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Results for “Progesterone Congeners”

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At least 19 recordsLinked to original sources
PubMed1987

Progesterone derivatives that bind to the digitalis receptor: synthesis of 14 beta-hydroxyprogesterone. A novel steroid with positive inotropic activity.

The synthesis of 14-hydroxy-14 beta-pregn-4-ene-3,20-dione (14 beta-hydroxyprogesterone) is described. This novel steroid is about 10 times more potent than progesterone and one-tenth as potent as ouabagenin in an [3H]ouabain radioligand binding assay and is the first in a series of progesterone congeners that interact at the cardiac glycoside receptor both to possess the C/D cis ring junction and to enhance contractility of isolated cardiac tissue.

Animals↗
PubMed1990

Inhibitory effect of synthetic progestins, 4-MA and cyanoketone on human placental 3 beta-hydroxysteroid dehydrogenase/5----4-ene-isomerase activity.

Human placental 3 beta-hydroxysteroid dehydrogenase/5----4-ene isomerase (3 beta-HSD) purified from human placenta transforms C-21 (pregnenolone and 17 alpha-hydroxy pregnenolone) as well as C-19 (dehydroepiandrosterone and androst-5-ene-3 beta, 17 beta-diol) steroids into the corresponding 3-keto-4-ene-steroids and is thus involved in the biosynthesis of all classes of hormonal steroids. Trilostane, epostane and cyanoketone are potent inhibitors of 3 beta-HSD with Ki values of approximately 50 nM. 4-MA, a well known 5 alpha-reductase inhibitor, is also a potent inhibitor of 3 beta-HSD with a Ki value of 56 nM. Synthetic progestin compounds such as promegestone and RU2323 show relatively strong inhibitory effects with Ki values of 110 and 190 nM, respectively. Cyproterone acetate, a progestin used in the treatment of hirsutism, acne and prostate cancer as well as norgestrel and norethindrone that are widely used as oral contraceptives also inhibit 3 beta-HSD activity at Ki values of 1.5, 1.7 and 2.5 microM, respectively.

3-Hydroxysteroid Dehydrogenases↗
PubMed1978

The effect of progesterone analogues, naturally occurring steroids, and contraceptive progestins on hypothalamic and anterior pituitary delta4-steroid (progesterone) 5alpha-reductase.

The effects of a number of steroids on the conversion of progesterone to 5alpha-dihydroprogesterone by hypothalamic and pituitary progesterone 5alpha-reductase have been investigated. Using enzyme preparations from female rats and 3H-progesterone as substrate, 5alpha-reduced products (5alpha-dihydroprogesterone and 3alpha-hydroxy-5alpha-pregnan-20-one) were analyzed by reverse isotopic dilution analysis. The amount of total 5alpha-reduced products formed was compared in the presence and absence of the test steroid. Derivatives lacking the delta4 and/or the 3-keto moiety were without effect. Corticosterone had no effect. 16beta-Methylprogesterone inhibited progesterone 5alpha-reduction in both tissues by at least 65%, while the 2alpha-, 6alpha-, and 7alpha-methylated derivatives had lesser effects. 3-Oxo-4-pregnene-20beta-carboxaldehyde and 21-fluoroprogesterone were potent inhibitors. 17-Hydroxyprogesterone was a competitive inhibitor (substrate) with Ki's of 0.27 micrometer (pituitary) and 0.29 micrometer (hypothalamus). Medroxyprogesterone exerted little inhibitory effect. Of the 19-nor-steroids examined, only norethindrone appreciably inhibited the 5alpha-reduction. These results suggest that some natural delta4-3-ketosteroids can modify enzymatic activity. Also, inhibitory analogues may be useful for studies on the role of this 5alpha-reduction of progesterone.

3-Hydroxysteroid Dehydrogenases↗
PubMed1980

Lysozyme (muramidase) and hemolytic complement (CH50U) in sera of beagle dogs and minipigs after longterm application of different preparations of estrogens and gestagens.

In studies for the chronic toxicity of estrogens and gestagens, lysozyme and hemolytic complement (CH50U) in sera of beagle dogs and minipigs were measured. Various doses of the sexsteroids were given: 0.01 mg, 0.1 mg and 1.0 mg/kg respectively. The influence of the steroids on the tested parameters after an application for 6 months was not significant, only in a single series with unphysiologically, high dosages of the preparations were some values changed significantly.

Animals↗
PubMed1978

Synthetic progestins: in vitro potency on human endometrium and specific binding to cytosol receptor.

The relative potency of six commonly used synthetic progestins has been evaluated in an organ culture system for human endometrium. The affinities of these progestins for endometrial progesterone receptor were also evaluated after removing the CBG-like protein by spheroidal hydroxylapatite chromatography. All six progestins induced an increase in tissue glycogen during culture at lower concentrations than did progesterone; only one (medroxyprogesterone acetate) had a relative affinity greater than progesterone. The relative potencies and affinities of the synthetic progestins were found to have the same relative order but to differ in relative magnitude.

Chromatography↗
PubMed1977

Production of antisera against contraceptive steroids.

A four step synthesis of 6-(0-carboxymethyl) oximinoethynylestradiol is reported. This compound, 6-(0-carboxymethyl) oximinomestranol, the 3-(0-carboxymethyl) oximes of norethindrone and norgestrel and the 3-hemisuccinate of ethynylestradiol were synthesized and conjugated with bovine serum albumin. Rabbits were immunized at 3 dose levels of haptene (20, 66 and 200 nmoles) and eight weeks later with a booster containing 66 nmoles of haptene. The antibody titer and association constant of responding rabbits was nearly independent of dose although most antibody production occurred after the booster injection. Antibodies to mestranol crossreacted more than 100 percent with ethynylestradiol and to a small extent with norethindrone and norgestrel.

Animals↗
PubMed1990

Comparison of the physical properties of the nuclear progesterone receptor, bound to antiprogestin RU 486 or progestin ORG 2058, following limited proteolysis.

The susceptibility of the progesterone receptor, liganded either by the antiprogestin RU 486 or by the progestin ORG 2058, to chymotrypsin and trypsin degradation was investigated. The nuclear fraction was isolated from T47D cells previously exposed either to 0.1 microM [3H]RU 486 or to 0.1 microM [3H]ORG 2058. The proteolytic digestion was performed on the micrococcal nuclease hydrolysate. The molecular weights of the receptor fragments were calculated, in high salt buffer, from the sedimentation coefficients determined on a sucrose gradient and from the Stokes radii estimated by gel filtration on an Agarose A-0.5 m column. Micrococcal nuclease solubilized receptor forms with molecular weights of 80,000 and 75,000 for the antiprogestin- or progestin-liganded receptor, respectively. Chymotrypsin degraded these receptor forms to fragments with molecular weights of 23,000 either for the antiprogestin- or progestin-liganded receptor. Similar molecular weights of 23,000 were calculated for the progesterone receptor liganded either by the antiprogestin RU 436 or the progestin ORG 2058 following trypsin cleavage. We conclude that the degradation pattern of the progesterone receptor liganded either by the antiprogestin RU 486 or the progestin ORG 2058 following chymotrypsin or trypsin digestion seems to be similar.

Cell Line↗
PubMed1980

Effects of progestin-estrogen combination and progestational contraceptives on pituitary gonadotropins, gonadal steroids and sex hormone-binding globulin.

The effects of three kinds of hormonal contraceptives on the levels of follicle-stimulating (FSH), luteinizing hormone (LH), estradiol, progesterone, testosterone, and sex hormone-binding globulins (SHBG) in three groups of normally menstruating women were analyzed. During the administration of a very low-dose combination of 150 micrograms of D-norgestrel and 30 micrograms of ethinylestradiol, a progressive suppression of LH, FSH, estradiol, and (to a lesser extent) testosterone levels was observed while progesterone stayed at levels found during the early follicular phase. SHBG levels in these subjects were within the normal range for women. Oral treatment with 0.5 mg of lynestrenol and the intramuscular administration of 200 mg of norethindrone enanthate produced a suppression of LH but not FSH in all cases. Estradiol levels showed peaks in the three women treated with lynestrenol and in half of those treated with norethindrone enanthate, suggesting follicular activity caused by the unsuppressed FSH stimulus; the subsequent elevation of progesterone in two subjects suggested some luteinization, although there was no evidence of an ovulatory surge of gonadotropins. The SHBG in four subjects treated with norethindrone enanthate fell within our normal range for men, and the mean serum testosterone levels fell 40% below the normal basal levels in these cases.

Adult↗
PubMed1984

Progesterone--specific binding sites in the kidney of the female baboon.

The uptake and retention of a radiolabeled synthetic progestin, ORG 2058, was studied in the urinary tract of the female baboon. Four estrogen-primed baboons were injected intravenously with 2.5 micrograms./kg. body weight of 3H-ORG 2058. One animal, which served as a control, received an additional injection of 2.5 mg./kg. body weight of unlabeled progesterone. One hour after the injections, the animals were killed and the kidneys, ureters and urinary bladder were removed and processed for autoradiography. Localization of progestin was observed in the nuclei of the convoluted and straight segments of the distal tubule, the ascending thick limb of the loop of Henle and both cortical and medullary collecting tubules. Connective tissue cells were also labeled in the medulla and cortex of the kidney. An absence of silver grains was noted in the renal corpuscle, all segments of the proximal tubule and the thin loop of Henle. Concentration of the tritiated steroid was not observed in either the ureter or bladder or in any portions of the urinary tract of the control animal. This study suggests that progesterone has a direct effect via a progesterone specific receptor on the various target cells that sequestered the 3H-ORG 2058.

Animals↗
PubMed1997

Effects of progesterone on the sexual behavior of castrated, testosterone-treated male cynomolgus monkeys (Macaca fascicularis).

In male cynomolgus monkeys the synthetic progestin, medroxyprogesterone acetate (MPA), decreases testosterone (T) levels and sexual behavior, binds to progestin receptors in brain, and reduces by about 70% the uptake of [3H]androgens by both brain and genital tract tissues. To examine the behavioral effects of progesterone (P) itself, eight castrated, T-treated males were each tested twice weekly with an estrogenized female before, during, and after they were treated with two SC Silastic P implants. Data from six 4-week treatment periods were analyzed to facilitate comparisons with our previous data using MPA: i) baseline, ii) weeks 4-7 of P treatment, iii) weeks 8-11 of P treatment, iv) weeks 1-4 after P implants were removed, v) weeks 5-8 after P withdrawal, and finally vi) weeks 9-12 after P withdrawal (384 1 h behavior tests). Weekly blood samples (N = 192) were analyzed by radioimmunoassay to determine plasma levels of both T and P. P treatment, which resulted in high plasma P levels (about 44 ng/ml), produced decrements in measures of male sexual behavior and motivation that were both qualitatively and quantitatively similar to those produced by MPA treatment but, unlike MPA, P did not decrease plasma T levels or change them in any way (about 850 ng/100 ml throughout). The findings suggest that P implants may be preferable to weekly MPA injections in the treatment of male sex offenders because they require less patient compliance and may not have MPA's troubling side effects.

Animals↗
PubMed1993

Systemic treatment in disseminated endometrial cancer.

Both hormonal agents and chemotherapy are of value in the treatment of selected patients with endometrial cancer. In unselected patients with advanced disease about 25% respond to progestational agents and 40% to combination chemotherapy. The choice between the two treatments is made on the basis of a number of prognostic factors, such as receptor status, tumour grade, performance status and tumour burden. Further improvement of treatment outcome is to be expected from new agents such as gonadotrophin releasing hormone analogues, taxol and modulation of 5-fluorouracil.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

New progestins and potential actions.

Newer, nonsteroidal, orally active, tissue-selective progestins are being developed through a molecular approach to compound selection with human progesterone receptor (hPR) serving as the molecular target. The co-transfection and binding assays are used to test receptor selectivity and cross reactivity with a panel of receptors. Transcriptional products are used to further profile new progestin compounds. Desirable new progestins will suppress estrogen-induced endometrial stimulation, show no or minimal proliferative activity, maintain pregnancy, inhibit ovulation, contain no androgenic, mineralocorticoid or glucocorticoid activity, and possess minimal adverse physiologic effects. Newer progestins that possess many of these desirable properties are in development.

Drug Design↗
PubMed2001

Medroxyprogesterone acetate enhances in vivo and in vitro antibody production.

In the present study we examine the effects of medroxyprogesterone acetate (MPA) on the specific antibody secretion to T-dependent antigens. Our results show that the in vivo administration of MPA to mice, 7 or 90 days before immunization with sheep red blood cells (SRBC), significantly enhanced both, primary and secondary antibody responses, without affecting delayed-type hypersensitivity (DTH). These effects could be counteracted by the anti-progestin onapristone or ZK 98299 (ZK) suggesting that MPA interacted with progesterone (PRG) receptors to increase B-cell response. To better understand the mechanisms involved in MPA activity we carried out cultures of splenocytes, bone marrow cells or lymph node cells from immunized mice in the presence of MPA, and evaluated the amount of antibody release to supernatants. We found that low doses of MPA (10(-9) M and 10(-10) M) significantly enhanced the in vitro production of specific immunoglobulin G (IgG) antibodies, an effect that appears to involve the interaction of the progestin with PRG receptors, as judged by the inhibition of MPA effects with ZK (10(-8) M) or RU486 (10(-9) M). These receptors were detected by flow cytometry analysis in a proportion of T lymphocytes. Because MPA did not increase the number of immunoglobulin-secreting cells, our findings suggest that MPA enhanced the capacity of individual cells to produce specific immunoglobulin.

Animals↗