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Biological Activity and Steroid Receptor Interactions of Pituitary Gland And

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Biological Activity and Steroid Receptor Interactions of Pituitary Gland And Biological activity and steroid receptor interactions of cyclofenil with the oestrogen target tissues of the brain, pituitary gland and uterus of the rat S. P. Bowman, A. Leaket and I. D. Morris Department ofPharmacology, Materia Medica & Therapeutics, Stopjord Building, Manchester University, Oxford Road, Manchester Ml3 9PT, U.K. Summary. In vitro cyclofenil [bis-(p-acetoxyphenyl)-cyclo-hexylidene methane] competitively inhibited the binding of [3H]oestradiol-17\g=b\to the uterine cytoplasmic receptor (Kdi = 9\m=.\41nmol/l). By 24 h after cyclofenil treatment of ovariectomized rats, cytoplasmic oestrogen receptors were altered, in a similar manner, in brain, pituitary gland and uterus. The lowest dose depleted the receptor concentration which was re-established at the intermediate dose and depleted again after the highest dose. Nuclear oestrogen receptors measured in the uterus were raised only after the highest dose of cyclofenil. Uterine cytoplasmic progesterone receptors were increased after cyclofenil, the concentration of progesterone receptor after the high dose of cyclofenil being greater than after a large dose of oestradiol-17\g=b\or oestradiol-17\g=b\benzoate. Cyclofenil was uterotrophic; the increase in uterine weight was apparently dose-related and at 24 and 48 h the increase was greater or similar to the increases produced by oestradiol-17\g=b\or oestradiol-17\g=b\benzoate. Accumulation of uterine luminal fluid was also observed but oestradiol-17\g=b\benzoate was more active in this respect. Cyclofenil antagonized all the uterine effects of oestradiol-17\g=b\ benzoate in the immature female rat but only the changes in uterine luminal fluid in the adult ovariectomized rat. Cyclofenil decreased serum LH and increased serum FSH concentrations, effects similar to those of oestrogen except when administered as three daily doses when, unlike oestrogen, no changes in FSH were observed. Antagonism of the activity of oestrogen upon the serum gonadotrophins was not seen. Serum prolactin concentrations were increased 24 h after 0\m=.\5and 50 mg cyclofenil/kg but not after 10 mg/kg. Cyclofenil was not active in inducing sexual receptivity in ovariectomized adult rats unless previously treated with progesterone when a high level of activity was observed. The results show that the cyclofenil molecule possesses high oestrogenicity which is probably mediated via the oestrogen receptor system. This would suggest that the mechanism by which cyclofenil induces ovulation is most probably related to its oestrogenicity rather than its antioestrogenicity. * Present address: Clinical Research Laboratory, Christie Hospital & Holt Radium Institute, Wilmslow Road, Manchester M20 9BX, U.K. t Present address: Department of Surgery, Medical School, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, U.K. 0022-4251/82/040355-12S02.00/0 © 1982 Journals of Reproduction & Fertility Ltd Downloaded from Bioscientifica.com at 09/27/2021 08:32:47PM via free access Introduction Cyclofenil [bis-(/?-acetoxyphenyl)-cyclo-hexlidine methane] has been extensively employed to induce ovulation in women in whom there is a functional disturbance of the hypothalamic- pituitary axis (Berger, 1972; Elmendorff & Kammerling, 1977). Ovulation may also be induced by clomiphene and tamoxifen and the pregnancy rates that have resulted from the three drugs are similar, which suggests that they have a common mode of action (MacGregor, Johnson & Bunde, 1968; Elmendorff & Kammerling, 1977). Clomiphene and tamoxifen have been shown to antagonize oestrogen by interacting with the oestrogen receptor system of the target cells. The oestrogen antagonists combine with the cytoplasmic receptor protein and the complex is trans¬ located to the nucleus; however, the nuclear 'complex' is inactive and unable to induce the oestro- genic response. Part of this response is the resynthesis of cytoplasmic receptor, and the inhibition of this response, combined with the long plasma half lives of these drugs, produces low levels of cytoplasmic receptor and the tissue becomes refractory to oestrogen (Clark & Peck, 1979; Furr, Patterson, Richardson, Slater & Wakeling, 1979; Katzenellenbogen et al, 1980). Cyclofenil is often grouped with the triarylethylene derivatives such as clomiphene and tamoxifen as an oestrogen antagonist and the basic mechanism by which these drugs are believed to induce ovulation is through oestrogen antagonism at the receptors of the hypothalamus and pituitary (Bishop, 1970; Lunan & Klopper, 1975; Furr et al. 1979; Leclercq & Heuson, 1979). However, it is possible that the mode of action of cyclofenil differs, because cyclofenil is administered continuously, while a short course of therapy is recommended for clomiphene and tamoxifen. In women the agonistic activity of clomiphene and tamoxifen is rarely seen and clomiphene produces a thick, scanty cervical mucus; in contrast, cyclofenil would appear to act as an agonist upon the cervix, producing mucus that is thin and copious (Sato, Ibuko, Hirondo, Igarashi & Matsumoto, 1969; Murray & Osmond-Clarke, 1971). The biological properties of cyclofenil do not appear to be well defined in the literature. Cyclofenil is both oestrogenic and antioestrogenic. In rodents, cyclofenil is uterotrophic and will inhibit gonadotrophin secretion, as indicated by atrophy of the gonads of either sex (Einer-Jensen, 1968; Carlborg, 1970). Einer-Jensen (1968) reported that cyclofenil would not produce the same maximum uterine weight as oestradiol benzoate, which suggests that the cyclofenil was a partial oestrogen agonist. Antiuterotrophic activity was demonstrated by Watnick & Neri (1968). Devleeschouwer, Leclercq, Danguy & Heuson (1978) described the ability of cyclofenil, as an antioestrogen, to produce mammary tumour regression in the rat, although oestrogens and antioestrogens can cause tumour regression. As part of a study designed to investigate the mechanism by which the oestrogen antagonists induce ovulation, the receptor interactions and the biological activity of tamoxifen, clomiphene and cyclofenil are being compared. Clomiphene and tamoxifen interact with the cytoplasmic oestrogen receptor of the brain and pituitary gland, but in vivo larger doses are required to affect the hypothalamic oestrogen receptors, access of the drug being prevented by the blood-brain barrier (Ginsburg, MacLusky. Morris & Thomas, 1977; Kurl & Morris, 1978). This paper describes experiments which were performed to see whether the oestrogen antagonist cyclofenil could be shown to interact with the oestrogen receptor system of the brain and pituitary, as well as the uterus, and whether exclusion of the drug from the brain is associated with all the ovulation-inducing antioestrogens. In addition, experiments were conducted to help define the biological activity of cyclofenil so that a comparison could be made with the more extensively investigated triarylethylene oestrogen antagonists. Materials and Methods Female Sprague-Dawley rats bred in the Medical School were used. Immature rats were 25 days old (approximately 60 g) and were used without further treatment. Adult female rats Downloaded from Bioscientifica.com at 09/27/2021 08:32:47PM via free access (approximately 290 g) were bilaterally ovariectomized and used 2 or 3 weeks later. The rats were kept under standard animal house conditions (lights on 05 :00-19 :00 h) and allowed food and water ad libitum. At the appropriate time cyclofenil (0-5-50 mg/kg; Roussel, Wembley Park, U.K. or Ferrosan, Malmo, Sweden), oestradiol-17ß (72 µg/kg; Sigma, Poole, Dorset, U.K.)or oestradiol- 17ß benzoate (100 µg/kg; Sigma) was administered after solution or suspension in warm arachis oil. Control animals received arachis oil only (1 ml/kg s.c). Cyclofenil was administered intra- peritoneally while oestradiol-17ß and oestradiol-17ß benzoate were administered subcutane- ously. The dose of oestradiol benzoate was adjusted so that the mass of oestradiol-17ß admin¬ istered to the rats was identical in each oestrogen treatment. Animals were killed by stunning and decapitation. Serum was prepared and then stored at 15°C until required for the assay of gonadotrophins. The uterine horns were ligated at both — ends in situ, dissected out and weighed. The amount of uterine luminal fluid was determined by the difference in weights after cutting the uterine horns, blotting the tissue dry and reweighing. The hypothalamus, pituitary gland and amygdala were dissected out as described previously (Ginsburg, Greenstein, MacLusky, Morris & Thomas, 1974), and weighed, and subcellular fractionation of the 4 tissues was carried out as described below. Cytoplasmic oestrogen receptor assay Homogenization, cytosol preparation and the determination of the number of oestrogen receptors and their affinity for oestradiol-17 ß was carried out as described by Ginsburg et al. (1974). Briefly, the tissues were homogenized in 0-01 M-phosphate buffer, pH 7-4, containing 0-1 M-2-mercaptoethanol and 0-25 M-sucrose. Homogenates were centrifuged at 105 000 g for 1 h at 4°C. Aliquots of the cytosol fraction were incubated at 30°C to equilibrium with 4 10~9- 2 10~10 M-[3H]oestradiol-17ß (sp. act. 90 Ci/mmol; The Radiochemical Centre, Amersham, Bucks, U.K.) with or without a 100-fold excess of diethylstilboestrol. When appropriate, non-radioactive compounds dissolved in absolute ethanol were added to the incubate (final concentration 3% v/v). After incubation, bound and free oestradiol were separated by the use of small columns of Sephadex LH-20 maintained
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