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Results for “Progesterone--pharmacodynamics”

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At least 19 recordsLinked to original sources
PubMed1990

Interactions with oral contraceptives.

The interaction of a range of different factors with the pharmacologic activity of oral contraceptives is reviewed. Pharmacokinetic interactions with oral contraceptives may occur (1) during absorption and extrahepatic circulation, (2) by interfering with protein binding, and (3) during hepatic metabolism. The hepatic mixed function oxidase system, which is mainly responsible for the metabolism of oral contraceptives, is affected by several different factors and is easily induced. Nutrition affects the activity of many drugs, but information regarding oral contraceptives is meager. Both pharmacokinetic and pharmacodynamic interactions, which may be synergistic or antagonistic, between the estrogen and gestagen components of oral contraceptives, are important, but there is no correlation between the rate of metabolism of the two components. Evidence suggests that some anticonvulsant, antibiotic, and antibacterial drugs may reduce the efficacy of oral contraceptives. Instances of interactions of other therapeutic agents are reported infrequently. The incidence of serious interactions is low and does not appear to have been reduced with low-dose oral contraceptives, probably because of large intersubject variability in the pharmacokinetics of oral contraceptives.

Blood Proteins↗
PubMed1990

Gastrointestinal disease and oral contraception.

Oral contraceptive steroids play a major role in modern family planning. With the present tendency to decrease the doses of both estrogens and progestogens, any factor that reduces the bioavailability of the lower-dose preparations may have an impact on contraceptive protection. Although ethinyl estradiol, the most commonly used oral estrogen, is liable to an enterohepatic circulation as unchanged drug, the commonly used progestogens are not. At present, no convincing evidence exists in the human subject that disruption of the enterohepatic circulation by antibiotics or antacids does reduce contraceptive efficacy of the pill. Oral contraceptive steroids are mainly absorbed from the small bowel, and contraceptive efficacy depends on its absorptive capacity. Enhanced passage of gastrointestinal contents or impaired absorption may thus contribute to contraceptive failures in patients who have chronic inflammatory disease, diarrhea, ileostomy, or jejunoileal bypass.

Antacids↗
PubMed1990

Effects on the endometrium, endo- and exocervix following the use of local progestogen-releasing delivery systems.

Some conflicting reports have appeared in the literature as to the effect of progestogens on the endometrium and on the endo- and exocervix in animals and humans. Hyperplasia of the endometrial and endocervical epithelium has been reported in some non-human primates following the administration of progestogens. In other studies no evidence has been found for such changes. In women using combined oral contraceptives, it has been claimed that the progestogen component causes adenomatous hyperplasia of the endocervix and that this hyperplastic transformation could be a precursor to adenocarcinoma of the cervix. So far, there is, however, no evidence in the literature to confirm this hypothesis. In view of the development of new delivery systems with a constant release of small amounts of progestogens, previous reports in the literature on hyperplasia and potential malignant transformation of the endometrium and the endocervix have been a matter of concern. The aim of the present study is therefore to review results from studies in animals and humans in particular with reference to the effect of a local release of various progestogens on the endometrium and the endo- and exocervix.

Animals↗
PubMed1992

Progesterone-releasing vaginal rings for use in postpartum contraception. II. Pharmacokinetic profiles in women.

Vaginal rings releasing progesterone with 3 different initial release rates (5, 8 and 20 mg/day) were used by 11, 10 and 10 women, respectively. The period of insertion was 90 days. The 5 and 8 mg/day rings consisted of a core loaded with progesterone, the 20 mg/day ring contained progesterone homogeneously distributed throughout the mass of the ring. Notwithstanding these differences, the total progesterone levels (areas under curve) were directly related to the release rates. So were the rates of decrease of progesterone levels during the 90 days of insertion of the ring. They were 25, 31 and 47% for the rings releasing 5, 8 and 20 mg/day, respectively.

Administration, Intravaginal↗
PubMed1996

Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy.

The concept of bioavailability is discussed with particular references to the sex steroids. Problems encountered in the measurement of bioavailability of these steroids and the various factors that may affect their bioavailability are briefly described. Information regarding the bioavailability of the estrogens and gestogens, some of which are prodrugs, used in oral contraception and hormone replacement therapy is summarized and the implications regarding the clinical use of these steroids are discussed.

Absorption↗
PubMed1987

Differences in the association of the progesterone receptor ligated by antiprogestin RU38486 or progestin ORG 2058 to chromatin components.

We assessed the hypothesis that due to variations in the conformation of the progesterone receptor induced by the antiprogestin RU38486 compared to the progestin ORG 2058, differences may result in the association of the receptor with some of the chromatin components. The physical properties of the receptor-bound chromatin fragments released by micrococcal nuclease digestion were characterized by sucrose gradient sedimentation and by gel filtration on Agarose A-1.5m or Agarose A-5m columns. The nuclear fraction was isolated from T47D cells previously exposed to 0.1 microM [3H]RU38486 or 0.1 microM [3H]ORG 2058. Micrococcal nuclease digestion solubilized two receptor forms sedimenting at 4.4 S and 6.3 S for the antiprogestin bound receptor and only one receptor at 4.4 S for the progestin ligated receptor. High-salt buffer dissociated either the antiprogestin or the progestin-bound receptor to smaller receptor forms sedimenting at 3.5 S. Chemical cross-linking with the cross-linker 2-iminothiolane of the micrococcal nuclease solubilized receptor forms resulted in 6.7-S and 4.4-S forms sedimenting on 0.4 M KCl gradients for the antiprogestin and progestin ligated receptors, respectively. Stokes radii of 7.3 nm and 6.4 nm were determined by gel filtration in 0.4 M KCl for the 6.7-S and the 4.4-S receptor forms, respectively. Using the sedimentation coefficient and the Stokes radius, molecular weights of 202,000 and 116,000 were calculated for the antiprogestin and progestin ligated receptors. We conclude that the micrococcal nuclease solubilized antiprogestin ligated receptor is associated with additional or different chromatin components compared to the progestin bound receptor.

Cell Line↗
PubMed1990

Pharmacokinetics of oestrogens and progestogens.

There are large inter- and intra-individual variations in the serum concentrations of natural and synthetic sex steroids irrespective of the route of administration. Oral ingestion of steroids has a stronger effect on hepatic metabolism than parenteral administration, as the local concentration in liver sinusoids are 4-5 times higher during the first liver passage. Oestradiol and oestrone are interconvertible, dependent on the local concentrations in liver and target organs, and oestrone sulphate serves as a large reservoir. The oestrone/oestradiol ratio has no physiological significance, as oestrone is only a weak oestrogen. Oestrone is both a precursor and a metabolite of oestradiol. Oestriol is extensively conjugated after oral administration. Therefore, the oestriol serum levels are similar after oral intake of 10 mg and after vaginal application of 0.5 mg oestriol resulting in similar systemic effectiveness. Conjugated oestrogens can easily enter the hepatocytes but are hormonally active only after hydrolyzation into the parent steroids. Ethinylestradiol which exerts strong effects on hepatic metabolism and inhibits metabolizing enzymes, should not be used for hormone replacement therapy. Among the progestogens, the progesterone derivatives have less effects on liver metabolism than the norethisterone derivatives (13-methyl-gonanes and 13-ethyl-gonanes). The highly potent 13-ethyl-gonanes are effective at very low doses, because of a slow inactivation and elimination rate due to the ethinyl group.

Estrogens↗
PubMed1991

Progesterone administration by nasal spray.

The bioavailability and the clinical usefulness of the P administered by nasal spray were investigated. Ten healthy menopausal women received an IN spray administration (4 doses of an oleic P solution 20 mg/mL, corresponding to nearly 11.2 mg of P) and the circulating P levels were calculated. Sixty minutes after administration, the maximum concentration (CMax, 3.75 +/- 0.214 ng/mL) was reached. High P levels (greater than 2 ng/mL) lasted until 360 minutes, and the AUC 0 to 720 was 1,481.6 +/- 343 ng.h/mL. Progesterone administration by spray formulation has proven to be effective in reaching therapeutic levels and to be acceptable to patients and, probably, clinically safe.

Absorption↗
PubMed1991

Comparative bioavailability of orally and vaginally administered progesterone.

OBJECTIVE: To study the pharmacokinetics of progesterone (P) in healthy premenopausal female volunteers to compare the bioavailability of orally or vaginally administered hormone. DESIGN: Subjects were randomly allocated to receive either oral P or a vaginal pessary then crossed over to the alternate preparation 1 month later. SETTING: The study was conducted in outpatient setting. SUBJECTS: All subjects were healthy, normal female volunteers who underwent a physical and gynecological examination before the study. None were using oral contraceptives. Ten subjects (mean age 32.6 +/- 7.3 years) entered the study and all completed it. INTERVENTIONS: Progesterone was administered as 200 mg of micronized hormone or as a pessary containing 400 mg. MAIN OUTCOME MEASURE: Plasma levels of P were measured by radioimmunoassay to test the apriori hypothesis of similar bioavailability. RESULTS: Peak plasma P concentrations attained within 4 hours after oral administration ranged from 8.5 to 70.6 ng/mL, whereas after vaginal administration the peak levels were attained within 8 hours and ranged from 4.4 to 181.1 ng/mL. Considerable interindividual variation was noted. Area under the plasma concentration-time curve for the two formulations was not significantly different (F = 1.09; P greater than 0.1; ANOVA). CONCLUSIONS: The two formulations had similar bioavailability.

Administration, Oral↗
PubMed1990

High progesterone receptor concentration in a variant of the ZR-75-1 human breast cancer cell line adapted to growth in oestrogen free conditions.

Culture of ZR-75-1 human breast cancer cells for 5 days in the absence of oestrogens (phenol red-free medium supplemented with dextran coated charcoal stripped 5% fetal calf serum) resulted in a slowing of growth rate and loss of progesterone receptors. Oestradiol at 10(-9) M markedly stimulated growth and progesterone receptor synthesis over a 5-day period. While medroxyprogesterone acetate (10(-10) to 10(-6) M) inhibited growth of ZR-75-1 cells growing in complete medium, in the short-term absence of oestrogens low concentrations were growth stimulatory. Cells deprived of oestrogens for 5 days retained sensitivity to growth inhibition by 4-hydroxy tamoxifen. ZR-75-1 cells were also adapted to growth in the absence of oestrogens over a 5-month period. These cells (ZR-PR-LT) failed to express binding sites characteristic of the type 1 oestrogen receptor but progesterone receptor expression was at a level normally associated with oestrogen induction. Adapted cells were growth inhibited by oestradiol, 4-hydroxy tamoxifen and medroxyprogesterone acetate, but despite elevated progesterone receptor expression the progestin was only marginally more inhibitory than in the parent line. Our data indicate a poor quantitative relationship between response to progestins in vitro and progesterone receptor concentration and support previous findings that acquisition of an oestrogen independent phenotype does not necessarily result in resistance to anti-oestrogens.

Antineoplastic Agents↗
PubMed1992

[Hormonal contraception and substitution therapy: the importance of progestogen for cardiovascular diseases].

Epidemiological data have demonstrated, that the progestogen component of oral contraceptives is involved in the development of hypertension, ischaemic heart diseases and stroke. It had been suggested, that atherosclerotic lesions due to the unfavourable effect on lipid metabolism of progestogens with androgenic properties, play a causal role. It has, however, been shown, that there is no development of atherosclerosis despite reduced HDL and elevated LDL, presumably because of the induction of hepatic LDL- and remnant-receptors by the strong effect of ethinyl-oestradiol upon the liver. A series of experimental and clinical findings indicates that vasospasms caused by the vasoconstrictory effect of progestogens are involved in the development of arterial thromboses. In postmenopausal women, the additional administration of progestogens to the oestrogen treatment may trigger ischaemic diseases, particularly in the presence of vascular lesions. Oestrogens exercise a pronounced vasodilatory effect and stabilize the vascular tonus--through changes in the responsiveness of endothelium and smooth muscle cells to vasoactive compounds, through modulation of neurotransmitter release from nerve endings, and through direct blocking of calcium channels. The effects depend essentially on an intact endothelium. By a direct action on the vascular wall, progestogens increase the sensitivity of arteries to vasoconstrictory compounds and reduce blood flow. As aldosterone increases the number of beta-adrenergic receptors in the arterial smooth muscle cells and thus act vasodilatorily, it cannot be excluded, that progestogens with high affinity to the aldosterone receptor and antimineralocorticoid properties, may exert a strong vasoconstrictory effect.(ABSTRACT TRUNCATED AT 400 WORDS)

Cardiovascular Diseases↗
PubMed1987

Effects on the breast of drugs used in fertility regulation.

The action of fertility-regulating drugs on the breast is discussed. Compounds such as steroids act directly on breast tissues, whereas others, such as clomiphene or gonadotrophin, act indirectly. There can be differential responses of the alveolar and ductal systems. Tissues of a breast tumour typical of epithelial tissues were analysed for changes in cytosolic and nuclear receptors for oestradiol-17 beta and progesterone following its exposure to these steroids. Effects on cell multiplication and receptor density were identified. The relationship of these findings to benign breast disease and oral contraceptives is discussed.

17-Hydroxysteroid Dehydrogenases↗
PubMed1984

Serum levels of progesterone and some of its metabolites including deoxycorticosterone after oral and parenteral administration.

Single 100-mg doses of progesterone were given orally and as intramuscular injections to four women during the follicular phase of the menstrual cycle. After oral administration serum levels of progesterone increased rapidly to reach luteal phase values (mean maximum level 55.6 nM) within 1-4 h and were still elevated after 12 h. The serum concentrations of 20 alpha-hydroxy-4-pregnen-3-one showed a similar pattern while there were only minor transient changes in 17 alpha-hydroxyprogesterone concentrations. The serum levels of cortisol and 4-androstene-3,17-dione were unaffected. In comparison, after intramuscular administration values two to three times higher than by the oral route were achieved. A significant increase in serum deoxycorticosterone was recorded in all women. The mean ratio between the change in deoxycorticosterone and progesterone was increased after oral administration. Oral treatment with natural progesterone may develop into an attractive alternative to synthetic progestogens but the conversion of progesterone into a potent mineralocorticoid may be a potential disadvantage.

17-alpha-Hydroxyprogesterone↗
PubMed1981

Minimal dose combined hormonal replacement therapy for menopausal women.

The problem of managing postmenopausal women with hormonal replacement therapy is reviewed. A case is clearly made for using progestogen in every instance when women receive oestrogen in the menopause. By this means the incidence of carcinoma is reduced to at least the rate found in non-treated patients and perhaps even lower. The biochemical changes leading to this reduction are summarized, and a suggestion is made regarding the optimal dosage of progestogen. This paper presents evidence to suggest that minimal doses of progestogen given for at least ten days in each month will protect endometrial target cells.

Biopsy↗
PubMed1992

Progestins and breast cancer: an epidemiologic review.

OBJECTIVE: To provide a worldwide review of all studies that have examined the relationship between progestins, as contained in both contraceptive and postmenopausal replacement therapies, and breast cancer risk. An overview of utilization patterns for progestins, as well as a review of possible biological mechanisms for progestins' action on breast tissue, are also presented. DATA IDENTIFICATION: All major epidemiologic studies conducted since 1980 have been identified through MEDLINE searches through the published literature and personal communications with prominent researchers in the area. STUDY SELECTION: Only studies that specifically examined the effects of progestin use are discussed here; these include investigations of progestins, in combination or singularly, as the main hypothesis or a subgroup analysis. RESULTS: The majority of studies have examined combination estrogen and progestin products (oral contraceptives), and subgroup analyses of progestins have been impeded by low statistical power and the fact that each progestin possesses different types of pharmacological activity. Only a few studies of long-acting injectable progestins exist, confirming a general lack of specific information on the progesterone-breast cancer relationship. Investigations of the effect on breast cancer of the addition of progestins to postmenopausal replacement therapy have also produced inconsistent results. CONCLUSIONS: To date, there is no consistent evidence of an association between progestins and breast cancer. There is need for further study, particularly of patients in potentially high-risk groups, including those with (1) extended hormone exposure before age 25 and/or first full term pregnancy and (2) exposure in the postmenopausal period.

Breast Neoplasms↗
PubMed1991

Antiprogesterones.

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Abortifacient Agents↗