary gonadotrophins. Oestrogenic nature of cyproterone acetate was investigated in intact and ovariectomized rats taking uterine weight and vaginal keratinization as an index of oestrogenicity. Cyproterone acetate in ovariectomized animals induced vaginal keratinization and increased the uterine weights. These effects were parallel to the effect of oestradiol dipropionate in ovariectomized animals, thus indicating oestrogenic activity of cyproterone acetate. We may conclude that the above compound caused antifertility effects due to its oestrogenic nature at the dose level of 2 mg/alternate day in rats when the compound was administered subcutaneously.

Topics: Animals; Atrophy; Body Weight; Castration; Cyproterone; Estradiol; Female; Fertility; Genitalia, Female; Hyperplasia; Hypertrophy; Keratins; Organ Size; Ovary; Rats; Reproduction; Uterus; Vagina

Widespread use of the Beagle dog for long-term toxicity studies of hormonal contraceptives including progestagens-only, have resulted in proliferative mammary gland changes. The "tumorigenic potency" of progestagens in the dog has been related to an interaction between progestagens and prolactin (PRL) or growth hormone (GH) secretion. We therefore investigated the effect of a hydroxy-progesterone type progestagen (cyproterone acetate, CPA) and a nortestosterone type progestagen (norethisterone oenanthate) on serum PRL and GH concentrations. Furthermore, the effect of CPA on the GH and PRL producing cells of the anterior pituitary was examined immunoenzyme-cytochemically. Regardless of the structural type of the progestagens tested and the presence of mammary gland enlargement, serum PRL and GH levels were not clearly enhanced. Similarly, the immunoenzyme-cytochemical investigations of the anterior pituitary gland after treatment with CPA showed the PRL cells to be unaffected. In contrast, the GH producing cells exhibited obvious morphological signs of increased secretory activity even before related changes in serum GH concentrations became detectable.

Topics: Animals; Carcinogens; Cyproterone; Dogs; Female; Growth Hormone; Hyperplasia; Mammary Glands, Animal; Norethindrone; Prolactin; Radioimmunoassay

Topics: Animals; Carrier Proteins; Castration; Cell Nucleus; Centrifugation, Density Gradient; Chromatography, Gel; Chromatography, Thin Layer; Cyproterone; Cytoplasm; Dihydrotestosterone; Epididymis; Humans; Hyperplasia; Male; Methyltestosterone; Norsteroids; Prostate; Prostatic Diseases; Protein Binding; Rats; Receptors, Cell Surface; Testis; Testosterone; Tritium