Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Promegestone”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 667 records · Page 37Linked to original sources
PubMed1982

Effects of gonadal steroid hormones on the hypothalamo-pituitary-liver axis in the control of sex differences in hepatic steroid metabolism in the rat.

The site of action of gonadal hormones in the regulation of hepatic steroid metabolism was investigated by measuring the effects of (i) implantation of estradiol into the pituitary gland or anterior hypothalamus of males and (ii) subcutaneous injection of a synthetic androgen in differentiated male and female rats. The hepatic responses measured in vitro were 5 alpha-reduction, and 6 beta- and 16 alpha-hydroxylation of androstenedione. After intrapituitary or intrahypothalamic implantation of oestradiol, 5 alpha-reductase activity increased and 6 beta- and 16 alpha-hydroxylase activity decreased in males relative to the enzyme activities of cholesterol-implanted animals, indicating a feminizing effect of the oestrogen. This effect could not be accomplished by subcutaneous injection of the same oestrogen preparation. Deafferentation had no effect on hepatic steroid metabolism in females, but caused a feminization in males. In addition, subcutaneous treatment of intact females with the synthetic androgen caused masculinization of hepatic steroid metabolism, but was without effect in differentiated animals. Treatment with synthetic androgens had no effect on the hepatic steroid metabolism in differentiated male animals. Subcutaneous injection of a potent synthetic progestagen had little effect on hepatic steroid metabolism in intact females. It is concluded that oestrogen feminizes hepatic steroid metabolism by an action at the hypothalamic-pituitary level and that an intact hypothalamic-pituitary axis is required for the masculinizing action of the synthetic androgen on hepatic steroid metabolism. It is possible that the site of action of androgens is in the anterior hypothalamus or in adjacent areas of the brain.

Androstenedione↗
PubMed1988

Effects of progestins on sexual behaviour in castrated lizards (Cnemidophorus inornatus).

In many male vertebrates, androgens stimulate, while progesterone inhibits, sexual behaviour. Testicular androgens also control sexual behaviour in males of the lizard Cnemidophorus inornatus. However, administration of progesterone will reinstate sexual behaviour in castrated animals. Increased doses of progesterone did not result in increased numbers of responders; at all doses tested approximately 36% (n = 45) of animals treated with progesterone responded as reliable courters. A high percentage (60-68%) of progesterone-sensitive individuals maintained their sensitivity over a period of months. A synthetic progestin 17,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione with low rates of metabolism and conversion, also stimulated sexual behaviour in castrated C. inornatus. Finally, the synthetic antiprogestin 11 beta-4-dimethylaminophenyl-17 beta-hydroxy-17 alpha-1-propinyl- 4,9-oestradiene-3-one inhibited the stimulatory effects of progesterone on sexual behaviour but failed to inhibit the stimulatory effects of androgens. These findings indicate an unusual departure from the characteristic pattern of steroid sensitivities of neural centres controlling sexual behaviour.

Animals↗
PubMed2002

Expression of the progesterone receptor and progesterone- metabolising enzymes in the female and male human kidney.

Due to high binding affinity of progesterone to the human mineralocorticoid receptor (hMR), progesterone competes with the natural ligand aldosterone. In order to analyse how homeostasis can be maintained by mineralocorticoid function of aldosterone at the MR, especially in the presence of elevated progesterone concentrations during the luteal phase and pregnancy, we investigated protective mechanisms such as the decrease of free progesterone by additional binding sites and progesterone metabolism in renal cells. As a prerequisite for sequestration of progesterone by binding to the human progesterone receptor (hPR) we demonstrated the existence of hPR expression in female and male kidney cortex and medulla at the level of transcription and translation. We identified hPR RNA by sequencing the RT-PCR product and characterised the receptor by ligand binding and scatchard plot analysis. The localisation of renal hPR was shown predominantly in individual epithelial cells of distal tubules by immunohistology, and the isoform hPR-B was detected by Western blot analysis. As a precondition for renal progesterone metabolism, we investigated the expression of steroid-metabolising enzymes for conversion of progesterone to metabolites with lower affinity to the hMR. We identified the enzyme 17alpha-hydroxylase for renal 17alpha-hydroxylation of progesterone. For 20alpha-reduction, different hydroxysteroid dehydrogenases (HSDs) such as 20alpha-HSD, 17beta-HSD type 5 (3alpha-HSD type 2) and 3alpha-HSD type 3 were found. Further, we detected the expression of 3beta-HSD type 2 for 3beta-reduction, 5alpha-reductase (Red) type 1 for 5alpha-reduction, and 5beta-Red for 5beta-reduction of progesterone in the human kidney. Therefore metabolism of progesterone and/or binding to hPR could reduce competition with aldosterone at the MR and enable the mineralocorticoid function.

20-Hydroxysteroid Dehydrogenases↗
PubMed1986

Gestrinone (R2323) binding to steroid receptors in human uterine endometrial cytosol.

To understand the mechanism of biological action of gestrinone (R2323), which has a therapeutic effect against endometriosis, the binding of gestrinone to numerous classes of intracellular steroid binding proteins was studied in the human uterine endometrium. Gestrinone bound to endometrial receptors for estrogen, progesterone and androgen, but seemed not to bind to endometrial intracellular corticosteroid-binding globulin and sex hormone-binding globulin. Gestrinone occupies all specific binding sites of steroids in the steroid target cells despite the presence of endogenous steroids. It is speculated that the binding behavior of gestrinone may be related to its therapeutic effect on endometriosis. Gestrinone's more avid affinity for estrogen receptor may be the reason for the ability to use a lower clinical dose of gestrinone.

Cytosol↗
PubMed1999

The pharmacological profile of a novel norpregnance progestin (trimegestone).

Trimegestone is a novel norpregnane progestin that is being developed, in combination with estradiol, for the treatment of menopausal symptoms. The pharmacological characteristics of trimegestone have been evaluated in both in vitro and in vivo test systems, and compared with reference progestins. Interaction with hormonal steroid receptors from animal tissues and with human recombinant receptors in vitro has demonstrated that trimegestone has a high specificity and potency for the progesterone receptor, no affinity for the estrogen receptor, and weak affinity for androgen, glucocorticoid and mineralocorticoid receptors. With respect to progestomimetic activity in vivo, trimegestone was more potent than reference progestins in the endometrial transformation test in the rabbit, preventing the uterotrophic effect of estradiol in the immature mouse bioassay, and had more effect on traumatic deciduoma formation and greater oral antiovulatory activity in the rat. In vivo, trimegestone effectively maintained pregnancy in the rat, but was devoid of any uterotrophic activity. Trimegestone showed no androgenic, glucocorticoid, antiglucocorticoid or mineralocorticoid activity, but did show some antiandrogenic and antimineralocorticoid activity at higher doses. Administration of trimegestone to ovariectomized rats, in combination with estradiol, inhibited the uterotrophic effects of estradiol. At doses up to 1 mg/kg intravenously and 30 mg/kg orally, trimegestone was not associated with any unwanted pharmacological effects. Overall, the results show trimegestone to have a favorable pharmacological profile with potent progestomimetic activity.

Administration, Oral↗
PubMedDate not supplied

An empirical basis for the competition by dexamethasone to progesterone receptors as estimated with the synthetic progestin R5020.

Normal mammary glands of mice contain both progesterone and glucocorticoid receptors and the levels of both these receptors are modulated as a function of development. Measurement of progesterone receptors using the synthetic progestin, R5020, has led to conflicting data both with regard to the presence of progesterone receptor during certain developmental stages of the mammary gland and the ability of the glucocorticoids to compete for specific R5020 binding sites. In this report we have identified experimental conditions which allow for the separate measurements of the progesterone and glucocorticoid receptors in the same cytosol. If sulfhydryl reducing agents such as dithiothreitol are excluded from the assay buffer, R5020 binds to only a single class of high affinity sites in mammary cytosol of virgin mice and these binding sites exhibit a strict steroid specificity characteristic of progesterone receptors. In contrast, if dithiothreitol is included in the buffers, R5020 binds not only to the high affinity sites but also to certain saturable lower affinity sites; these lower affinity sites for R5020 also bind glucocorticoids such as dexamethasone. These findings should facilitate more accurate quantitation of both progesterone and glucocorticoid receptors in normal and neoplastic tissues and also be applicable to studies on the mechanism(s) of progesterone action.

Animals↗
PubMed1985

Estrogen and progesterone receptors in the uterus of the vervet monkey.

Experimental conditions for the optimal measurement of estrogen (ER) and progesterone (PR) receptors in normal vervet monkey (Cercopithecus aethiops pygerythrus) uteri are described. The uteri of this primate were found to contain relatively high concentrations of both ER and PR. Levels of ER ranged from 151 to 822 femtomoles per mg protein (mean for group assayed is 327 +/- 165 femtomoles per mg protein). PR assays were performed on the same cytosols and the levels ranged from 444 to 2267 femtomoles per mg protein (mean of 1285 +/- 511 femtomoles per mg protein). Mean Kd values for the ER- and PR-ligand complexes were found to be 3.15 +/- 1.4 X 10(-10)M and 2.38 +/- 0.2 X 10(-9)M respectively, within the group analysed (n = 21). The ratio of PR to ER varied between 1.1 and 13.1 with a mean of 4.5 +/- 2.4. Ligand specificity studies revealed that [3H]-17 beta-estradiol binding to the ER could only be inhibited by estrogens or estrogen analogues. The PR however exhibited an affinity for a wider range of ligand types. In low ionic strength buffers both ER and PR sedimented as approximately 8S type molecules in the presence or absence of 10mM sodium molybdate. Both receptors dissociated into smaller components, following a short exposure to 0.4 M KCl and subsequent centrifugation in a gradient containing 0.4 M KCl.

Animals↗
PubMed1987

Quantification of progesterone binding in mammary tissue of pregnant ewes.

Progestin-binding sites in mammary tissue from 14 prepartum, multiparous ewes at 50, 80, 115, and 140 d of gestation were demonstrated by the binding of [3H] R5020 (17,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione) to ovine mammary cytosol in the presence of sodium molybdate and excess cortisol. Homogenization extracted 89% of total mammary receptors (nuclear) into cytosol. Binding was specific for progestins and was of high affinity. The average dissociation constant for [3H] R5020 specifically bound to receptors extracted into mammary cytosol was 1.9 (+/- .4) X 10(-9) M (n = 14) and did not change significantly over the test period. However, binding capacities (fmol/mg cytosolic protein) differed according to stage of gestation with averages of 125 +/- 53, 149 +/- 26, 656 +/- 216, 57 +/- 22 at 50, 80, 115, and 140 d of pregnancy, respectively. Increased number of progestin-binding sites at 115 d of gestation (whether data are expressed per unit of tissue weight, DNA, or cytosolic protein) suggests that an increase per mammary epithelial cell may be necessary to produce the full lobuloaveolar proliferation observed at this stage of gestation.

Animals↗
PubMed1991

Comparison of glucocorticoid receptors liganded with dexamethasone or progesterone.

The initial goal of this work was to examine directly the properties of glucocorticoid receptors bound with antagonists. Cortexolone, progesterone, and R-5020 were the antagonists studied. The tritiated agonists, dexamethasone and triamcinolone acetonide, served as controls. Although the three antiglucocorticoids interfered with agonist binding to the glucocorticoid receptor, direct binding of the tritiated antagonists could not be reproducibility demonstrated using either a charcoal assay or rapid techniques like high performance liquid chromatography or vertical tube rotor ultracentrifugation. Ultraviolet radiation was used to attach covalently tritiated steroid to the receptor. This technique allowed the identification of species that bound agonist or antagonist. That the two classes of steroids bound to the same receptor was shown using a monoclonal antibody directed against the glucocorticoid receptor. These labeled species had the same physical properties upon ultracentrifugation, DEAE cellulose chromatography, and high performance liquid chromatography. It is concluded that although the interaction of antiglucocorticoids like progesterone with the glucocorticoid receptor may be fleeting, antagonists do interact with the glucocorticoid receptor and form complexes with grossly similar properties as those derived from an interaction with agonists.

Animals↗
PubMed2001

Human progesterone receptor shows differential sensitivity to carboxyl group modifying agents when bound to agonist and antagonist ligands.

BACKGROUND: Modulation of human uterine progesterone receptor (PR) in relation to its binding to synthetic steroids with known agonist (R5020) and antagonist (triamcinolone acetonide, T.A.) properties was studied in the presence of the specific carboxyl group modifiers, N,N'-dicyclohexylcarbodiimide (DCCD) and 1-ethyl-3-carbodiimide hydrochloride (EDC). METHODS: Uterine cytosol was treated with DCCD or EDC. The amounts of total bound were detected using the steroid binding measurements. The formation and transformation of progesterone-receptor complexes (PRc) were analyzed using sedimentation rate analysis. RESULTS: Our studies show that the modification of the COOH group differentially influences the properties of mammalian PR binding with either R5020 or T.A. DCCD and EDC affect the steroid binding of PR by decreasing the binding sites, not by the changing the affinity. CONCLUSION: Our studies indicate the importance of the carboxyl group in steroid binding by PR. This implies that both aspartic acid and glutamic acid residues, which have the carboxyl group, may play an important role when PR binds with steroid ligands.

Cytosol↗
PubMed2001

A 1-year comparison of the efficacy and clinical tolerance in postmenopausal women of two hormone replacement therapies containing estradiol in combination with either norgestrel or trimegestone.

This double-blind, randomized, multi-center study compared the efficacy and clinical tolerance of a combined formulation containing 2 mg estradiol (E2) and 0.5 mg trimegestone (TMG) with a standard hormone replacement therapy containing estradiol valerate (E2V) and norgestrel (NG) in the treatment of climacteric symptoms. The study was conducted over 13 cycles, each of 28 days, and involved 634 subjects, of whom 481 completed the study. The primary efficacy variable was the percentage of subjects who showed at least a 50% reduction from baseline in the mean daily number of hot flushes in cycle 3. This was observed in 98.5% of the subjects in the E2 + TMG group and 93.3% of the subjects in the E2V + NG group (95% confidence interval of the difference, -8.6, -1.9). Significant differences in favor of the E2 + TMG combination were observed in the reduction in the mean daily number and severity of hot flushes, and in the percentage of subjects who had hot flushes at baseline but no hot flushes during treatment. There were no significant differences between the treatments in the Kupperman index and in urogenital signs or symptoms. Treatment with the E2 + TMG combination was well tolerated and the incidences of adverse events were similar in the two treatment groups. Breast pain was the main adverse event, possibly related to treatment that resulted in discontinuation. The mean number of bleeding days per cycle was significantly lower with the E2 + TMG combination than with the E2V + NG combination. The incidences of endometrial hyperplasia were low and comparable in both treatment groups. It was concluded that the E2 + TMG combination was either equivalent or superior to the E2V + NG combination in the treatment of hot flushes and other climacteric symptoms, and that its bleeding profile was favorable.

Double-Blind Method↗
PubMed2001

Acceptability and patterns of endometrial bleeding in estradiol-based HRT regimens: a comparative study of cyclical sequential combinations of trimegestone or norethisterone acetate.

OBJECTIVE: This randomized, double-blind, multicenter study was planned to compare the efficacy and tolerance of a novel oral regimen containing estradiol (2.0 mg) sequentially combined with trimegestone, at a daily dose of either 0.25 mg or 0.5 mg, with a standard hormone replacement therapy containing estradiol and norethisterone acetate (E2 + NETA) in the treatment of climacteric symptoms. METHODS: The study was conducted over 13 cycles, each of 28 days, and involved 487 subjects, of whom 349 completed the study. RESULTS: All three treatments were equally effective in alleviating hot flushes and showed a progressive and significant reduction in the value of the Kupperman index. The treatments diminished equally effectively urogenital signs and symptoms. All treatments were well tolerated and the incidences of adverse events associated with each treatment were similar across the treatment groups. The duration of expected withdrawal bleeding was shorter in the estradiol + trimegestone 0.5 mg group than in the estradiol + trimegestone 0.25 mg or E2 + NETA group. CONCLUSION: All treatments were effective and well tolerated, providing significant relief from climacteric symptoms. Treatment with estradiol + trimegestone 0.5 mg provided the most favorable bleeding pattern.

Argentina↗
PubMed2002

Assessment of the metabolic tolerance in postmenopausal women over a 1-year period of two hormone replacement therapies containing estradiol in combination with either norgestrel or trimegestone.

This double-blind, randomized, multi-center study compared the metabolic tolerance of a combined formulation containing estradiol (E2) and trimegestone (TMG) with a standard hormone replacement therapy (HRT) containing estradiol valerate (EV) and norgestrel (NG). Blood lipids, glucose and fibrinogen concentrations were measured in the study which was conducted over 13 cycles, each of 28 days, and included 634 subjects in two randomized groups. A total of 481 subjects completed the study. The circulating concentrations of high density lipoprotein (HDL), HDL2, HDL3 cholesterol and apolipoprotein A1 were increased in the E2 + TMG group and reduced in the EV + NG group. Total cholesterol, low density lipoprotein (LDL) cholesterol, apolipoprotein B and lipoprotein(a) concentrations were decreased in both treatment groups; however, the reduction in LDL cholesterol was greater in the E2 + TMG group. Similar lipid findings were found in a subgroup that excluded subjects who had less than 3 months washout from a previous HRT, who provided a blood sample outside the day 17-28 window, or who were taking beta-blockers or thiazide diuretics. Blood glucose concentrations were reduced slightly in both treatment groups. A significant reduction in fibrinogen was also seen in both groups over the course of the study. The changes in lipid profile, especially HDL cholesterol, were more beneficial in the E2 + TMG group in comparison with the EV + NG group. This reflects the lack of androgenic action of trimegestone in comparison with norgestrel, which exhibits an androgenic effect and prevents the estrogen-induced increase in HDL cholesterol. The results of the study suggest that the use of trimegestone in combination with E2 may be preferable to norgestrel because of the more favorable lipid profile.

Apolipoprotein A-I↗