onapristone and Body-Weight

The antiprogestin mifepristone has been demonstrated to inhibit the growth of R3327HI rat prostatic carcinoma. A comparable antitumor effect of onapristone (ON) on rat Dunning tumors was found in our laboratories. We found the localization of progesterone (P4) receptors (PR) in prostate and prostatic tumors. These findings suggest the involvement of P4 in the mechanism of hormone-dependent growth of prostate and tumors. To study the influence of P4 on the growth of ventral (VP) and dorsolateral prostate (DLP), orchiectomized rats were treated (s.c.) daily with P4 (0.3, 1.0, 3.0 or 10.0 mg), dihydrotestosterone (DHT, 0.05 mg), estradiol (E2, 3.0 microg), ON (3.0 mg), ICI 182780 (1.0 mg) or flutamide (FL, 3.0 mg) for 12 days. One day after the last treatment, animals were sacrificed, and the organ weight of VP and DLP was determined. P4 increased the organ weight of VP and DLP in a dose-dependent manner. In contrast to DHT, which preferentially stimulated the growth of VP, P4 led rather to an increase in the weight of DLP. The effect of P4 on the DLP was enhanced by a simultaneous application of DHT or E2. The antiprogestin ON and the pure antiestrogen ICI 182780 had no appreciable effect on the P4-induced growth of VP and DLP. ON inhibited, however, the E2/P4-induced growth of DLP without affecting the growth of the VP. In contrast the antiandrogen FL suppressed the stimulatory effect of P4 on both the VP and DLP. These findings suggest that the stimulatory effect of P4 on the rat DLP may be partly due to androgenic products derived from P4 and may be also mediated by PR.

Topics: Androgens; Animals; Body Weight; Dihydrotestosterone; Dose-Response Relationship, Drug; Estradiol; Gonanes; Hormone Antagonists; Male; Orchiectomy; Organ Size; Progesterone; Prostate; Rats; Rats, Wistar; Receptors, Progesterone; Stimulation, Chemical

Treatment of lactating rats with the anti-progestin Mifepristone or Onapristone adversely affects growth of their litters. The present studies aimed to elucidate the underlying mechanism. The treatment did not interfere with the behavioural interactions between mothers and pups, which are required for normal litter growth. Treatment with the antagonists had a stimulatory action on ovarian oestrogen production. However, ovarian hormones did not play a role in litter growth impairment, as this also occurred with lactating ovariectomized rats. Treatment with anti-progestins did not affect the concentrations of the macronutrients in milk (protein, lactose and lipid), nor did it change the fatty acid composition of lipid. Reduced litter growth was not related to a possible direct effect of exposure of the suckling young to the drugs via the milk. Direct injections into them unequivocally affected adrenal gland and testicular development, but did not affect their body-weight development. Milk secretion, as measured by the milk weight accumulating during 6 or 24 h following sudden removal of litters in advanced lactation, was not impaired by the treatments. However, the ingestion of food and water by dams treated with Mifepristone was significantly below that of control animals. It is concluded that litter growth impairment during treatment of lactating rats with anti-progestin results from the reduction of the intake of food and water by the mother.

Topics: Animals; Animals, Newborn; Body Weight; Drinking; Eating; Female; Gonanes; Lactation; Male; Mifepristone; Milk; Ovariectomy; Pregnancy; Progesterone; Rats; Rats, Inbred Strains

Treatment of female rats for 3 weeks with the antigestagen 11 beta-(4-dimethylaminophenyl)-17 beta-hydroxy-17 alpha-(prop-1-ynyl)-estra- 4,9-dien-3-one (mifepristone) results in pituitary and ovarian enlargement. The present study dealt with the possible mechanism(s) of these responses. Ovarian enlargement appeared to be dependent upon prolactin. In the absence of prolactin, during combined treatment with mifepristone and the dopamine agonist 2-Br-alpha-ergokryptine, ovarian growth was significantly suppressed. It was unclear why persistent hyperprolactinaemia, due to treatment with mifepristone, resulted in persistence of functionally active corpora lutea despite intermittent ovulation, while persistent hyperprolactinaemia due to ectopic pituitary grafts did not. Pituitary enlargement appeared to be dependent upon the persistence of ovarian oestrogen secretion during the treatment period. Ovariectomy or lactation fully inhibited this response. Pituitary enlargement and prolactin secretion in ovariectomized rats in response to exogenous oestrogen (injections of oestradiol benzoate) were significantly enhanced by additional treatment with mifepristone. It is concluded that mifepristone facilitates the effect of oestrogen on pituitary lactotrophs, thereby enhancing pituitary growth. Ovarian enlargement during treatment with mifepristone may be specific for rats due to the luteotrophic action of prolactin in these animals. Pituitary enlargement due to facilitation of oestrogen-induced pituitary growth may become a focus of attention when this or similar antigestagenic drugs are being used for prolonged periods in clinical trials, e.g. for limiting steroid-sensitive tumour growth.

Topics: 20-alpha-Dihydroprogesterone; Adrenal Glands; Adrenocorticotropic Hormone; Animals; Body Weight; Bromocriptine; Delayed-Action Preparations; Female; Gonanes; Hypothalamo-Hypophyseal System; Mifepristone; Organ Size; Ovary; Pituitary Gland; Progesterone; Prolactin; Rats; Uterus