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. Insulin has been proposed as a major physiological regulator of plasminogen activator inhibitor, and hyperinsulinemia is associated with increased blood coagulability and decreased fibrinoloysis. There is a close relationship between insulin and triglyceride metabolism, and this may affect factor VII activity in blood. There are many interactions between lipid metabolism and hematological factors. The apoprotein of lipoprotein (a) is structurally similar to plasminogen. Tissue factor pathway inhibitor, a regulator of coagulation, circulates in blood bound to LDL and HDL. Some fatty acids may act as a contact surface for activation of hematological factors. Dietary factors also need to be considered. Changes not only in the quantity but also in the composition of dietary fat influence lipid metabolism and also blood levels of a number of hematological factors. Other aspects of pharmacodynamic studies that require consideration and other factors that affect metabolic interrelationships are discussed.

PIP: Previous studies of the pharmacodynamics of sex steroids in vivo have tended to focus on single metabolic processes, with scant attention to their integration. This paper reviews the human in vivo research evidence on the effects of diet on metabolism, the central role of insulin in metabolic control, and the interaction between lipid metabolism and hematologic factors. There is a need for more attention to events occurring within vascular tissue itself, especially at the site of atherosclerosis and thrombus formation. Insulin has been proposed as a major physiologic regulator of plasminogen activator inhibitor, and hyperinsulinemia is associated with increased blood coagulability and decreased fibrinolysis. There is a close association between insulin and triglyceride metabolism, and this may affect factor VII activity in blood. Changes in both the quantity and composition of dietary fat influence lipid metabolism as well as blood levels of a number of hematologic factors. Sex steroid-induced changes in aspects of metabolism such as blood lipid concentrations may not be as central to cardiovascular disease risk as originally believed. Changes in carbohydrate metabolism and in hematologic parameters induced by the currently used doses of sex steroids appear to be minor, although more intensive studies are recommended. Evidence suggests that genetic and early life influences are more important to the development of insulin resistance than later acquired causes.

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. Women with a known thrombophilia or a personal history of VTE should consider alternative methods of contraception to the COC.

PIP: The risk of venous thromboembolism (VTE) associated with low-dose combined oral contraceptive (OC) use has been estimated at 15-30 cases/100,000 women-years. This risk increases in women with thrombophilias associated with antithrombin III, protein deficiencies, and Factor V Leiden (FVL) mutation. Under debate has been whether all women, or at least those with a family history of VTE in a first-degree relative, should be screened for thrombophilia before OCs are prescribed. This article considers two assessment models salient to this debate. The first model considers family history and hereditary thrombophilia based on data from several epidemiologic studies. It suggests that screening 1 million women would result in the detection of 41,080 women with a hereditary thrombophilia; of these, 92 would experience VTE, and there would be 0.92 associated deaths. Screening of 1 million women with a family history of VTE would result in the identification of 672 VTE cases, with a fatality rate of 6.7/year. The second model, based on data concerning FVL mutation, also failed to provide support for the efficacy of a thrombophilia screening program. Women with a family history of thrombophilia, nonetheless, should be offered the option of screening and urged to use an alternative contraceptive method if a thrombophilia is detected.

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.

PIP: This review examines the bioavailability of sex steroids used in oral contraceptives and hormone replacement therapy and the implications of the clinical use of these steroids. These steroids include the estrogens (estradiol, estrogen sulfates, ethinyl estradiol) and the gestogens (progesterone, norethisterone, levonorgestrel, desogestrel, gestodene, norgestimate, and medroxyprogesterone acetate). The naturally occurring sex steroids are estradiol, estrogen sulfates, and progesterone or their derivatives. The synthetic sex steroids are ethinyl estradiol, norethisterone, levonorgestrel, desogestrel, gestodene, norgestimate, and medroxyprogesterone acetate. Factors influencing bioavailability of these sex steroids revolve around drug formulation (dosage form, disintegration rate, and dissolution rate), drug characteristics (chemical properties and stability in the gastrointestinal tract), user's characteristics (gastrointestinal and hepatic functions), and possibly smoking, diet, and other drugs. A wide variation exists in the bioavailability values both within any study and between the different studies with the same steroid. Possible reasons for the variability include experimental error, a small number of subjects, the rate and extent of absorption of the compound, the compound's rate of metabolism and elimination (especially hepatic metabolism and elimination), differences in dose, and interaction between the estrogen and the gestogen. Some of the synthetic sex steroids are prodrugs.

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. Only 4 follicles were detected in 17 women in Group T compared to 10 follicles in 15 women in Group P and 7 follicles in the women in Group C; all follicles were 25 mm or less in diameter except for 3 follicles in 2 women. The differences between the groups were not statistically significant. Four enlarged follicles were detected in 3 women during 53 scans in Group T, 15 in 8 women (45 scans) in Group P, and only 1 in 31 scans in Group C. Based upon the proportions of scans with enlarged follicles, the difference between Groups T and P was statistically significant, indicating that the incidence of enlarged follicles was lower in women using a combined oral contraceptive than in those using a progestogen-only pill. Furthermore, the study shows that any enlarged follicles which occurred were transient.

PIP: In 1990, researchers in England enrolled 42 healthy women aged 21-46 attending the family planning clinic in Reading in a study designed to determine whether a triphasic oral contraceptive (OC) affected ovarian cyst formation any differently than did a progestogen-only pill (POP). They also wanted to ascertain the life span of any ovarian cysts detected. 17 women used the triphasic OC containing various doses of ethinyl estradiol and levonorgestrel (LNG). 15 women used either the POP Microval (30 mcg LNG) or Micronor (350 mcg norethisterone). The remaining 10 women had used neither a steroidal contraceptive nor an IUD for at least six months. The researchers depended on ultrasonography to detect enlarged ovarian follicles (10 mm and 30 mm in diameter) and cysts (30 mm detected in 2nd half of cycle that persisted for more than 2 cycles). The women in the OC group underwent 53 ultrasonic scans. Those in the POP group underwent 45 ultrasonic scans. Controls underwent 31 ultrasonic scans. Only four women in the OC group had ovarian follicles, while 10 women did in the POP group and 7 in the control group. Except for three follicles in two women, all the follicles were no more than 25 mm in diameter. The POP group had a significantly higher proportion of ultrasonic scans detecting the presence of enlarged follicles than did the OC group (14/45 vs. 4/53; p = 0.01). Since none of the enlarged follicles lasted for more than two cycles, there were no functional ovarian cysts. These findings show that women using the triphasic OC had a lower incidence of enlarged follicles than those using the POP and that the enlarged follicles were temporary.

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. subcutaneous, intravaginal and intra-uterine administration, also included. There is a large variability among the different studies for both serum concentration and pharmacokinetic parameters and not all of this is due to the large interindividual variability demonstrated in all of the studies. The factors responsible for the inter- and intraindividual variability have not been discovered. Sex hormone binding globulin (SHBG) plays an important role in levonorgestrel pharmacokinetics since: (i) levonorgestrel binds strongly to this protein; and (ii) serum SHBG levels are influenced by a large number of different factors including the administration of levonorgestrel and ethinylestradiol. However, not all of the anomalies in the metabolism of levonorgestrel can be ascribed to its interaction with SHBG.

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 0.12) were due to method failure. The incidences of breakthrough bleeding and spotting after 6 treatment cycles varied from 0.1-6.0% and 2.8-11% of subjects, respectively, and at this time they were not significantly different from pretreatment in most trials. About 90% of subjects maintained regular cycles. The incidence of subjective side effects (approximately 5% for headache, 4% for breast tenderness, 2% for nausea) was low. No significant changes occurred in body weight or blood pressure. In all trials, the COC was well accepted and the rates of discontinuation were similar to those in other COC trials. Pharmacodynamic effects have been widely investigated. There were no significant changes in glucose metabolism or in haematological factors except for possibly minor increases in factors VII and X, fibrinogen and plasminogen. Over thirty studies of the effect of the COC on lipid metabolism have been published; significant increases occur in serum triglycerides, HDL-C and apoprotein A1. SHBG concentrations increase 2-3 fold with a consequent decrease in the levels of free testosterone. This effect can be particularly important therapeutically in women with hyperandrogenic skin disorders and 14 trials in women with these disorders have demonstrated significant clinical improvement with the COC. The findings from the various trials show the COC to be effective and acceptable with no adverse metabolic effects.

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. However, the older low-dose COCs, despite many years of use, have not resulted in a high incidence of adverse effects. The increasing use of the new COCs, as evidenced by their increasing market share throughout Europe, does indicate that they have been well accepted in clinical practice.

PIP: European researchers have conducted most of the clinical tests of the 3 new progestogens used in low-dose, combined oral contraceptive (OC) formulations: desogestrel (DSG), gestodene (GSD), and norgestimate (NGM). Enough clinical trial data for GSD and DSG OCs exist to compare with those of other low-dose OCs. The newer OCs are at least as effective and have at least as good cycle control as other low-dose OCs. Minor side effects of the newer OCs correspond to those of other OCs. Various flaws in studies make it hard to compare major adverse side effects of the different OCs. To compare OCs, parameters must be accurately measured. Continuation rates, measurement of blood pressure, and incidence of specific side effects can be accurately measured, but only in large comparative trials using standardized assessment methods. Other possible comparative parameters are metabolic parameters, but trials must be well-designed and adequately controlled. Almost all studies show that the new OCs do not affect fasting levels of glucose and insulin. More research is needed on the validity of a glucose tolerance test to stimulate any changes in carbohydrate metabolism, however. Recent data show that lipid metabolism may vary among the new OCs, but the research is largely limited to assessing the serum levels of various lipids. Yet, assessment of various ratios or an assay of the apoproteins are better indicators of the risk of cardiovascular disease. An assay of just high density lipoprotein-cholesterol allows researchers to distinguish between OCs. Hematologic factors are not a good basis for comparison, due to a variety of problems with measurement. Accurate measurements of serum proteins (e.g., sex hormone binding globulin) can be made, however. New OC use has increased 2-fold in 4 years in some European countries, attesting to their popularity and acceptability.

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. The 36 pregnant women were randomized into four groups which were given a single dose of 25, 100, 400 or 600 mg RU 486. Blood samples were taken up to 120 h after dosing. Peak concentrations of RU 486 occurred on most occasions within 2 h. Plasma concentrations at 1 h and at 24 h increased in proportion to log dose. There was a wide variability (up to ten-fold) in the pharmacokinetic parameters within each dose group. Plasma concentrations of RU 42633 were similar to those of RU 486 but concentrations of RU 42848 and RU 42698 were much lower. As with RU 486, the plasma concentrations of the metabolites were maintained at high levels for up to 48-72 h after dosing. The findings were consistent with a rapid metabolism of RU 486 to RU 42633; removal of the second methyl group leading to RU 42698 occurred much more slowly and to a much less extent than removal of the first. There appeared to be no significant differences between the non-pregnant and pregnant women in either the plasma concentrations or pharmacokinetic parameters of RU 486 and its metabolites.

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 0.5, 1.5 or 3.0 mg per day from days 5 to day 18 of the cycle. Blood samples were taken on days 5, 8, 11, 14, 17, 20, 23, 26 and 29 of the cycle. Serum oestradiol (E2), progesterone (P), sex hormone binding globulin (SHBG), high density-lipoprotein cholesterol (HDL-C), and NET concentrations were measured. Ovulation, delayed ovulation, ovulation inhibition and follicular activity were classified by the analysis of the peripheral serum levels of sex hormones. Ovulation occurred in 7 women in the 0.5 mg group, in 2 women in the 1.5 mg group and in none of the 3.0 mg group. Mean serum SHBG levels were reduced progressively by 6.6% (Group 0.5), 15.5% (Group 1.5) and 23.4% (Group 3.0). There were no significant changes in HDL-C levels in any group. There was a significant correlation of mean serum NET concentrations with dose. The lack of complete inhibition of ovulation in most women in the 1.5 mg and 0.5 mg groups might suggest that the dose of NET required when used as a visiting pill could not be reduced below 3.0 mg.

PIP: In Shanghai, China, 45 25-35 year old women took a daily norethisterone (NET) "visiting pill" (vacation pills) on menstrual cycle days 5-18 as part of a clinical study comparing various doses of NET on ovarian function, sex hormone binding globulin (SHBG), and high density lipoprotein-cholesterol (HDL-C). The aim of the study was to determine the lowest effective dose of the NET visiting pill. Even though some ovarian activity occurred at all 3 doses (0.5, 1.5, and 3 mg), no woman experienced ovulation at 3 mg NET/day during days 5-18 of the cycle. It suppressed ovulation in 11 (73.3%) of the 15 women. Follicular activity occurred in the remaining 4 women. Ovulation occurred in 33% of women taking the 1.5 mg dose and in 66% of those taking the 0.5 mg dose. The higher the NET dose, the greater was the fall in mean serum SHBG levels from control levels (3 mg, 23.4%; 1.5 mg, 15.5%; and 0.5 mg, 6.6%). Both the regression equation and log dose regression equation showed a significant correlation between mean serum NET levels and dose (p .001). HDL-C levels remained basically the same as control levels. Since, at the 1.5 mg dose, ovulation occurred in 5 women and only 5 women experienced complete inhibition, a dose no lower than 3 mg should be used for the NET visiting pill.

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. Cycle control was good; as with all oral contraceptives, the incidence of breakthrough bleeding and spotting was highest in the first treatment cycle and by the sixth treatment cycle the values were usually < 5% and < 7%. More than 80% of women had regular cycles. Side effects were few, the most common being headache, nausea and breast tenderness with incidences in the sixth treatment cycle of less than 2%, 6% and 6%, respectively. There were no significant changes in body weight or blood pressure. Pharmacodynamic investigations showed no adverse effects. Only 1 of 5 studies found an increased response to a glucose tolerance test compared to the pretreatment test. In 8 of 10 studies, serum HDL-C concentrations increased on treatment and this was associated with increases in apoproteins A1 and A2. Serum triglyceride levels also increased but no change occurred in serum cholesterol or LDL-C levels. Haematological factors were assessed in 8 studies and only minor changes were observed. Serum binding protein (SHBG, CBG, caeruloplasmin) concentrations increased and serum androgen levels decreased. Measurements of blood FSH, LH, oestradiol and progesterone indicated adequate inhibition of ovulation. Mercilon is the only oral contraceptive containing 20 micrograms ethinyloestradiol to have high efficacy, to have no adverse pharmacodynamic effects and, importantly, to produce an acceptable bleeding pattern not significantly different from that of oral contraceptives with a higher content of ethinyloestradiol.

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). Age, ethnic group, body-mass index and a close family history of cardiovascular disease were taken into account, as were various lifestyle factors: diet, exercise, alcohol consumption and smoking. In a smaller group, levels of apoproteins A and B were also assayed. There was a significant reduction in apoprotein A between controls and all users, but the significance was lost on adjusting for confounding variables. Consideration was given to the ratio of total cholesterol to high density lipoprotein cholesterol as an index of coronary risk. There were no significant differences in the total cholesterol:HDL-C ratio between controls and user groups. There was a significant interaction with ethnic group (Caucasian or Afro-Caribbean) in the response to duration of use.

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. The latter however increased the glucose and insulin responses to a glucose tolerance test whereas Marvelon and Mercilon had no effect. HDL-C increased with Marvelon, was unchanged with Mercilon and was decreased with Microgynon. Apoprotein AII was increased by all three OCs but only the DSG OCs increased apoprotein AI. All OCs produced similar increases in caeruloplasmin but the increase in SHBG was much greater with Marvelon and Mercilon than with Microgynon. Testosterone was reduced more with Microgynon than with the DSG OCs. Many of the changes reflect the strong anti-oestrogenic action of LNG on metabolic parameters compared to DSG. Except for the effect on HDL-C, there was little difference between Marvelon and Mercilon on metabolic parameters and this complements the findings from large-scale clinical trials of the two OCs. Mercilon, therefore provides a very satisfactory alternative to Marvelon.

PIP: 12 healthy volunteers attending the family planning clinic at Shanghai, First Maternity and Infant China, Hospital, enrolled in the study, Oral contraceptives (OCs) were prescribed: Marvelon (150 mcg of desogestrel--DSG), Mercilon (150 mcg of DSG), and Microgynon (150 mcg of levonorgestrel--LNG). The patients were divided into 6 groups of 2 persons each in a randomized cross-over study. OCs were taken on day 6 of the cycle up to day 21, then stopping for 7 days. Each OC was used for 3 months. During the pretreatment cycle between days 6 and 9 of the follicular phase and 21 and 22 of the luteal phase a blood sample was taken after fasting for determination of lipids, sex hormone binding globulin (SHGB), ceruloplasmin, and testosterone. After glucose loading, significant increases of glucose and insulin occurred at 1, 2, and 3 hours during treatment with Microgynon only. The ratio for total areas of insulin to glucose did not change significantly nor did glycosilated hemoglobin A1 levels. Serum triglyceride concentrations increased significantly for both Marvelon (27%-43%) and Mercilon (29-40%). Serum high density lipoprotein (HDL) cholesterol concentrations were significantly elevated with Marvelon but less so with Mercilon, while HDL-C decreased significantly with Microgynon. The serum low density lipoprotein (LDL) cholesterol changes were not significant, but LDL-C concentrations declined with DSG formulations and increased with Microgynon. Apoprotein A1 and A2 increased significantly for both Marvelon and Mercilon. Apoprotein A2 increased with Microgynon. Serum SHBG increased markedly with Marvelon (335-380%). Serum testosterone concentrations decreased significantly (33.2-40.4% with Microgynon) and so did ceruloplasmin values. The antiestrogenic effect of strong LNG in Microgynon produced significant metabolic changes. The effect of 30 mcg EE in Marvelon and 20 mcg EE of Mercilon was equal.

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. The intrasubject variability for Tel and AUC was 31 and 17%, respectively, and intersubject variability 66 and 95%. The intersubject range of values was more than 3-fold for both Tel and AUC and the intrasubject range about 2-fold. The pharmacokinetics of EE were not influenced by LNG; mean values for Tel and AUC were 17.3 +/- 5.5 h and 11.1 +/- 3.8 ng/ml/h, respectively, when EE was administered alone compared with 16.4 +/- 4.8 h and 12.5 +/- 3.9 ng/ml/h when given with LNG. However, EE influenced the metabolism of LNG; Tel for LNG was 19.3 +/- 4.2 h when administered alone and significantly higher (30.0 +/- 11.2 h) when given with EE. There was no correlation between the rate of metabolism of EE and that of LNG. The intrasubject variability shown in this and other studies suggests that genetic factors are less important in intersubject variability than previously thought. Some implications of intrasubject variability are discussed.

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.

PIP: Pharmacokinetic interactions between oral contraceptives (OCs) and other drugs and nutrients may occur during absorption and extrahepatic circulation, through interference with protein binding, and during hepatic metabolism. However, the most significant locus of drug interaction is the mixed function oxidase system of the liver endoplasmic reticulum. Increased activity of the mixed function oxidase system produced by other drugs tends to reduce the half-life of elimination of sex steroids and consequently of their serum concentrations and biological effect. At the same time, OC administration generally has an inhibitory effect on the metabolism of other drugs and consequent reductions in their pharmacologic activity. The rate of drug metabolism will vary according to genetic and environmental factors such as diet, alcohol use, smoking, and pathologic conditions. Although the influence of nutrition on the absorption and bioavailability of contraceptive steroids has not yet researched adequately, high-protein diets appear to stimulate the activity of the hepatic drug-oxidizing system and increase the metabolism of other drugs. Pharmacokinetic and pharmacodynamic interactions between the estrogen and gestogen components of OCs may be synergistic or antagonistic, but no correlation has been found between the rate of metabolism of the 2 steroids as reflected in their elimination half-lives. Despite evidence that some anticonvulsant, antibiotic, and antibacterial drugs reduce the efficacy of OCs, this interaction is severe enough to lead to OC failure in less than 5% of cases. It can be postulated that women in whom drug interactions lead to contraceptive failure are fast metabolizers or have liver enzyme systems especially susceptible to induction.

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. The remaining 358 women used the POP for up to 150 months, giving a total of 18,125 women-months of use. Three pregnancies occurred, giving a Pearl Index of 0.2 per 100 women-years. Non-menstrual side effects were minor and were reported by 77 women. For the women who discontinued the POP, the main reason was menstrual irregularity (47.5%). However, despite the long-term use by most of the women, almost 40% maintained a mostly regular menstrual pattern. Our findings suggest that the POP provides a very acceptable method of oral contraception for many women and that it should be more actively promoted.

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. Minor changes in carbohydrate metabolism occurred and these were particularly noticeable when the incremental areas under the serum concentration-time curves for both glucose and insulin in response to a glucose tolerance test were calculated. No changes occurred in the serum glycosylated haemoglobin levels. The serum concentrations of all the lipids measured (total cholesterol, triglycerides, LDL-C, HDL-C and apolipoproteins AI, AII and B) were significantly increased on treatment as were levels of Factor X, SHBG and caeruloplasmin whereas antithrombin III decreased. In 38 of the 40 treatment cycles, ovulation was suppressed. In one cycle serum oestradiol and progesterone levels showed a typical ovulatory pattern and in another there was evidence of follicular activity without ovulation. Serum EE concentrations showed a similar pattern in both treatment cycles showing that co-administration of NET did not affect EE metabolism. Serum NET levels were higher in the 6th than in the first treatment cycles. On comparing pharmacodynamic and pharmacokinetic parameters, the only statistically significant correlations were between the percentage change in triglycerides and SHBG and serum NET, but not EE concentrations, and between apolipoproteins AI and serum EE.

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. The results showed that in both groups, prothrombin time and fibrinogen fluctuated significantly, and leucocyte count was not significantly changed during the whole course. Factor VIII-related antigen and antithrombin III (AT-III) antigen showed minor changes, although in the 3rd treatment cycle, the differences between the two groups in both parameters reached statistical significance. A progressive and significant decrease in Factor X and AT-III functional activity occurred with the monthly injectable treatment, decreasing by about 14% and 20%, respectively, after 12 months of treatment. Haemoglobin levels were increased in the treatment group after the 3rd injection and remained at the higher level during the study period. It is doubtful whether these changes are likely to be of clinical relevance.

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. There is also a marked difference in the parameters when derived under single-dose or steady-state conditions. The role of sex hormone-binding globulin in the metabolism of levonorgestrel is questioned. Large intra- and inter-subject variations in the parameters exist, and a subject may show a large month-to-month variation when one levonorgestrel formulation is used and smaller variations when another formulation is used. This wide variability in the pharmacokinetic parameters, problems that arise in the derivation and interpretation of the parameters, the biologic significance of most of these parameters, and their lack of correlation with pharmacodynamic responses severely limit the usefulness of pharmacokinetic studies of the gestagens.

PIP: The results of previously published studies of the pharmacokinetics of levonorgestrel (LNG), a widely used gestagen, were tabulated, reviewed, and subjected to new analyses. The mean half-life of elimination, usually calculated using two-compartment open modeling, ranged from 8 to 18 hours. Such large variations in half-life of elimination have been noted in studies of other steroid contraceptives as well. Recalculation of half-life of elimination by simply plotting the 8- and 24-hour serum concentrations against time yielded values in general agreement with those obtained with the original investigators' pharmacokinetic values. The pharmacokinetics of gestagens are influenced not only by dose and formulation but also by high levels of intrasubject and intersubject variation. In most studies, sampling is not continued beyond 24 hours, and this may cause an underestimation of half-life, particularly for long-lived gestagens. Another common parameter, mean pharmacokinetic bioavailability of LNG (as calculated by the area under the curve method), ranged from 20 to 35 ng/ml/hour in patients given 150 mcg of LNG with 30 mcg of ethinyl estradiol. Bioavailability increased with higher doses. Since half of the LNG in serum is bound to sex hormone-binding globulin (SHBG), changes in the serum concentration of this protein may affect LNG pharmacokinetics. Estrogens induced SHBG. Some investigators have proposed that the higher LNG levels observed in serum when a gestagen is administered together with an estrogen is due to increased amounts of SHBG in serum. However, a number of studies have shown that estrogens administered with gestagens do not induce SHBG and may actually decrease its concentration. In general, studies of the pharmacokinetics of estrogens report a high degree of variation in common pharmacokinetic parameters, as well as a frequent lack of correlation with biologic response. This raises the question of whether these types of studies are providing useful information.