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At least 19 recordsLinked to original sources
PubMed1999

Norpregnane glycosides from a Thai soft coral, Scleronephthya pallida.

Two new norpregnane glycosides, 19-norpregna-1,3,5(10), 20-tetraen-3-O-alpha-fucopyranoside (3) and 19-norpregna-1,3,5(10), 20-tetraen-3-O-beta-arabinopyranoside (4), were isolated from the soft coral Scleronephthya pallida, along with two known steroids, pregna-1,20-dien-3-one (1) and 19-norpregna-1,3,5(10), 20-tetraen-3-ol (2). 19-Norpregna-1,3,5(10), 20-tetraen-3-O-alpha-fucopyranoside (3) exhibits moderate antimalarial and cytotoxic activities. The chemical structures of 1-4 were elucidated from spectroscopic data.

Animals↗
PubMed1992

Synthetic approaches toward total synthesis of 12 beta-methyl- and 12-methylene-19-norpregnanes.

The effect of a substituent in the 12-position of progestagens was studied. To this end, various approaches toward the preparation of 12 beta-alkyl- and 12-alkylidenenorpregnanes were investigated. Eventually, the desired compounds 17 beta-hydroxy-12 beta-methyl-18a-homo-19-nor-17 alpha-pregn-4-en-20-yn-3-one (37) and 17 beta-hydroxy-12-methylene-18a-homo-19-nor-17 alpha-pregn-4-en-20-yn- 3-one (38) were obtained in racemic form by total synthesis; they were shown to lack progestagenic activity.

Desogestrel↗
PubMed2001

The metabolism of norethandrolone in the horse: characterization of 16-, 20- and 21-oxygenated metabolites by gas chromatography/mass spectrometry.

After oral administration to a thoroughbred gelding, the anabolic steroid norethandrolone was converted into a complex mixture of oxygenated metabolites. These metabolites were extracted from the urine, deconjugated by methanolysis and converted to their O-methyloxime trimethylsilyl derivatives. Gas chromatographic/mass spectrometric analysis indicated the major metabolites to be 19-norpregnane-3,16,17-triols, 19-norpregnane-3,17,20-triols and 3,17-dihydroxy-19-norpregnan-21-oic acids. Some minor metabolites were also detected.

Animals↗
PubMed1987

Studies on the mechanism of the antiandrogenic effect of a putative 5 alpha-reductase inhibitor.

The mechanism of the antiandrogenic effect of 5,10-seco-19-norpregnane-4,5-diene-3,10,20-trione (secosteroid), reputedly an irreversible inhibitor of 5 alpha-reductase, was investigated. Its addition (10 microM) to culture media effectively suppressed the synthesis of rat epididymal proteins specifically induced by 0.1 microM testosterone (T) or dihydrotestosterone (DHT). Under the same conditions, secosteroid did not change the rate at which labeled T was metabolized to 5 alpha-reduced compounds. In a comparative study, secosteroid inhibited 5 alpha-reductase in an isolated microsomal fraction while not affecting the enzyme activity in minced tissue. Secosteroid was shown to be a competitor of the binding of [3H]T and [3H]DHT (both at 4 nM) to the epididymal cytosol androgen receptor, with ID50 of 1 microM for the former and 4 microM for the latter, thus explaining the mechanism involved in its antiandrogenic properties.

5-alpha Reductase Inhibitors↗
PubMed1987

Steroid analogs inhibit hormone binding by an extract from Nippostrongylus brasiliensis (Nematoda).

1. An extract from the rodent nematode Nippostrongylus brasiliensis contained putative receptors that bound radiolabeled sex hormones, based on isoelectric focusing. 2. Binding of radiolabeled testosterone by receptors at pH 4.4 was highly inhibited by the androgen analogs, testosterone-3-oxime and 4-aza-5-androsten-3-on-17 beta-ol. 3. Binding of radiolabeled progesterone by receptors at pH 6.4 was highly inhibited by the progesterone analogs 3,5-seco-4-norpregnan-5-on-3-oic acid and 19-norethisterone or 21-deoxycorticosterone. 4. Binding of radiolabeled 17 beta-estradiol by receptors at pH 4.9 was highly inhibited by epiandrosterone. 5. In vivo development of N. brasiliensis to the adult was partially inhibited by selected steroid analogs.

Animals↗
PubMed2004

[Observational study of criteria involved in the choice of hormone replacement therapy (HRT), when initiated and subsequently adapted].

OBJECTIVES: Multicentre observational longitudinal prospective study in France; search for criteria involved in the choice of the initial dose of oestrogen at the initiation of hormone replacement therapy (HRT); search for explicative and predictive factors for treatment adaptation. PATIENTS AND METHODS STATISTICS: description and analysis (factorial analysis of multiple correspondences) of the criteria involved in the choice of the initial dose of oestrogen; percentage of women with treatment adaptation ; analysis (univariate, multivariate) of predictive factors for adaptation. RESULTS: Six hundred and fifty postmenopausal women, first treated with HRT, with complete data on modification (or not) of their treatment were included. Initial estrogen dose was dose 1 (or low dose) in 66% of patients, dose 2 (or standard dose) in 34 % of patients (N = 643). The preponderant type of HRT use was discontinuous sequential therapy and transdermal formulation. Criteria involved in the choice of the low initial dose (dose 1) were moderate hot flushes, complaint about weight gain, choice of the patient, breast tolerability, uterine bleeding, general safety, hepatic first pass. Criteria involved in the choice of the standard initial dose (dose 2) were important hot flushes, and prevention of postmenopausal osteoporosis. Treatment was adapted in 369 patients e.g. 56.8% of the population (95% CI: 53-60.6 %). The main changes (N = 291) were in 37.5% of the cases (N = 109) a decrease in the dose of estrogen (16.7% of the women (N = 37) initially under dose 2 - or standard dose) or an increase in the dose of oestrogen (17.1% of the women (N = 72) initially under dose 1 - or low dose). In 25% of the cases, there was a change in the dose or type of progestogen, in favor of norpregnane or pregnane derivates. DISCUSSION AND CONCLUSION: The following factors were associated with a decreased probability of treatment adaptation: more than 5 hot flushes at enrolment, initial dose chosen taking into account tolerance factors, history of hysterectomia, and known diabetes. Conversely, the existence of antihypertensive treatment was associated with an increased probability of treatment adaptation.

Dose-Response Relationship, Drug↗
PubMed2003

All progestins are not created equal.

A variety of progestins are available for therapeutic use. It is convenient to classify them into those related in chemical structure to progesterone or testosterone. Progestins related to progesterone can be subdivided into pregnanes and 19-norpregnanes, whereas those related to testosterone can be subdivided into those with and without a 17-ethinyl group. 17-Ethinylated progestins consist of the families of norethindrone (estranes) and levonorgestrel (13-ethylgonanes). Progestins administered orally undergo extensive hepatic first pass metabolism primarily by reduction and conjugation, and in most instances, relatively high progestin doses are required for therapeutic use. There are limited reliable data on the pharmacokinetics of most progestins. Some progestins are prodrugs, requiring transformation prior to exhibiting progestational activity. Qualitative and quantitative tests utilizing either human or animal species have been used to establish progestin potency. However, profound differences in progestational activity are often observed between human and animal tissues. Also, there is a misconception about androgenicity of progestins due largely to extrapolation of data from rat studies to the human. Progestins differ widely in their chemical structures, structure-function relationships, metabolism, pharmacokinetics, and potencies; they are not created equal.

Animals↗
PubMed2003

Clinical experience with trimegestone as a new progestin in HRT.

Trimegestone (TMG) is a novel, 19-norpregnane progestin, which demonstrates endometrial selectivity with a reduced progestin-related side effect profile when compared to several other currently marketed progestins. TMG has been studied in combination with 17beta-estradiol (17beta-E2) and conjugated equine estrogens (CEE). TMG-containing HRT agents were effective in relieving vasomotor symptoms and providing protection from endometrial hyperplasia with < or =1% hyperplasia. In clinical trials with sequential regimens, TMG provided predictable withdrawal bleeding associated with a low incidence of irregular and prolonged bleeding. Clinical studies of continuous combined regimens of estrogen/TMG combinations demonstrated high levels of amenorrhea. Both 17beta-E2 and CEE/TMG combinations have shown improved bone mineral density and quality-of-life assessments. Both continuous combined and sequential regimens of 17beta-E2/TMG and CEE/TMG have a favorable clinical profile. TMG provides an important new option for the treatment of postmenopausal symptoms and the prevention of osteoporosis.

Adult↗
PubMedDate not supplied

In vitro characterization of trimegestone: a new potent and selective progestin.

Trimegestone (TMG) is a novel 19-norpregnane progestin under development for hormone replacement therapy and oral contraception. The objective of the current study was to characterize the potency and steroid receptor selectivity of TMG in several in vitro assays and to compare its activity to that of medroxyprogesterone acetate (MPA). TMG and MPA had a similar competitive binding affinity for human and rabbit progesterone receptor (PR). However, TMG had a significantly higher affinity for rat PR (IC(50) = 3.3 nM) than MPA (IC(50) = 53.3 nM). In T47D cells, both compounds increased alkaline phosphatase activity and cell proliferation with comparable potencies (EC(50s) of 0.1 nM and of 0.02 nM, respectively). To further characterize the progestational activity and steroid receptor selectivity, we established an immortalized human endometrial stromal cell line (HESC-T). This cell line lacks endogenous estrogen receptor (ER) and PR but does have functional glucocorticoid receptors (GR). When ER is transiently expressed in the cells, 17beta-estradiol (E(2)) induces PR, allowing the study of PR-regulated genes. In HESC-T cells expressing exogenous ER, and therefore PR, both TMG and MPA increased HRE-tk-luciferase activity tenfold with an EC(50) of 0.2 nM. In HESC-T cells without exogenous ER, and therefore no PR, TMG did not induce HRE-tk-luciferase activity, whereas MPA induced the reporter activity with an EC(50) of about 10 nM. This MPA-induced reporter activity is believed to be mediated through GR. The steroid receptor selectivity of TMG was further evaluated using the HRE-tk-luciferase assay in the human lung carcinoma cell line A549, which contains GR but no PR. In these cells TMG had no effect on luciferase activity, whereas MPA increased the reporter activity in a dose-dependent manner with an EC(50) of approximately 30 nM. Furthermore, HRE-tk-luciferase assay in mouse fibroblast cell line L929, which expresses androgen receptor (AR) but no PR, showed that TMG had weak antiandrogenic activity whereas MPA had androgenic activity. In summary, data from several in vitro assays demonstrate that TMG is a potent progestin with a better receptor selectivity profile than MPA.

Adult↗
PubMed2003

The preclinical biology of a new potent and selective progestin: trimegestone.

Trimegestone (TMG) is a 19-norpregnane progestin being developed, in combination with an estrogen, for the treatment of postmenopausal symptoms. TMG binds to the human progesterone receptor with an affinity greater than medroxyprogesterone acetate (MPA), norethindrone (NET), and levonorgestrel (LNG). In contrast, TMG binds with low affinity to the androgen, glucocorticoid and mineralocorticoid receptor and has no measurable affinity for the estrogen receptor. Compared to other progestins, TMG demonstrates an improved separation of its PR affinity from its affinity to other classical steroid hormone receptors. In vivo, TMG has potent progestin activity. For example, TMG produces glandular differentiation of the uterine endometrium in rabbits and is about 30 and 60 times more potent than MPA and NET, respectively. In the rat, TMG maintains pregnancy, induces deciduoma formation, inhibits ovulation and has uterine anti-estrogenic activity. With respect to these endpoints, TMG appears to be more potent and selective on uterine epithelial responses than other classical progestin responses. In vivo, TMG does not have significant androgenic, glucocorticoid, anti-glucocorticoid or mineralocorticoid activity but does have anti-mineralocorticoid activity and modest anti-androgenic effects. This overall profile is qualitatively similar to progesterone. When TMG is administered chronically, it antagonizes the effect of estradiol on the uterus but does not antagonize the beneficial bone sparing activity of estradiol. In rat studies evaluating CNS GABAA receptor modulatory activity, TMG is less active on this likely undesirable endpoint than progesterone and norethindrone acetate, which may translate into fewer mood-related side effects. The results indicate that TMG is a potent and selective progestin with a preclinical profile well suited for hormone replacement therapy.

Animals↗
PubMed2005

[Propause survey: profile of patients treated with progestins in perimenopause].

UNLABELLED: Progestins are widely used in France for treatment of perimenopause. OBJECTIVES: To evaluate the real use of progestins in daily practice. MATERIAL AND METHODS: A transverse epidemiological survey conducted between May and June 1998, by 284 gynecologists representative of French private practitioner gynecologists, who selected the first 4 patients treated with progestins for perimenopause. RESULTS: For 887 observations collected, the most frequent indications of prescription were: functional disorders of perimenopause (57%), mastalgia (47%), premenstruel syndrome (38%), endometrial pathology (29%) and ovulation inhibition (28%). Multiple reasons were present in 81% of patients: when progestin was prescribed more than 10 days per cycle, breast pathologies were the most frequent indication and the length of treatment was more than one year; when progestin was prescribed 10 days per cycle, isolated menstrual irregularities (without breast or endometrium pathology) predominated and the length of treatment was one year or less. The most widely used progestin classes were pregnanes and norpregnanes; there was an estrogene co-prescription in 17% of cases, more frequently in women with perimenopause disorders. CONCLUSION: We found the following pattern for progestin prescription in perimenopause: 10-day prescription for one-third of the women, 11 to 15 days for one-third, and 20 days per cycle for one-third. We thus observe some differences with recommended use. This difference is observed either with the initial prescription or with symptom-related dose adaptation.

Drug Prescriptions↗
PubMed1993

Synthesis of 20-hydroxy-, 20-amino-, and 20-nitro-14-hydroxy-21-nor-5 beta,14 beta-pregnane C-3 glycosides and related derivatives: structure-activity relationships of pregnanes that bind to the digitalis receptor.

The preparation of derivatives of 14-hydroxy-21-nor-5 beta,14 beta-pregnane and 5 beta,14 beta-pregnane C-3 alpha-L-rhamnosides and tris-beta-D-digitoxosides is described. These derivatives, possessing a C-17 beta COCH2OH, CH2OH, CO2H, CO2Me, CH2NH2, or CH2NO2 group, bind to the digitalis receptor recognition site of heart muscle as measured in a radioligand binding assay. The 21-norpregnane derivatives consistently show greater binding affinity than the corresponding 20 alpha- and 20 beta-pregnane analogs. The C-20 nitro rhamnoside is comparable to digitoxin in binding affinity. The 17 beta-CH2NO2 group is the most effective replacement for the unsaturated lactone in the binding assay found so far, showing binding affinity comparable to that of the cardiac glycosides.

Binding Sites↗
PubMed2001

[New gestagens--advantages and disadvantages].

Due to their high oral bioavailability synthetic progestagens are used for therapy, hormone replacement therapy and contraception There are different types of progestogens. There are progesterone derivatives, nortestosterone derivatives (13-methyl-gonanes and 13-ethyl-gonanes), spirolactone derivatives and norpregnance derivatives which differ in their efficacy and hormonal profile. All progestagens show antiestrogenic activities, inhibit the estrogen-induced proliferation of the endometrium and, hence, decrease the risk of endometrial hyperplasia. With the exception of Dienogest, the derivatives of 19-nortestosterone are characterized by a 17-alpha-ethynyl group and show slight androgenic properties which may antagonise some estrogen-dependent alterations of hepatic serum parameters. Tibolone which is a derivative of norethynodel also belongs to this group. Among the nortestosterone derivatives, there are the so-called "Prodrugs". Prodrugs are rapidly transformed after intake to the active progestagens. Progesterone derivatives partly exert moderate androgenic or antiandrogenic effects, while the spirolactone derivative Drospirenone shows antimineralocorticoid and antiandrogenic activities. The progesterone derivatives as well as Gestodene and Desogestrel have certain glucocorticoid activities which, at the doses used, are not clinically relevant, but possibly may influence vascular function. The effects of 19-norpregnane derivatives are comparable with those of progesterone derivatives. According to their different hormonal profiles and activities, the various available progestogens allow the choice of preparations which are best suitable for the individual woman for contraception or hormone replacement therapy.

Biological Availability↗
PubMed2001

Effect of trimegestone alone or in combination with estradiol on bone mass and bone turnover in an adult rat model of osteopenia.

The effects of trimegestone (1 mg/kg/day orally), a novel norpregnane progestin, and 17 beta-estradiol (10 micrograms/kg/day subcutaneously), alone and in combination, on bone mass and turnover were investigated using an experimental model of osteoporosis involving ovariectomized rats. An equivalent dose (1 mg/kg/day orally) or norethisterone was used as a reference progestin. Six-month-old rats were ovariectomized and left untreated for 2 months to allow the development of osteopenia. Treatment with a progestin, alone or in combination with estradiol, was then started and continued for 2 months. Bone was assessed by a combination of static and dynamic histomorphometric measurements, by densitometry and by the use of biochemical markers of bone turnover. Ovariectomy induced a pronounced uterine atrophy, which was reversed by estradiol. Trimegestone effectively counteracted the uterotropic effect of estradiol, whilst norethisterone showed a less pronounced antagonistic effect. A severe osteopenia was established in the initial 2 months after ovariectomy, and further bone loss occurred during the 2-month treatment period in animals not receiving estradiol. This effect was associated with a marked increase in both biochemical and dynamic histomorphometric markers of bone turnover, reflecting in an imbalance between resorption and formation. 17 beta-estradiol given alone prevented further bone loss, but neither trimegestone nor norethisterone alone had a beneficial effect on bone mass and turnover. When given in combination with 17 beta-estradiol, however, trimegestone significantly improved its effect on bone mass and turnover. This effect was more potent than that induced by combined 17 beta-estradiol and norethisterone therapy. We conclude that trimegestone, when combined with 17 beta-estradiol, is a more effective progestin than norethisterone in preventing bone loss in adult ovariectomized rats.

Administration, Oral↗
PubMed2001

Effects of 17 beta-estradiol and trimegestone alone, and in combination, on the bone and uterus of ovariectomized rats.

Trimegestone is a novel norpregnane progestin, which is being developed, in combination with 17 beta-estradiol, for the treatment of menopausal symptoms and prevention of postmenopausal osteoporosis. A model of osteoporosis in the ovariectomized rat has been used to evaluate the effects of 17 beta-estradiol and trimegestone, alone and in combination, on bone and uterus in these animals. Two treatment protocols were investigated, preventive with treatment starting immediately after ovariectomy and curative with treatment starting 1 or 6 months after ovariectomy. 17 beta-Estradiol was administered subcutaneously at a dose of 10 micrograms/kg/day with trimegestone or norethisterone being administered orally at a dose of 1 mg/kg/day; treatment was given 5 days per week. Treatment on both protocols was for 6 months. Given alone, 17 beta-estradiol maintained bone mass, either partially or completely, when given on the preventive protocol, or on the curative protocol with treatment starting 1 month after ovariectomy; it did not restore bone mass when given on the curative protocol with 6 months lapsing between ovariectomy and start of treatment. Trimegestone did not block the beneficial effects of 17 beta-estradiol on bone. 17 beta-Estradiol induced uterine hypertrophy on all these protocols and this was blocked completely by trimegestone. Trimegestone administered alone had no effect on bone or uterus but, when given in combination with 17 beta-estradiol, it did not inhibit the effect of 17 beta-estradiol in maintaining bone mass but completely blocked its uterotropic effect. Norethisterone at a similar dose did not inhibit the effects of 17 beta-estradiol on bone but also did not block its uterotropic effect.

Animals↗