Can a change in screening and prescribing practice reduce the risk of venous thromboembolism in women taking the combined oral contraceptive pill?

The risk of Venous thromboembolism (VTE) associated with low dose combined oral contraceptive pills (COCs) is low at between 15 and 30 cases per 100 000 women years of use. Screening the total population or even those women with a family history of VTE in a first degree relative is unlikely to have a major impact on the number of cases of VTE associated with COC. Women with a known family history of an inherited thrombophilia should have this defect excluded before taking COCs.

Metabolic interrelationships, cardiovascular disease, and sex steroids.

Future studies of the pharmacodynamics of oral contraceptives should encompass interactions between various areas of physiology rather than concentrate on single metabolic processes. Changes in one area of metabolism may affect other areas. Insulin plays a central role in metabolic control and, in addition to profound effects on carbohydrate and lipid metabolism, also affects the hematological system.

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.

Enlarged follicles in women using oral contraceptives.

Ultrasound examination of the ovaries was performed in the first and/or second half of three consecutive cycles in 3 groups of women; Group T who had been using a levonorgestrel triphasic oral contraceptive for at least 6 months, Group P who had been using a progestogen-only pill for at least 6 months, and Group C, a control group. Any follicles greater than 10 mm in diameter and any cysts were measured. Fifty-three scans were performed in Group T, 45 in Group P and 31 in Group C.

Levonorgestrel. Clinical pharmacokinetics.

Published values for the serum concentrations and pharmacokinetic parameters of levonorgestrel after administration of various doses of levonorgestrel alone or with ethinylestradiol are reviewed. Most data apply to oral administration of the gestagen, with the smaller amount of data for other modes of administration, e.g.

Twelve years of clinical experience with an oral contraceptive containing 30 micrograms ethinyloestradiol and 150 micrograms desogestrel.

The clinical experience with a combined oral contraceptive (COC) containing 150 micrograms desogestrel and 30 micrograms ethinylestradiol is reviewed. Fourteen clinical trials have been reported involving over 44,000 women for more than 190,000 cycles. None of the 17 pregnancies which occurred (overall Pearl Index 0.

New progestogens in oral contraception.

The major developments in combined oral contraceptives (COCs) have been a reduction in the total dose of both the oestrogen and progestogen administered per cycle and the introduction of new progestogens which are claimed to be more 'selective' than the older ones. This review examines in detail the clinical efficacy of the new COCs, where possible in comparison with those containing levonorgestrel or norethisterone, and their pharmacological effect on carbohydrate and lipid metabolism, haematological factors, pituitary-ovarian function and serum protein and androgen concentrations. Based mainly on the pharmacological evidence, the newer COCs are an improvement over the older low-dose formulations and are clearly preferable to the high-dose ones.

Pharmacokinetic study of RU 486 and its metabolites after oral administration of single doses to pregnant and non-pregnant women.

RU 486 and three of its metabolites (RU 42633-monodemethyl, RU 42848-didemethyl, and RU 42698-hydroxymetabolite) were determined by HPLC in plasma from nine non-pregnant and 36 pregnant women. Each non-pregnant subject took an oral dose of RU 486 (25, 100, 400 and 600 mg consecutively) once per menstrual cycle. Six of the nine women also received a dose of 200 mg.

Effects of different doses of norethisterone on ovarian function, serum sex hormone binding globulin and high density lipoprotein-cholesterol.

The ovarian effects of different doses of norethisterone (NET) were compared in 45 normally menstruating women in order to find the lowest effective dose of the Chinese NET "visiting pill". Subjects were randomly divided into 3 groups. Each subject in each group was taking 0.

Clinical experience and pharmacological effects of an oral contraceptive containing 20 micrograms oestrogen.

The performance of a new low-dose oral contraceptive (Mercilon) containing only 20 micrograms ethinyloestradiol combined with 150 micrograms desogestrel is reviewed. Eight multicentre clinical trials have been completed and provide information on 10,672 women studied over 73,477 cycles. The high efficacy of Mercilon was indicated by the finding that only 10 pregnancies were reported; nine of these occurred in women who omitted to take Mercilon on a number of days and only one in a woman who took all the tablets according to instructions.

Long-term use of depot-norethisterone enanthate: effect on blood lipid fractions.

This is the third report of a metabolic study on 56 long-term users (24 for 2-5 yr; 32 for over 5 yr) of the injectable contraceptive norethisterone enanthate (Net-En) and deals with the effects on the blood levels of lipoprotein fractions. There was no significant difference between this group and a group of 30 non-users in serum concentrations of triglycerides, total cholesterol, low density and very low density lipoproteins. There was a significant reduction in mean high density lipoprotein levels between the controls and the user groups (16% for the intermediate duration and 12% for the longer duration).

A cross-over study of three oral contraceptives containing ethinyloestradiol and either desogestrel or levonorgestrel.

A randomised cross-over trial was performed to compare the pharmacodynamic actions of three low-dose oral contraceptives (OCs): Marvelon (150 micrograms desogestrel (DSG)+ 30 micrograms ethinyloestradiol (EE)), Mercilon (150 micrograms DSG + 20 micrograms EE) and Microgynon (150 micrograms levonorgestrel (LNG) + 30 micrograms EE). None of the OCs produced any significant changes in serum cholesterol, LDL-C and apoprotein B. Triglycerides were increased by the desogestrel OCs but not by Microgynon.

Intrasubject variability in the pharmacokinetics of ethynyloestradiol.

Intrasubject and intersubject variability in the metabolism of ethynyloestradiol (EE) was assessed in a cross-over randomized study of 6 women who each received 3 months treatment with 50 micrograms EE and 50 micrograms EE with 250 micrograms levonorgestrel (LNG). Blood samples were collected at the end of each treatment month, assayed for EE and the half-life of elimination (Tel) and bioavailability (area under the serum concentration-time curve, AUC) calculated. Intrasubject variability for Tel and AUC varied markedly; the variability was random and not correlated with the formulation administered.

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.

Clinical experience with the progestogen-only pill.

Experience with the progestogen-only pill (POP) in a family planning clinic is presented. From the clinic records, 408 women were identified who had opted to use a POP. Of these, 50 women had used the POP during lactation and these were excluded from the analysis.

A pharmacodynamic and pharmacokinetic study of the Chinese No. 1 pill.

A pharmacodynamic and pharmacokinetic study of the Chinese No. 1 pill, a combined oral contraceptive containing 35 micrograms ethynyloestradiol (EE) and 600 micrograms norethisterone (NET), was performed in 29 women over a period of six months. Blood samples for analysis were taken during a pretreatment cycle, the first and 6th treatment cycles and post-treatment.

Hemostatic changes in women using a monthly injectable contraceptive for one year.

The effect of consecutively injecting a one-a-month contraceptive (norethisterone enantate 50 mg with estradiol valerate 5 mg) for one year on haematological parameters was evaluated in 42 Chinese women. The healthy volunteers were randomly allocated to either the treatment group (22) or a control group (20). Blood samples were collected in the follicular and luteal phases of a pretreatment cycle, on days 28 +/- 3 after the 1st, 3rd, 6th, 12th injections and in the luteal phase of the post-treatment cycle.

Pharmacokinetics of gestagens: some problems.

Various approaches to studying the pharmacokinetics of gestagens and the factors that influence derivation of the parameters are described with levonorgestrel used as an example. Published studies of the pharmacokinetics of levonorgestrel are reviewed, and new information is presented regarding intra- and intersubject variation. Differences between various formulations of levonorgestrel are apparent when the formulations are compared in the same subjects.

Potency and pharmacokinetics of gestagens.

Serum concentrations of gestagens were compared after single doses and after multiple doses (steady-state conditions) of four widely used oral contraceptives containing norethisterone (NET), levonorgestrel (LNG), desogestrel (DSG) and gestodene (GSD). There were marked differences among the gestagens with respect to the serum concentrations. Under steady-state conditions 12 h after dosing, the relative concentrations were approximately GSD, 4.

Comparative cross-over pharmacokinetic study on two types of postcoital contraceptive tablets containing levonorgestrel.

A pharmaceutical and pharmacokinetic study was carried out on levonorgestrel tablets from two different sources (Hungarian- and Chinese-made). Both preparations contained 0.75 mg levonorgestrel and had been shown to have similar contraceptive efficacy and side effects when used for postcoital contraception.

Pharmacokinetic study of orally administered RU 486 in non-pregnant women.

A method based on HPLC was devised for the estimation of RU 486 in blood and utilised to study the pharmacokinetics of a single dose of 50 mg RU 486 administered orally to 12 women on day 7 of the cycle. The dose was rapidly absorbed with peak plasma concentration between 1 and 2 hours. Distribution was also rapid (mean t1/2 alpha: 1.

Effect of some oral contraceptives on serum concentrations of sex hormone binding globulin and ceruloplasmin.

Serum SHBG and ceruloplasmin (CP) concentrations were measured in women throughout a cycle of treatment with four oral contraceptives. In women receiving 150 micrograms levonorgestrel (LNG) daily both SHBG and CP decreased. SHBG also decreased, but CP increased, in women receiving ethynyloestradiol (EE) 30 micrograms with LNG 150 micrograms.