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PubMed1977

Investigation of the liver glycogen level in rats treated with anticonceptives.

The results of our experiments with carbohydrate metabolism confirmed that 1. the gestagen component of norethynodrel (Infecundin) causes a more explicit increase of the liver glycogen level than that of ethynodioldiacetate (Bisecurin); 2. among oestrogens mestranol (Infecundin) gives a higher glycogen production in the liver than ethinyloestradiol (Bisecurin); 3. the greatest increase of liver glycogen level is in the course of the acute (14 days') treatment period; 4. the active substances of Infecundin (first of all mestranol) produce a longer lasting effect on the quantity of liver glycogen than those of Bisecurin; 5. to this action of the drug molecules of both anticonceptives (Infecundin, Bisecurin) there is a tendency to habituation. After a treatment lasting 48 days, the liver glycogen level in comparison with the control did but slightly increase; 6. evaluable changes occur sooner in the glycogen level of rats treated with hormonal contraceptives prior to the generally used so-called liver function test becoming positive.

Animals↗
PubMed1980

Plasma lipid levels and systolic blood pressure in ovariectomized and intact rats treated with contraceptive and other sex steroids.

Ovariectomized rats were treated for three weeks with cottonseed oil, estraiol, progesterone, mestranol-norethynodrel, or testosterone, and intact female rats were treated with cottonseed oil, or testosterone. Plasma total cholesterol, plasma triglycerides, and systolic blood pressure were then measured. Estradiol administration resulted in an increase in plasma cholesterol and triglycerides. Administration of testosterone to intact rats produced a decrease in cholesterol. Rats administered estradiol had significantly higher systolic blood pressure than any other group except the contraceptive treated group. By use of the ovariectomized rat model, the individual effects of sex hormones are delineated and it is demonstrated that estrogen has more effect than progestogen on both plasma lipids and systolic blood pressure.

Animals↗
PubMed1998

Progestin regulation of vascular endothelial growth factor in human breast cancer cells.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor associated with the degree of vascularity, progression, and metastasis of breast cancer, and cases of this disease with increased vascular density have a poor prognosis. We show that in T47-D human breast cancer cells, progesterone induces a dose-dependent increase of 3-4-fold in media VEGF levels, with a maximum response occurring at a concentration of 10 nM. This effect is blocked by the antiprogestin RU 486. In addition to progesterone, a number of synthetic progestins used in oral contraceptives (e.g., norethindrone, norgestrel, and norethynodrel), hormone replacement therapy (medroxyprogesterone acetate), and high-dose progestin treatment of breast cancer (megestrol acetate) also increase VEGF in the media of cultured T47-D cells. This effect is hormone specific and is not produced by estrogens, androgens, or glucocorticoids. Collectively, these observations suggest that the increase in VEGF caused by progestins is mediated by progesterone receptors present in T47-D cells. The induction of VEGF by progestins is also cell type specific and does not occur in human breast cancer cell lines MCF-7, ZR-75, or MDA-MB-231, nor in Ishikawa cells derived from a human endometrial carcinoma. This is the first report that progestins regulate VEGF expression in human breast cancer cells and raises the possibility that increased angiogenesis in response to endogenous progesterone or its therapeutically used analogues may play a role in cell growth or metastasis in a subset of human breast tumors.

Breast Neoplasms↗
PubMed1993

The estrogenic activity of synthetic progestins used in oral contraceptives.

BACKGROUND: Oral contraceptives (OC) contain an orally active estrogen in combination with an orally active synthetic progestin derived from 19-nortestosterone. OC have had an enormous positive impact on public health for the past three decades, and in the main, there has been a remarkably low incidence of troublesome side effects. Although estrogens are implicated in an increased incidence of breast and endometrial cancer, epidemiologic studies have not provided convincing evidence to support a direct correlation between OC use and an increase in breast cancer incidence. By contrast, OC do cause a decrease in the incidence of endometrial and ovarian carcinoma. During the past decade, several isolated reports have linked an increased incidence of breast cancer with the use of synthetic progestins. No mechanism for the proliferative potential of progestins has been offered. Therefore, the authors investigated this problem to formulate a hypothesis, based on laboratory data, that might be evaluated in populations at risk. METHODS: The synthetic progestins (19-nortestosterone derivatives) chosen for the study were norethynodrel, norethindrone, norgestrel (levonorgestrel), and gestodene. These were compared with the actions of medroxyprogesterone acetate (MPA). To determine whether the progestins produced their effects via the ER, the cells were transfected with a chloramphenicol acetyl transferase (CAT) reporter gene containing an estrogen response element only activated by ER. RESULTS: The 19-nortestosterone derivatives all stimulated the growth of estrogen receptor (ER)-positive but not ER-negative breast cancer cells in culture. Antiestrogens, but not the antiprogestin mifepristone (also known as RU 486), inhibited progestin-stimulated cell proliferation. MPA did not stimulate cell proliferation. All the synthetic progestins that increased replication also activated CAT. Activation was blocked by antiestrogens but not by mifepristone; the synthetic progestin MPA was inactive. CONCLUSIONS: These studies provided direct evidence that some synthetic progestins exert estrogenic effects through the ER. The results demonstrated that progestins can have a dual effect on estrogen target tissues either to stimulate or differentiate cells. The results suggest that some beneficial estrogen-like effects could be produced by synthetic progestins (e.g., bone preservation), but epidemiologic studies of OC use should focus of the "total estrogen" content to establish whether some formulations place some groups of women at greater risk of having breast cancer.

Breast Neoplasms↗
PubMed1993

Studies for a genotoxic potential of some endogenous and exogenous sex steroids. I. Communication: examination for the induction of gene mutations using the Ames Salmonella/microsome test and the HGPRT test in V79 cells.

The mutagenicity results and data of nine progestins (cyproterone acetate, dehydrospirorenone, gestodene, gestonorone caproate, levonorgestrel, norethisterone, norethisterone acetate, norethisterone enanthate, norethynodrel), one hypothetical metabolite (6,7-epoxy-cyproterone acetate), four estrogens (estradiol, ethinylestradiol, cyclodiol, cyclotriol), and four other sex steroids (atamestane, lilopristone, onapristone, propylmesterolone) are reported. All 17 sex steroids were investigated using the Ames salmonella/microsome direct plate incorporation protocol, and seven were additionally tested using the preincubation modification. Seven sex steroids were also studied in the HG-PRT test with V79 cells for the induction of gene mutations in mammalian cells. The metabolite was examined in the Ames salmonella/microsome assay using the standard protocol and the preincubation modification. In all assays the test compounds were investigated up to concentration levels where cytotoxicity and/or visible precipitation occurred or at least the solubility limit of the test compound was reached. For all assays, evaluation of the data indicates that neither any of the sex steroids nor the hypothetical metabolite was able to induce gene mutations whether in the absence or the presence of an extrinsic metabolizing system (S9 mix).

Animals↗
PubMed1996

Differential effects of progestins and estrogens on long control regions of human papillomavirus types 16 and 18.

We have studied effects of a series of progestins and estrogens on regulation of human papillomavirus (HPV) types 16 and 18 gene expression via long control region (LCR), using a transient expression assay which represented the episomal state of HPVs in precancerous lesions. Results showed that HPV gene expression induced by these steroid analogs were diverse. Gene expression via HPV16-LCR was upregulated 2-3 fold under treatment with 10(-7) M estriol, 17 beta-estradiol, and several progestins including pregnenolone, 17 alpha-hydroxy-progesterone, norethynodrel and cyproterone acetate. However, transcription via HPV18-LCR was not or weakly stimulated by these analogs. Our results can divide these analogs into HPV-enhancing and HPV-nonenhancing groups and accordingly impact the relative risk of individual oral contraceptive ingredient in cervical carcinogenesis.

Base Sequence↗
PubMed1997

Progesterone in Periplaneta americana and Neobellieria bullata adults from the procuticle phase until first progeny production.

A significant amount of progesterone-like immunoreactive material (150 ng/g) was measured by EIA in the procuticle phase of adult of both sexes of Periplaneta americana. This peak markedly decreased to 1-10 ng/g during sclerotization and was unlikely to be of dietary origin. In the case of 0-hr-old P. americana adults 96-98% of progesterone-like material was localized in the digestive tract and Malpighian tubules. In contrast, a relatively low level of progesterone-like immunoreactive material was measured in 0-hr-old Neobellieria bullata adults. Activity of 3beta-HSD/isomerase converting pregnenolone to progesterone was high (22-43 fmol/mg protein/20 min) in 0-hr-old P. americana adults and significantly fell during sclerotization. High progesterone levels (13-16 ng/g), measured by HPLC-RIA, coexist with high levels of 3beta-HSD/isomerase activity. Orally active human contraceptives (ethisterone, ethynodiol, ethynodiol diacetate, lynestrenol, mestranol, norgestrel, norethynodrel, tamoxifen citrate, and mifepristone) which act on mammalian steroid receptors had no significant effects on progeny production in either polytrophic or meroistic insect ovaries even at concentration of 5000 mg/kg.

3-Hydroxysteroid Dehydrogenases↗
PubMed1986

Studies of the inactivation of human placental aromatase by 17 alpha-ethynyl-substituted 10 beta-hydroperoxy and related 19-nor steroids.

The inactivation of human placental aromatase by 17 alpha-ethynyl-10 beta-hydroperoxy-17 beta-hydroxy-4-estren-3-one (SCH 10015) was investigated. In either the presence or absence of added NADPH, SCH 10015 (Ki = 41 microM) caused a time-dependent loss of aromatase activity (e.g. 50% loss after 20 min with 20 microM SCH 10015). Evidence for the oxidation of an active site sulfhydryl group as the molecular basis for SCH 10015 inactivation is presented. The contraceptive 17 alpha-ethynyl-substituted 19-nor steroids, norethisterone (Ki = 48 microM) and norethynodrel (Ki = 38 microM), were evaluated and found not to inactivate aromatase, suggesting that the potential conversion of either compound to SCH 10015 did not occur to a significant extent in these microsomal incubations. It is speculated that the previously observed potent contraceptive effects of SCH 10015 may have been the result of irreversible inhibition of estrogen biosynthesis.

Aromatase Inhibitors↗
PubMed1976

Interactions of various 19-nor steroids with human placental microsomal cytochrome P-450 (P-450hpm).

Each of seven 19-nor steroids exhibited the capacity to facilitate the binding of carbon monoxide (CO) to human placental microsomal cytochrome P-450 although quantitative differences were shown to exist. In every case the facilitation was antagonized by androstenedione. 19-Norandrostenedione produced the most pronounced effect followed by 19-nortestosterone, nandrolone decanoate, norethandrolone, norgestrel, norethynodrel and norethindrone in that order. All steroids investigated produced typical type I binding spectra when added to placental microsomes. Scatched plots also indicated binding of each steroid to two sites--a high-affinity, low-capacity binding site and a low-affinity, high-capacity binding site. Correlations between affinity for either site and capacity to facilitate binding of CO to the cytochrome were not observed nor were there good correlations between maximal absorbance differences (approximately390-420 nm) producible and facilitation capacity. It was therefore concluded that no definitive relationships existed between facilitation capacity and qualitative or quantitative aspects of the steroid-binding spectra. The capacity to facilitate CO binding appeared to reside in the absence of a chemical group substituted at the 10 position on molecules of androgenic steroids since all investigated steroids possessing 10-methyl or other 10-substituted groups either had no effect on the CO-binding spectrum or caused a displacement of CO from ferrous heme. In contrast, all steroids studied that lacked a substitution at C-10 (19-nor steroids) produced a facilitating effect on heme-ligand binding.

Androstenedione↗
PubMed1980

Cytotoxic effects of norethindrone-4 beta,5 beta-epoxide to Walker cells in culture and to rat liver in vivo.

1. Norethindrone-4 beta,5 beta-epoxide was toxic to Walker cells in culture. The concentration required to produce a 50% reduction in the increase in cell numbers 72 h after exposure (ID50) was 0.05 mM. In this assay, the parent contraceptive steroid, norethindrone, was at least four times less toxic than the epoxide. 2. Norethandrolone-4 beta,5 beta-epoxide and norethynodrel-5 beta,10 beta-epoxide were as toxic as norethindrone epoxide to the Walker cells. 3. The cytotoxicity of norethindrome epoxide was dependent on the time of exposure of the cells to this compound if excess unreacted epoxide was removed by washing the cells with cysteine. The results are consistant with norethindrone epoxide causing cell death by reacting with sulphydryl groups of cellular proteins. 4. No metabolites toxic to Walker cells could be detected when the cells were incubated with norethindrone, rat liver microsomes and a NADPH generating system. 5. Cells treated with an ID50 of norethindrone epoxide for 1 h showed marked cytoplasmic vacuolation 3 hr after exposure. This vacuolation was much less marked in cells treated with an ID50 of norethindrone or in the controls. Neither group showed any nuclear abnormalities. 6. Norethindrone epoxide when given to rats in large doses (50 mg/kg) by lateral tail vein injection also caused cytoplasmic vacuolar degeneration of the liver hepatocytes, especially in the perilobular areas 3 days after dosing. When this compound was administered at a similar dose level via the hepatic portal vein massive haemorrhagic necrosis of the liver resulted. No damage to either lungs or kidneys was evident, irrespective of the route of administration.

Animals↗
PubMed1981

Effects of steroids on the in vitro forward migration of human spermatozoa.

The effects of 14 steroids at concentrations between 0.1 and 10 micrograms/ml on human spermatozoal forward migration in vitro were tested. Oestradiol-17 beta at a concentration of 0.1 microgram/ml significantly activated spermatozoal forward migration in ejaculated human semen. However, the effect of oestradiol-17 beta at concentrations of 2 and 10 micrograms/ml on ejaculated human sperm motility was not significantly different from the control where no steroid was added. Progesterone, testosterone, oestriol, oestrone, oestradiol-17d, and ethinyl oestradiol significantly inhibited human spermatozoal forward migration at concentrations of 10 micrograms/ml. Chlormadinone acetate and medroxyprogesterone acetate at concentrations of 2 and 10 micrograms/ml significantly inhibited human spermatozoal forward migration, while norethynodrel, ethynodiol diacetate, norgestrel and lynoestrenol significantly inhibited human spermatozoal forward migration at concentrations between 0.1 and 10 micrograms/ml. However, norethindrone had no demonstrable effect on human spermatozoal forward migration at the above concentrations.

Dose-Response Relationship, Drug↗
PubMed1990

Metabolism of levonorgestrel, norethindrone, and structurally related contraceptive steroids.

There is limited information on the metabolism of levonorgestrel, norethindrone and structurally related contraceptive steroids. Both levonorgestrel and norethindrone undergo extensive reduction of the alpha, beta-unsaturated ketone in ring A. Levonorgestrel also undergoes hydroxylation at carbons 2 and 16. The metabolites of both compounds circulate predominantly as sulfates. In urine, levonorgestrel metabolites are found primarily in the glucuronide form, whereas norethindrone metabolites are present in approximately equal amounts as sulfates and glucuronides. Of the progestogens structurally related to norethindrone, norethindrone acetate, ethynodiol diacetate, norethindrone enanthate, and perhaps lynestrenol, undergo rapid hydrolysis and are converted to the parent compound and its metabolites. There is no convincing evidence that norethynodrel is converted to norethindrone. Of the progestogens structurally related to levonorgestrel, it appears that neither desogestrel nor gestodene are transformed to the parent compound. However, there is evidence that norgestimate can be, at least partly, converted to levonorgestrel. Further studies on the metabolism of these progestogens are required before we can understand their mechanism of action.

Animals↗
PubMed1990

Mechanism of action of gestagens.

In the mid-1950s it was shown that ovulation can be inhibited by oral administration of progesterone or of synthetic progestogens such as norethynodrel. The idea that progestogens may interfere with fertility even when administered in doses so small, that they do not invariably inhibit ovulation was launched in the mid-1960s by a group of Mexican investigators. Since then a large number of studies have been conducted on the mechanism of action of gestagens when used as contraceptives. The objective of this communication is to review the information collected so far on this topic.

Drug Administration Routes↗
PubMed1987

Mechanisms of physiological and pharmacological sex hormone action on the mammalian liver.

Androgen and oestrogen receptors have been demonstrated in mammalian liver, but since it is generally accepted that they are probably non-functional at endogenous steroid concentrations, it is not apparent how they mediate physiological influences on this organ. Nor is it certain to what extent pharmacological actions of sex hormones reflect overstimulation of physiological routes or whether alternative mechanisms become available once threshold values have been reached. In this presentation an attempt has been made to answer some of these questions using data obtained from a study of the regulation of the activities of microsomal 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSDH) and 5 alpha-reductase in rat liver. Androgens exert their primary physiological and pharmacological influences at the level of the hypothalamus. Oestrogens can elicit three different types of effect-physiological, antiandrogenic and pharmacological--of which the first two involve primary effects on the pituitary. Hepatic oestrogen receptors only become activated when oestrogen concentrations reach pharmacological levels. Progestins probably have no physiological influence on the livers of non-pregnant rats. Their pharmacological actions may either be traced back to secondary androgenic (e.g. medroxyprogesterone acetate, levonorgestrel) or oestrogenic (e.g. norethynodrel, lynestrenol) properties, involving the routes described above, or to independent effects on the central nervous system (e.g. cyproterone acetate modulation of 5 alpha-reductase activity).

Animals↗
PubMed1990

In vitro evaluation of estrogenic, estrogen antagonistic and progestagenic effects of a steroidal drug (Org OD-14) and its metabolites on human endometrium.

The human endometrial model for in vitro evaluation of estrogenic, estrogen antagonistic, and progestagenic effects of endogenous steroids, natural products or synthetic drugs was applied to the study of Org OD-14, an analog of norethynodrel developed by Organon International, Oss, The Netherlands, and some of its metabolites. Estrogen antagonistic actions of Org OD-14 and its 4-ene isomer were evident from their ability to suppress the enhancement of PGF2 alpha output elicited by estradiol on fragments of secretory endometrium and to decrease the rate of output of the prostaglandin by proliferative tissue, already stimulated by endogenous estrogens. These inhibitory effects were similar to those obtained with progesterone and do not appear to involve competition for the estrogen receptor since the antiestrogen 4-hydroxyamoxifen was not active in parallel incubations of proliferative endometrium. The progestagenic effects of Org OD-14 and its 4-ene isomer were also evident from their capability to enhance estradiol 17 beta-dehydrogenase activity and glycogen accumulation in specimens of proliferative endometrium. Estrogenic effects of the 3 alpha- and 3 beta-hydroxy metabolites of Org OD-14 were demonstrated by their stimulatory actions on PGF2 alpha output during incubations of secretory endometrium. The estrogenic and progestagenic actions of these compounds are in general agreement with their relative affinity for binding to the estradiol and progesterone receptors, although their actions may be influenced by intracellular metabolism in the endometrial tissue. For instance, the similarity in progestagenic activity of Org OD-14 and the 4-ene isomer, contrasting with their different affinities for the progesterone receptor, may result from in situ isomerization of Org OD-14 to the 4-ene metabolite.

Cells, Cultured↗
PubMed1984

Structural requirements for progesterone binding to the hepatic endoplasmic reticulum in the female rat.

Microsomes isolated from the liver of the female rat specifically bind progesterone. The progesterone-microsomal complex shows highly specific characteristics. The binding is probably associated with the carbonyl groups at positions C-20 and C-3. Other steroids compete for microsomal binding sites less effectively. Competition for progesterone binding sites by other steroids in percentages: testosterone 33; testosterone propionate, 9; 17-methyltestosterone, 23.2; cortisol, 6.4; estradiol-17 beta, 1.8; 17 alpha-ethynyl estradiol, 4.7; mestranol, 1.0; norethynodrel, 4.5; ethisterone, 7.1; lynestrenol, 4.3; medroxyprogesterone, 23.3; medroxyprogesterone acetate, 15.2; 5 alpha-pregnane-3,20-dione, 47.6; 5 beta-pregnane-3,20-dione, 20.7; pregnenolone, 14.8; 6-methylpregnenolone, 1.2; 16 alpha-methylpregnenolone, 3.8%; 20 beta-hydroxy-4-pregnen-3-one, 2.8; 3 beta-hydroxy-5 alpha-pregnan-20-one, 5.2; 4-pregnene-3 beta, 20 beta-diol, 2.1; 11 alpha-hydroxyprogesterone 21.0; 16 alpha-hydroxyprogesterone, 7.9; 17-hydroxyprogesterone, 26.7; 16 alpha, 17-epoxyprogesterone, 2.7; 16 alpha-methylprogesterone, 3.8; 6-methylpregnenolone, 1.2; 16 alpha-methylpregnenolone, 3.8; promegestone, 27.0. 3 beta-Hydroxy-5 beta-pregnan-20-one, 3 alpha-hydroxy-5 beta-pregnan-20-one, 5-pregnene-3 beta,20 beta-diol, 5-pregnene-3 beta, 20 alpha-diol; 5 alpha-pregnane-3 beta, 20 beta-diol, 5 alpha-pregnane-3 beta, 20 alpha-diol, 5 beta-pregnane-3 alpha, 20 alpha-diol, 5 beta-pregnane-3 alpha, 20 alpha-diol diacetate, 5 beta-pregnane-3 alpha, 20 beta-diol, 3 alpha, 17-dihydroxy-5 beta-pregnan-20-one, 17-hydroxypregnenolone, 6-methyl-17-hydroxypregnenolone, pregnenolone-16 alpha-carbonitrile, dihydrotestosterone and cholesterol show no competition at all. The varying degree of competition by different steroids is unrelated to their lipid solubility.

Animals↗
PubMed1984

The effect of five synthetic progestational compounds on 5 alpha-reductase activity in genital skin fibroblast monolayers.

The suggestion has been made that prenatal exposure to synthetic progestogens contributes to an increased incidence of hypospadias. One potential mechanism for such an effect might be inhibition of 5 alpha-reductase, a key enzyme in normal male sexual differentiation. We have examined the effect of progesterone and of five synthetic progestogens upon 5 alpha-reductase activity in fibroblast monolayers from 12 genital skin cell lines obtained from normal newborn infants, boys with phimosis and hypospadias and a normal adult male. Basal enzyme activities ranged from 0.8-12.1 pmoles 5 alpha-reduced product/micrograms DNA/hour. Progesterone and norethindrone inhibited 5 alpha-reductase activity in a dose dependent manner to a maximum of 95% and 50% of basal levels respectively at 10(-5) M. Similar concentrations (10(-5) M) of norethynodrel, ethisterone, dl-norgestrel and d-norgestrel had little or no effect. Studies of cell viability showed that the effects of progesterone and norethindrone were specific for 5 alpha-reductase and not non-specific toxic effects.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMedDate not supplied

Development of a monoclonal antibody for use in radioimmunoassay of ethynylestradiol.

Production of monoclonal antibodies (MABs) to a 17 alpha-ethynyl-1,3,5 (10)-estratriene-3,17 beta-diol (ethynylestradiol, EE2) hapten is described. Culture antibodies generated by hybridized cells tested in enzyme-linked immunosorbent assay (ELISA) bound the 6-oxoethynyl-estradiol-6-(0-carboxymethyl) oxime-bovine serum albumin conjugate (EE2-6-0 CMO-BSA) but not BSA. On radioimmunoassay (RIA) with tritiated ethynylestradiol (3H-EE2), some of the antibodies demonstrated high binding affinity (Ka = 2.8 X 10(10) M-1) to EE2. Estradiol-17 beta, estrone and estriol did not show any displacement of 3H-EE2 from the MABs even at high concentration (1 X 10(4) ng/mL). Among the widely used progestins, norethynodrel and norethisterone exhibited considerable cross-reactivity (25.7-100% and 0.3-54.1%, respectively) but not levonor-gestrel with the MABs. The high affinity demonstrated by the MABs to EE2 3-sulfate but not to EE2 17-sulfate and EE2 3,17-disulfate suggests the dominant role of the 17 beta-hydroxyl group in immunogenicity.

Antibodies, Monoclonal↗