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Combinations of 3 progestins, ethynodiol diacetate, norethynodrel and norgestrel, and 2 oestrogens, ethinyloestradiol and mestranol, were fed to larval Oregon-R fruit flies. None of the steroids studied induced X-linked recessive lethal mutations above the control level in Drosophila melanogaster.
This review summarizes some recent findings in human sperm which show that progesterone and 17 alpha hydroxyprogesterone are able rapidly (within seconds) to elevate [Ca2+]i and elicit the acrosome reaction (AR) via a non-genomic cell surface receptor. Progesterone promotes a transient elevation in [Ca2+]i which is blocked by extracellular La3+ and Ni2+ and removal of extracellular Ca2+ following chelation with EGTA. Some studies suggest that polyamines, trypsin-like proteases, and progesterone receptor aggregation are involved in progesterone-induced Ca2+ influx and AR. The receptor is not stimulated by the potent synthetic progestigins (e.g. promegestone, norethynodrel, megestrol acetate, cyproterone acetate) and is weakly antagonized by the genomic anti-progestins RU 486 and ZK 98.299. The sedative-hypnotic 3 alpha hydroxyl A-ring reduced pregnane steroids, which are powerful activators of the GABAA Cl- channel, are weak activators of Ca2+ influx and the AR. These data suggest that human sperm have a cell surface steroid receptor which is unlike the genomic progesterone receptor and the GABAA Cl- channel steroid receptor.
The intrinsic estrogenic activity of some progestins cannot be properly evaluated by using hormone responsive systems when the chosen end-points are also sensitive to progestagenic activity, usually antagonistic of estrogenic actions. We have therefore applied to the evaluation of some drugs commonly used in contraceptive and hormone replacement formulations a recently developed in vitro method to estimate estrogenic activities, which is based on measurements of the estrogen-stimulated alkaline phosphatase activity in cells of the Ishikawa-Var I human endometrial adenocarcinoma line, a response not influenced by progestins. Whereas progesterone, medroxyprogesterone acetate and danazol were found to be devoid of estrogenic activity in this assay, Org OD-14, norethynodrel, gestrinone (R 2323), norethindrone and dl-norgestrel provoked half maximal increases in alkaline phosphatase activity at concentrations (EC-50) of 7, 14, 140, 200 and 2900 nM, respectively, under conditions in which the corresponding value for estradiol was 8 pM. This intrinsic estrogenic activity can be inhibited by antiestrogens, as verified by reversing the effect of R 2323 with 4-hydroxytamoxifen. Since prostaglandin F2 alpha output by secretory endometrium is increased by estrogens and diminished by progestins, this end-point can serve to evaluate the net effect of drugs with intrinsic estrogenic and progestagenic activities. For instance, R 2323 showed estrogenic activity in this assay whereas Org OD-14 did not. The same in vitro system can be used to evaluate estrogen antagonistic activities of test compounds, using estradiol as the agonist. These in vitro systems are useful in establishing a profile of activities of a drug on a relevant human target tissue, in the screening of synthetic or natural compounds under investigation, and in studies on structure/action relationships.
In vitro conversion in human endometrial tissue of Org OD 14 [17 alpha-hydroxy-7 alpha-methyl-19-norpregn-5(10)-en-20-yn-3-one, a 3-keto-delta 5-10-19-nortestosterone derivative structurally related to norethynodrel] to its 4-ene isomer was demonstrated and measured spectrophotometrically and by chromatographic separation of the labeled metabolite from the tritiated precursor. The endometrial isomerase catalyzing this conversion is the 3 beta-hydroxy-steroid dehydrogenase/isomerase (3 beta HSD/isomerase), detected by Western blotting as a 42 kDa band, as confirmed by the inhibition of Org OD 14 isomerization with an antibody against this enzyme. The endometrial isomerase activity was found to be higher in secretory than in proliferative tissue and to be influenced by progestins, as suggested by the small but significant increase in activity resulting from exposure of proliferative endometrium to medroxyprogesterone acetate under organotypic culture conditions. In addition to the expected physiologic importance of endometrial 3 beta HSD/isomerase in the local metabolism of circulating steroids of adrenal origin, its presence in the endometrium is likely to have pharmacologic relevance, as illustrated by the local conversion of Org OD 14 to the 4-ene isomer, a metabolite with higher progestagenic and lower estrogenic potencies than those of its precursor. The local, tissue-specific, modification of the precursor would yield intracellular concentration ratios of Org OD 14 to 4-ene isomer in the endometrium significantly lower than those in blood. As a result, the estrogenic effects of Org OD 14 or of its 3-hydroxy metabolites on endometrial cell proliferation are minimized by the local formation of the progestagenic 4-ene isomer. This is a favorable feature of Org OD 14 since it selectively prevents undesirable proliferative stimulation of the endometrium in postmenopausal users while preserving its beneficial effects on other tissues, including bone.
Estrogen receptors of human endometrial cancer Ishikawa cells were found to be present in moderate amounts (160-200 fmol/mg protein), and to specifically bind moxestrol (R2858) with a very high affinity characterized by a Kd around 60 pM, when measured under equilibrium conditions. The binding specificity respected a decreasing order as follows: estradiol (E2: 100%) > 4-hydroxy-tamoxifen (4OHTAM: 52.7%) > estriol (E3: 5.7%) > estrone (E1: 2.1%) > TAM (0.2%). The induction of alkaline phosphatase activity (APase) used as an estrogen-specific response, confirmed the intrinsic estrogenicity of progestins derived from 19-nor-testosterone (19NT): norethindrone (NOR), norethynodrel and levonorgestrel, at concentrations ranging from 10(-8) to 10(-6) M. The effect of NOR was partially blocked by the antiestrogen 4OHTAM, which was also partially agonistic in this model, but neither by the antiprogestin mifepristone (RU486) nor by the aromatase inhibitor aminoglutethimide. A simulatory effect was also detected at 10(-7) or 10(-6) M with ethindrone, the testosterone- (T) derived progestin homologous to NOR, and with both androgenic parent-compounds, i.e. T and 19NT themselves. In contrast, progesterone (P) derivatives like medroxyprogesterone acetate (MPA) and chlormadinone acetate (CMA) remained totally inactive, as well as 19-nor-progesterone (19NP) itself or its progestagenic derivatives: ORG 2058 and nomegestrol acetate (NOM). Structure-activity relationships deduced from these studies suggest that it is not the absence of the 19-methyl group which can account for the estrogenic potential of the so-called "19-norprogestins", but rather their steroid structure derived from T in a broad sense (including the 19NT derivatives), as opposed to the non-estrogenic therapeutic progestins derived from P like MPA or CMA, or from 19NP like NOM.
Tibolone is used for the treatment of climacteric symptoms in postmenopausal women. It is metabolised in a tissue-specific manner so that while some metabolites exert estrogenic effects on bone and the CNS, others are thought to protect the breast and endometrium from estrogenic stimulation. Tibolone is a 7alpha-methyl derivative of 19-norethynodrel. Since the introduction of synthetic progestagens for therapeutic use there has been considerable controversy as to whether they can undergo aromatisation to give rise to the potent estrogen, ethinylestradiol. In this study, we examined whether the delta-4-ene (7alpha-methyl norethisterone) metabolite of tibolone, which has a similar delta-4-ene A-ring structure to that of the estrone precursor, androstenedione, could undergo aromatisation to the potent estrogen, 7alpha-methyl ethinylestradiol. For these studies, JEG-3 choriocarcinoma cells were employed as they have a very high level of aromatase activity. TLC and HPLC procedures were developed to separate phenolic from non-phenolic compounds and were initially used to confirm that JEG-3 cells readily aromatised androstenedione to estrogens (up to 74%). The aromatisation of androstenedione to estrogens by these cells could be completely blocked with the potent aromatase inhibitor letrozole. When [(3)H] 7alpha-methyl norethisterone was incubated with JEG-3 cells no evidence for its conversion to [(3)H] 7alpha-ethinylestradiol was obtained. Radioactivity detected on the TLC plate or HPLC fractions where standard 7alpha-methyl ethinylestradiol was located, revealed that similar levels were present when 7alpha-methyl norethisterone was incubated with culture medium alone or with JEG-3 cells in the absence or presence of letrozole. From these investigations, it is concluded that 7alpha-methyl norethisterone does not undergo aromatisation to an estrogenic derivative.
All steroid hormones are structurally similar, but relatively minor differences cause profound alterations in biochemical activity. The 21-carbon series (pregnane nucleus) includes the corticoids and the true progestins (e.g., medroxyprogesterone acetate). The 19-carbon series (androstane nucleus) includes all the androgens, among them the progestins used in most oral and parenteral contraceptives. The removal of carbon 19 from testosterone changes the major hormonal effect from androgenic to progestogenic, but these "19-nor" steroids retain varying degrees of androgenic activity. (They can also have limited estrogenic activity, but this is insignificant at the low doses used for contraception.) Some of the 19-nortestosterone progestins are metabolized to other compounds (e.g., norethynodrel, ethynodiol diacetate, and lynestrenol to norethindrone), and some (levonorgestrel, desogestrel) are active unchanged. The lingering androgenic effects of 19-nor progestins are dose-related, opposed by estrogen, and are manifested metabolically (e.g., glucose tolerance, lipoprotein synthesis) and symptomatically (e.g., acne, weight gain). The effect of 19-nortestosterones on lipoproteins prompted the development of less androgenic compounds, but the obvious benefit of the new progestins (desogestrel, gestodene, norgestimate) is a reduction in the symptoms associated with the androgenicity of the older compounds. Mitigation of androgenic effects on lipoprotein and carbohydrate metabolism could have long-term benefits, especially for women who are at risk of arteriosclerotic vascular disease; however, these effects remain to be epidemiologically demonstrated.
The binding of steroids to human ejaculated spermatozoa and the effect of steroids bound to spermatozoa on sperm migration and motility in vitro was examined. A correlation between progestogens that bind to steroid-binding sites on human spermatozoa and progestogens that inhibit sperm migration was established. The results indicated that there is a direct and specific steroid effect on human spermatozoa, as some steroids such as progesterone, lynestrenol, and norethynodrel markedly inhibited sperm migration and motility, whereas other steroids such as estrone had no detectable effect on sperm migration and motility. The significance of these findings was discussed in relation to the contraceptive action of steroids applied directly to the lumen of the female genital tract.
OBJECTIVES: Tibolone, a synthetic norethynodrel derivative, is effective at alleviating climacteric complaints and for osteoporosis prophylaxis. Concerning the cardiovascular system little data are available on possible direct effects on the vasculature compared with hormone replacement therapy. Since tibolone is pharmacologically best comparable to an estradiol/norethisterone combination (E2/NET), the aim of the present study was to compare these treatment regimens with respect to their effects on human vascular cells, this being the first study to investigate this question. - MATERIAL AND METHODS: Human female coronary arteries were used, the most appropriate vessels for our issue in question. The experiments were conducted with endothelial cells as well as smooth muscle cells. Tibolone and E2/NET were tested at the concentrations 0.1, 1 und 10 microM. Incubation time was 24 h for endothelial cell cultures and 7 days for smooth muscle cell cultures. The effects on markers of pathophysiologically different problems were studied in a comparable manner: Markers of endothelial function such as prostacyclin, endothelin and plasminogen-activator-inhibitor-1 (PAI-1), markers of plaque initiation such as the adhesion molecules E-Selectin, ICAM-1 and the monocyte attraction protein-1 (MCP-1) and markers of plaque stability such as the precursor of the matrix-metalloproteinase-1 (pro-MMP-1). - RESULTS: Tibolone reduced the synthesis of endothelin as well as the concentrations of E-Selectin, PAI-1 and pro-MMP-1. The magnitude of the effects on these markers varied and was in the range of 11-42 %. similar inhibitions were seen for E2/NET; yet a significantly stronger inhibitory effect was found for pro-MMP-1. Moreover, E2/NET also reduced concentrations of ICAM-1 and MCP-1. Concerning smooth muscle cells only E2/NET was able to elicit an anti-proliferative effect. - CONCLUSIONS: Tibolone can positively influence the synthesis of markers in cell cultures of human female coronary artery which modulate vascular tone and which play a decisive role in the various stages of atherosclerosis. In this respect estradiol combined with norethisterone is as potent as tibolone, in addition this combination is partially more effective and able to influence a wider range of markers which are important in the early stages of atherogenesis or for the stability of atherosclerotic plaques. Experimental studies such as the present one are useful to explore mechanisms, but clearly cannot replace clinical studies.
The effect of the widely employed oral contraceptive steroid, Enovid, on the cytolytic action of the staphylococcal alpha toxin was investigated as an extension of previous studies in which it was shown that steroids were capable of suppressing induced staphylococcal infection in experimental animals. The cytotoxic action of alpha toxin for tissue cultures was evaluated by use of such parameters as total and viable cell counts, glucose and protein determination, and cytopathic effects in the presence and absence of Enovid. To 3-day-old primary rabbit baby kidney tissue cultures a mixture of 20 mug of norethynodrel per ml [17alpha-ethynyl-hydroxy-5(10)-estren-3-one] and 5 mug of mestranol per ml (17-ethynelestradiol-3-methyl ether) was added; growth of tissue cultures in Eagle medium was continued till the sixth day, and then one tissue cytopathic dose of alpha toxin per ml was added and the subsequent fate of tissue cultures was assayed. Such cultures yielded higher total and viable cell counts, utilized more glucose, and contained more protein than the control cultures. In control cultures, cytopathogenicity appeared on the third day after the addition of alpha toxin, and it was complete in 24 hr, whereas in tissue cultures treated with Enovid cytopathogenicity was significantly reduced. Thus the mixture of synthetic hormones known as Enovid, in pharmacological concentrations, was found capable of reducing the cytopathic action of alpha toxin, but only to a slightly lesser degree than such natural hormone as progesterone.
The effect of three oestrogens (including an oestrogen-progestogen combination) on the postexercise electrocardiogram was studied in 33 men and 18 women who earlier had shown ST segment abnormalities after exercise. When pretreatment exercise tests were compared with tests after two weeks of treatment, the postexercise ST segments which were abnormal before treatment became even more abnormal in 18 (90%) of 20 subjects treated with conjugated oestrogens 10 mg daily, in 16 (89%) of 18 subjects treated with stilboestrol 5 mg daily, and in 12 (92%) of 13 subjects treated with norethynodrel (9-85 mg) and mestranol (0-15 mg)1 daily. The ST segment abnormalities reverted to pretreatment appearance within 6 weeks of stopping oestrogens. When 10 subjects with normal near-maximal exercise tests were treated for 2 weeks with conjugated oestrogens 10 mg daily, the tests remained unchanged in 9. The hypothesis favoured to explain these findings is that of an oestrogen-induced increase in coronary artery smooth muscle tone. An increase in arterial tone would also account for the increased incidence of myocardial (and cerebral) infarction that has been reported among individuals treated with oestrogen, either alone or in combination with progestogen.
Properties of progestin binding sites in adult male rabbit lung cytosol were analyzed using [3H] promegestone ([3H]R5020). At concentrations of 0.05-10 nM, [3H]R5020 bound to two saturable sites with differing affinities: a high affinity site (Kd = 0.34 nM, Bmax = 57 fmol/mg protein) and a moderate affinity site (Kd = 60 nM, Bmax = 540 fmol/mg protein). [3H]R5020 binding, under conditions selected to favor binding to the high affinity site, was reversible, protease-sensitive and inhibited in a concentration-dependent manner by steroids with the following order of potency: R5020 greater than norgestrel greater than norethindrone greater than progesterone greater than norethindrone acetate greater than norethynodrel greater than deoxycorticosterone greater than lynestrenol greater than quingestanol greater than testosterone greater than 17 beta-estradiol greater than cortisol. Upon sucrose density gradient ultracentrifugation analysis, a peak of [3H]R5020 binding activity was observed in the 6-7S region in the absence of KCl and in the 3-4S region in the presence of KCl. The progestin-binding activity of adult male rabbit lung cytosol thus possesses those characteristics conventionally accorded to a hormone receptor and suggests that lung tissue may be progesterone-responsive.
Using an equilibrium dialysis method, the competition was investigated between tritated-progesterone and a range of synthetic steroids for binding to 20,000 g. supernatants of human uterine endometrium and myometrium. Both types of uterine tissue showed similar patterns of progestogen binding and probably contain similar, or even identical, progesterone receptors. The gonane progestogen norgestrel binds strongly to the uterine receptors, but only the d-isomer is active. All three pregnane progestogens used in this study (chlormadinone acetate, medroxprogesterone acetate, megestrol acetate) also showed significant binding to receptors, but for the estrane progestogens, norethisterone was the only compound to show a high binding capacity. Other estranes (ethynodiol diacetate, lynestrenol, norethisterone acetate, norethynodrel) showed insignificant binding to the receptors and probably require prior metabolic activation to norethisterone before they can induce progestogenic effects.
Sex steroids are supposed to contribute to the normal glucose homeostasis and to the altered glucose and insulin metabolism in pregnancy and during contraception. In the present study isolated mouse pancreatic islets were maintained in tissue culture medium RPMI 1640 supplemented with 0.5% newborn calf serum and 100 ng/ml of one of the following steroids: oestradiol, progesterone, testosterone, megestrol acetate, medroxyprogesterone, chlormadinone acetate, norethynodrel, norethindrone acetate, and ethynyloestradiol. Release of insulin to the culture medium was measured during a 2 week culture period, and the islet content of insulin, glucagon, and DNA was measured at the end of the period. It was found that progesterone and its derivatives megestrol acetate, medroxyprogesterone, and chlormadinone caused a 2-fold increase in insulin release during the culture period. When islets cultured in the presence of oestradiol, progesterone, or testosterone were subjected to 30 min stimulation with 5.5, 11, 22 mmol/l glucose, only the progesterone-treated islets released more insulin in response to glucose than the control islets. It is concluded that progesterone and its derivatives have a direct effect on the glucose-stimulated insulin release probably by increasing the glucose sensitivity. The results suggest that the alterations in glucose and insulin metabolism in pregnancy and during treatment with certain oral contraceptives may in part be due to a direct effect of progestins on the beta-cell.
Villous tissue from 26 placentae of 7-17 weeks was incubated with radioactive pregnenolone alone and with pregnenolone in the presence of progesterone and 9 synthetic gestagenic steroids and the progesterone formation was measured after 30 min. When progesterone was present in a concentration of 31 or 310 mumol/1 the conversion rate of labelled pregnenolone to progesterone was reduced to 88.6 and 82.2% of that of the respective control incubations. Dydrogesterone, allyloestrenol, lynoestrenol and norethynodrel under similar conditions did not inhibit the formation of progesterone. The inhibitory effects of megoestrol acetate, medroxyprogesterone acetate and norgestrel were close to that of progesterone. Norethisterone and methyloestrenolone were the most effective inhibitors of progesterone formation: when incubated in an equimolar concentration (35 mumol/1) with pregnenolone (50 microgram) the progesterone formation was reduced to 60.0-62.7% and 29.1-34.0% respectively of that of the respective control experiments.
Contrary to previous thinking, the brain is now recognized as a plastic organ whose structure and function adapt to the functional demands of the sensory environment. This paper examines the interaction between sensory and nonsensory brain-modifying factors in determining the psychobiological outcome in animals reared under conditions of environmental complexity and deprivation. Stimulant drugs appear to enhance complexity effects and depressants to reduce them. Hormones affected by hypophysectomy or castration do not appear to interfere with sensory effects, though a progestogen norethynodrel does appear to interact with them. For genetic effects, strain, species and sex may interact, with male hybrids being perhaps most susceptible to environmental effects. The picture which is emerging is of the brain as inextricably linked to its environment and suggests that a full study demands a recognition of the ecological context. This picture of multiway inter-dependencetrain species and sex may interact, with male hybrids being perhaps most susceptible to environmental effects. The picture which is emerging is of the brain as inextricably linked to its environment and suggests that a full study demands a recognition of the ecological context. This picture of multiway inter-dependencetrain species and sex may interact, with male hybrids being perhaps most susceptible to environmental effects. The picture which is emerging is of the brain as inextricably linked to its environment and suggests that a full study demands a recognition of the ecological context. This picture of multiway inter-dependence and interdetermination or "omnideterminism" is similar to the holistic orgnaismic picture of the universe of the millenia-old yogi-consciousness disciplines and of modern physics.
We investigated the effects of sex steroids on silver-stained nucleolar organizer regions (Ag-NORs) and DNA/RNA kinetics in Ishikawa cells. Norethindrone and its isomer norethynodrel exclusively caused Ag-NORs to scatter in the nuclear matrix, from the nucleolus. No such effect occurred with the other sex steroids tested, including progestational, androgenic, and estrogenic compounds. Nuclear argyrophilic substances induced by norethindrone, as well as nucleolar ones, were neither DNA nor RNA but protein. Electron microscopy showed that norethindrone caused nucleolar segregation, in which the fibrillar components disappeared, and it produced islets, consisting of dense fibrillar materials, in the nucleoplasm. Ag-NORs observed on the fibrillar components in control nucleoli were translocated onto the dense fibrillar materials in the nucleoplasm. Although scattering was preferentially found in the cells synthesizing DNA, the scintillation assay of DNA/RNA kinetics suggested that scattering was related to the inhibition of RNA synthesis. These results imply that norethindrone preferentially interacts with intranucleolar DNA when its duplication is occurring and then interferes with rRNA synthesis. Scattering of Ag-NORs might not be caused by the hormonal activity of these agents but by a pharmacological effect derived from their molecular structures.
The first therapeutic trials to evaluate the treatment of climacteric symptoms by the administration of ovarian tissue were reported in 1896, i.e. before the endocrine function of the ovary was known or estrogens had been discovered. These were followed by investigations using various ovarian, placental and urine extracts, implantation of ovarian tissue and by oral treatment with dried ovarian tissue. However, reasonably acceptable hormonal drugs did not become available until the third decade of this century, while drugs meeting modern requirements, including that of oral activity, have been available only since the 1940s. It took at least 20 more years before publications for lay people and intensive endocrinological research convinced both the affected women and the medical profession of the value and even the necessity of hormonal treatment for ovarian-deficiency sequelae. Nowadays the treatment of climacteric and post-climacteric symptoms with estrogens and progestogens is a highly effective and indeed common practice. However, their use is of less value for the therapy of post-climacteric cardiovascular diseases and osteoporosis. As regards the latter, it may be said that androgenic-anabolic steroids and Org OD 14, a steroid related to norethynodrel, have usefully extended the available therapeutic armamentarium. Estrogens and progestogens are widely used for the prophylaxis of post-climacteric osteoporosis and cardiovascular diseases because their exceptional efficacy is well proven. Intensive research has resulted in the development of highly effective and virtually harmless hormonal drugs that are available in a great variety of formulations for all possible modes of administration.(ABSTRACT TRUNCATED AT 250 WORDS)