Inhibition of folliculogenesis and ovulation by the antiprogesterone RU 486.

Healthy, regularly menstruating women were treated with the antiprogesterone RU 486, Mifepristone (Roussel-Uclaf, Romainville, France) during the follicular phase of the cycle. Three women were given 25 mg of RU 486 on days 1 to 14 of the cycle and five received 25 mg on days 1 to 21 of the cycle. Venous blood samples were collected three times per week during a control cycle and during one treatment cycle in each subject.

Effects of the antiglucocorticoid RU 486 on adrenal function in dogs.

We studied the antiglucocorticoid effects of RU 486 given orally in doses of 5 (low), 20 (intermediate), and 50 mg/kg (high) daily for 10 days to seven female mongrel dogs. No changes in plasma ACTH or cortisol levels were produced by the 5 mg/kg dose. Plasma ACTH levels increased 3-fold with both intermediate and high dosages.

Effects of the antiprogesterone RU 486 in normal women. I. Single-dose administration in the midluteal phase.

The response to a single oral dose of the antiprogesterone RU 486 was studied in the midluteal phase in 26 normal women. Each subject received a dose between 50 and 800 mg RU 486 on days 6 to 8 after the luteinizing hormone surge and blood samples were taken over the following 48 hours. Another group of five patients received a single oral dose of 200 mg RU 486 and blood sampling was extended for 14 days.

Intravaginal administration of RU 486 in humans and rats: inadequate absorption in humans.

Vaginal absorption of the antiprogesterone steroid RU 486 was studied in humans and rats. In rats, RU 486 was sufficiently absorbed to terminate early pregnancy following vaginal, oral or intramuscular administration. The quantitation of RU 486 in serum showed that the ratios of the areas under the concentration curves per mg administered were 1:2.

Metabolism and serum binding of RU 486 in women after various single doses.

The metabolism of RU 486 was studied in female volunteers following a single oral administration of 100, 400, 600 or 800 mg of RU 486. The serum concentrations of RU 486 were generally not affected by the dose within the range examined and they stayed at micromolar concentrations during the 48 h studied. RU 486 was metabolized extensively in a dose-dependent manner by two-step demethylation, and by hydroxylation.

Termination of early gestation with the anti-progestin steroid RU 486: medium versus low dose.

RU 486 is a synthetic steroid which has antiprogesterone and antiglucocorticoid activity. In order to determine the optimal dosage of this drug to terminate early pregnancy, we treated 106 healthy women with normal pregnancies by real time ultrasound examination whose gestational duration was less than 49 days from onset of last menses with either a medium or low dose treatment regimen. A total of 66 patients received the medium dose regimen (100 mg/day X 7 days).

Plasma concentrations and receptor binding of RU 486 and its metabolites in humans.

Using Chromosorb chromatography and HPLC, we measured the plasma concentrations of RU 486, and its monodemethylated (RU 42633), didemethylated (RU 42848) and alcoholic nondemethylated (RU 42698) metabolites up to 72 h following oral ingestion of 100 mg of RU 486 by five female volunteers. The peak plasma level of RU 486 (4.5 mumol/l) occurred within 1 h after ingestion of the compound; at this point significant amounts of the metabolites were also present in the plasma.

Pharmacokinetics and metabolism of RU 486.

The effects of dose on the initial pharmacokinetics and metabolism of an antiprogesterone steroid RU 486 (mifepristone) were studied in healthy female volunteers after administration of RU 486 as a single dose of 50-800 mg. The concentrations of RU 486 and its monodemethylated, dimethylated and hydroxylated non-demethylated metabolites were measured specifically after Chromosorb-column chromatography by HPLC. Their relative binding affinities to the human uterine progesterone receptor were also determined.

Quantitation of RU 486 in human plasma by HPLC and RIA after column chromatography.

Chromosorb column chromatography was used for separation of RU 486 from its immunologically cross-reacting metabolites prior to quantitative analysis by radioimmunoassay (RIA) or high-performance-liquid chromatography (HPLC). The results of the two assay methods were in good agreement with each other (r = 0.99, n = 29).

Sustained intrauterine release of levonorgestrel over five years.

Two models of levonorgestrel-releasing intrauterine devices were studied. Model A was designed to deliver 20 micrograms/day, and model B was designed to deliver 30 micrograms/day. Plasma concentrations of levonorgestrel were determined in blood samples taken from women who used the levonorgestrel-releasing intrauterine devices (IUDs) and who participated in a clinical trial for more than 5 years.

Five years' experience with levonorgestrel-releasing IUDs.

Two levonorgestrel-releasing IUDs and a copper-releasing IUD of the same shape were studied in a randomized comparative study over five years. The levonorgestrel-releasing IUDs released 20 micrograms or 30 micrograms per day. The Pearl index during the 10,600 woman-months of LNG-IUD use was 0.

Hormonal and morphologic effects of bromocriptine on normal rat pituitary and GH3 tumor cells.

Bromocriptine in concentrations up to 5 X 10(-4) mol/L was studied for any deleterious effects upon normal rat pituitary cells, as well as on the rat GH3 cell line. Normal rat pituitary glands were obtained by decapitation from 50-day-old female Wistar rats and dispersed with 0.25% trypsin.

Concentration-dependent mechanisms of ovulation inhibition by the progestin ST-1435.

We summarize the hormonal profiles of women at different stages of inhibition of ovarian function during sustained-release subcutaneous treatment with a progestin, ST-1435. In the highest release group of ST-1435, a decrease in the luteinizing hormone (LH)follicle-stimulating hormone (FSH) ratio was found; and in spite of follicular phase levels of plasma FSH, inhibition of folliculogenesis, as judged by plasma estradiol (E2) concentrations below 60 pg/ml, occurred during the entire treatment period of 230 days. This may be indicative of a direct action of ST-1435 on the ovaries.

Contraception with subdermal ST-1435 capsules: side-effects, endocrine profiles and liver function related to different lengths of capsules.

One Silastic capsule of 15 mm, 20 mm or 30 mm length was inserted subcutaneously into the ventral aspect of the left forearm or upper arm of 28 healthy women during menstrual bleeding or not later than on the seventh day of the menstrual cycle. A new capsule of the same length was inserted after six months and both capsules were removed twelve months after the first insertion. Side-effects, including changes in body weight, blood pressure, menstrual bleeding and liver function test results, were registered.

Immediate postabortal contraception with Norplant: levonorgestrel, gonadotropin, estradiol, and progesterone levels over two postabortal months and return of fertility after removal of Norplant capsules.

Six Silastic levonorgestrel-releasing capsules, Norplant, were introduced subcutaneously into the ventral aspect of the left forearm or upper arm of thirteen patients immediately after first trimester pregnancy termination. Blood samples were taken twice a week over two months after abortion and from one subject over one month after removal of Norplant capsules. Plasma concentrations of levonorgestrel were measured by radioimmunoassay and the effects of treatment on pituitary and ovarian function were determined by assaying plasma concentrations of LH, FSH, estradiol and progesterone.

Pharmacokinetic observations on ST-1435 administered subcutaneously and intravaginally.

Plasma levels of ST-1435 were determined by radioimmunoassay in 36 women and three men during treatment with subdermal capsules releasing ST-1435. The total lengths of the capsules used were 180 mm, 90 mm, 30 mm, 15 mm and 7.5 mm.

Intestinal absorption of ST-1435 in rats.

The intestinal absorption of a 19-norprogesterone (ST-1435) was studied in rats after an oral dose of 5 mg ST-1435/kg body weight. Blood samples were collected simultaneously from the portal vein and by cardiac puncture. Plasma ST-1435 concentrations were measured from the samples by radioimmunoassay (RIA).

Intracervical release of ST-1435 for contraception.

Seven women used an ST-1435-releasing intracervical contraceptive device (ST-ICD), inserted immediately after the cessation of menstrual bleeding. Patterns of bleeding and clinical performance were evaluated and plasma concentrations of ST-1435, estradiol, progesterone and gonadotropins were measured by radioimmunoassays. The results of ten months of treatment are presented.

Pituitary and ovarian function and clinical performance during the use of a levonorgestrel-releasing intracervical contraceptive device.

A levonorgestrel-releasing intracervical device (ICD) was inserted postmenstrually to twenty-one voluntary women. Eight subjects gave blood samples twice a week during the initial three months of use of the ICD and during the seventh and twelfth months of use. Clinical performance was studied; plasma concentrations of levonorgestrel were measured by radioimmunoassay and the effects of the treatment on pituitary and ovarian function were determined by assaying plasma concentrations of LH, FSH, estradiol and progesterone.

Ovarian function in amenorrheic and menstruating users of a levonorgestrel-releasing intrauterine device.

The ovarian function of 20 healthy users of a levonorgestrel-releasing intrauterine device was studied by measurements of plasma estradiol, progesterone, and levonorgestrel concentrations. Eight subjects were amenorrheic, and 12 had regular menstrual bleeding. Seventy-five percent of the subjects in both groups had ovulatory cycles.

Postabortal contraception with norethisterone enanthate injections.

Intramuscular injection of 200 mg norethisterone enanthate (NET-EN) was given to five women on the day of first trimester abortion. The injection was repeated twice at eight-week intervals, and thereafter at twelve-week intervals for one year. Plasma samples were collected for FSH, LH/hCG, estradiol, progesterone and norethisterone (NET) determinations.