Effect of oral contraceptives on triazolam, temazepam, alprazolam, and lorazepam kinetics.

The effects of low-dose estrogen oral contraceptives (OC) on the elimination of the oxidized benzodiazepines triazolam (TRZ) and alprazolam (ALP) and the conjugated benzodiazepines temazepam (TMZ) and lorazepam (LOR) were studied in two parallel crossover studies of 20 women each. Women taking OC steroids containing low doses of estrogen and women matched for age, weight, and cigarette smoking received single oral doses of TRZ (0.5 mg) and TMZ (30 mg) or ALP (1 mg) and LOR (2 mg). Kinetics were determined as plasma concentrations during 48 hr after dosing. OCs inhibited the metabolism of ALP: The AUC increased and the elimination rate constant was greater in users of OCs. For TRZ, which has an intermediate extraction ratio, the AUC was increased by OCs but not significantly so. In contrast, OCs decreased the AUC for TMZ and the elimination rate constants for LOR and TMZ. The AUC of LOR was not affected by OCs. Low-dose estrogen OCs may therefore inhibit the metabolism of some oxidized benzodiazepines and accelerate the metabolism of some conjugated benzodiazepines.

PIP: Because benzodiazepines and oral contraceptives (OCs) are among the most widely prescribed drugs and have a potential for interaction, 2 parallel crossover studies were conducted to determine the effects of OCs on the elimination of the oxidized benzodiazepines triazolam (TRZ) and alprozolam (ALP) and the conjugated benzodiazepines temazepam (TMZ) and lorazepam (LOR). 20 healthy women taking OCs containing does of under 35 mcg of ethinyl estradiol for 3 months or more and 20 women matched for age, weight, and cigarette smoking received single oral doses of TRZ (.5 mg) and TMZ (30 mg) or ALP (1 mg) and LOR (2 mg). Treatments were seperated by 28 days to control for effects of menstural cycle on drug metabolism. Kinetics were determined as plasma concentrations during 48 hours after dosing. The data indicated that OCs differentially affect the elimination of the benzodiazepines studied. OCs inhibited the metabolism of ALP: the area under the curve (AUC) increased and the elimination rate constant was greater in users of OCs. For TRZ, which has an intermediate extraction ratio, the AUC was increased by OCs but not significantly so. OCs decreased the AUC for TMZ and the elimination rate constants for LOR and TMZ. The AUC of LOR was not affected by OCs. It was concluded that low-dose estrogen OCs may inhibit the metabolism of some conjugated benzodiazepines and accelerate the metabolism of some conjugated benzodiazepines, but the clinical implications are unclear. The relationship between plasma concentration and effect has not been determined for most benzodiazepines, but the results suggest that the time required to achieve steady-state concentrations would be longer and that there would be higher steady state concentrations of ALP in OC users. Because both TMZ and LOR are eliminated more rapidly by OC users, women taking OCs should achieve steady-state concentrations more rapidly than nonusers. Because TMZ clearance is increased by OCs, mean plasma concentration may be decreased. The usual 30 mg dose of TMZ may therefore be less effective as a hypnotic in OC users.

Lorazepam and oxazepam kinetics in women on low-dose oral contraceptives.

Women on low-dose estrogen oral contraceptives (OC) and drug-free control women matched for age, weight, and cigarette smoking habits, received single 2-mg IV doses of lorazepam or single 30-mg oral doses of oxazepam, two benzodiazepines metabolized by glucuronide conjugation. Kinetics were determined from multiple plasma concentrations measured during 48 hr after dosing. Mean kinetic variables for lorazepam in control and OC groups (n = 15 in each group) were: volume of distribution (Vd), 1.33 and 1.45 l/kg; elimination t1/2, 13.1 and 12.2 hr; total clearance, 1.25 and 1.50 ml/min/kg; free fraction in plasma, 10.3% and 10.3% unbound. For oxazepam, kinetic variables in the two groups (n = 14 and 17) were: Vd, 1.05 and 1.19 l/kg; t1/2, 7.6 and 7.2 hr; total clearance, 1.60 and 2.03 ml/min/kg; free fraction, 4.6% and 4.9% unbound. None of these differences were significant. Thus, metabolic clearance by glucuronidation of lorazepam and oxazepam is not significantly affected by OC, in contrast with the highly significant reduction in clearance of the oxidized benzodiazepine diazepam.

PIP: Women taking low-dose estrogen oral contraceptives (OCs) and drug-free control women matched for age, weight, and cigarette smoking habits, received single 2-mg intravenous doses of lorazepam or single 30-mg oral doses of oxazepam, 2 benzodiazepines metabolized by glucuronide conjugation. Kinetics were determined from multiple plasma concentrations measured during the 48 hours after dosing. Mean kinetic variables for lorazepam in control and OC groups (n=15 in each group) were: volume of distribution (Vd), 1.33 and 1.45 1/kg; elimination t1/2, 13.1 and 12.2 hours; total clearance, 1.25 and 1.50 ml/minute/kg; free fraction in plasma, 10.3% and 10.3% unbound. For oxazepam, kinetic variables in the 2 groups (n=14 and 17) were: Vd, 1.05 and 1.19 1/kg; t1/2, 7.6 and 7.2 hours; total clearance, 1.60 and 2.03 ml/minute/kg); free fraction, 4.6% and 4.9% unbound. None of these differences were significant. Thus, metabolic clearance by glucuronidation of lorazepam and oxazepam is not significantly affected by OCs, in contrast with the highly significant reduction in clearance of the oxidized benzodiazepine diazepam.

Influence of nutritional status on pharmacokinetics of contraceptive progestogens.

PIP: In response to recent studies from India suggesting that malnutrition, as assessed by anthropometric indexes, affects metabolism of oral progestogens, this study administered a mini-pill containing .35 mg of norethindrone (NET) and combination pills containing 250 or 150 mcg of d-norgestrel (d-NG) and either 50 or 30 mcg ethinyl estradiol as a single dose for fasting women of high and low income. Blood samples were collected for up to 24 hours for NET and 80 hours for the combination pills. Pharmacokinetics were evaluated by a least-squares method. Anthropometric measurements were also made. Peak NET levels occurred within 1-2 hours; half-life of plasma NET was shorter among low income, malnourished women compared with high income, well-nourished women. A direct correlation between weight/height and half-life of the drug suggests that malnutrition enhanation rate and reduces NET's half-life. Peak levels for d-NG also were reached between 1 and 2 hours after dosing. In well-nourished women, the decline in plasma d-NG was tri-exponential; malnourished women showed a biphasic curve with a neglible alpha-phase. Therefore, the lower the nutrition status, the faster the plasma clearance of these 2 orally administered compounds. Studies inn rabbits designed to elucidate this connection showed a significant elevation in specific activities of liver microsomal glucuronyl transferase and cytochrome-p450 in undernourished compared with control animals. There was also an increase in the amount (but not affinity) of uterine progesterone receptors in undernourished animals. Another study of a small group of Thai and Indian women showed positive correlation between anthropometric indexes and post peak plasma NET levels; however, an obesity study of Thai women found no such correlation.^ieng

Influence of oral contraceptive use and cigarette smoking, alone and together, on antipyrine pharmacokinetics.

The pharmacokinetics of antipyrine following a single 1-g intravenous dose was determined in 63 healthy women. Subjects were divided into 4 groups as follows: 1) cigarette smokers using low-dose oral contraceptives (n = 15); 2) nonsmokers using low-dose oral contraceptives (n = 12); 3) cigarette smokers not using oral contraceptives (n = 10); and 4) controls, neither cigarette smokers nor oral contraceptive users. Plasma antipyrine concentrations during 24 to 48 hours after dosage were measured by high-performance liquid chromatography. Mean kinetic variables in the nonsmoking, non-oral contraceptive using control group were: volume of distribution, 37.7 L; elimination half-life, 13.2 hours; and clearance, 34.4 mL/min. In cigarette smoking, non-oral contraceptive users versus controls, elimination half-life was reduced (8.0 vs. 13.2 hours, P < 0.05) and clearance increased (56.0 vs. 34.4 mL/min, P < 0.05). In nonsmoker oral contraceptive users, the reverse was true (elimination half-life was significantly increased: 16.6 vs. 13.2 hours, P < 0.05; and clearance was significantly decreased: 24.8 vs. 34.4 mL/min, P < 0.05). In smokers who were using oral contraceptives, values were not significantly different from controls (elimination half-life, 11.2 hours; clearance, 39.5 mL/min). Volume of distribution did not differ among the four groups. Thus the opposing effects on antipyrine clearance of the induction of metabolism by cigarette smoking and the inhibition due to low dose oral contraceptive use in effect negate each other when combined in humans.

The effect of oral contraceptive use and pregnancy on the daily rhythm of cortisol and cortisone.

The effect of oral contraceptives and of pregnancy on the daily rhythm of cortisol, and its metabolite cortisone in plasma and saliva has been investigated. In both conditions the total plasma cortisol levels were raised to the same extent, the mean values in saliva in the oral contraceptive users being intermediate between those in pregnancy and in the controls, particularly in the morning. Salivary cortisone levels were more related to salivary cortisol than to total plasma cortisone which exhibited a rather flat daily rhythm. There was a shift in peak values for salivary cortisol and cortisone towards late morning: this may be due to a delay in the daily activation of the hypothalamic-pituitary-adrenal axis in these patients.

PIP: The daily rhythm of plasma free cortisol and its metabolite cortisone in pregnancy or during oral contraceptive (OC) use was investigated in 10 pregnant women, 11 users of low-dose OCs, and 12 nonpregnant controls who were not using OCs. Radioimmunoassay was performed in the analysis of citric-acid stimulated saliva samples collected from 5 AM to midnight at 1-2-hour intervals and plasma samples were obtained from 10 women. Both pregnancy and OC use were found to produce significantly elevated levels of salivary cortisol and cortisone as well as a delay in the peak time of each hormone. The plasma analyses revealed significant increases in cortisol concentrations in both pregnant women and OC users, but plasma concentrations of cortisone increased only in pregnant women. Peak concentrations of salivary and total plasma cortisol were significantly higher in the first half of pregnancy, while cortisone was significantly higher during the second half of pregnancy. The shift in the peak of cortisone and cortisol values was from about 7 AM in control to 8 AM during pregnancy, with OC users in an intermediate position. Unexpectedly, the values for free plasma cortisol were normal during the afternoon but raised in saliva. It is postulated that the observed shifts in the peak time of the daily rhythm of cortisol and cortisone during pregnancy and OC use reflect an estrogen-induced increased synthesis of corticosteroid-binding globulin. Of interest would be a 24-hour measurement of these two hormones in saliva, free plasma, and total plasma.

Glucose and lipid metabolism with triphasic oral contraceptives in women with history of gestational diabetes.

The glucose and lipid metabolism in a group of women with previous history of gestational diabetes were evaluated before and after 6 months treatment with a low-dose triphasic oral contraceptives pill (TP). This group was compared with a control group of women, also with history of gestational diabetes, using intrauterine devices (IUD). In the TP group, 26.7% of the women developed impaired glucose tolerance which reverted to normal in all but one after cessation of the TP. The IUD group showed no change in glucose tolerance. The integrated insulin response to a 75g OGTT in the TP group increased by 48.3% at 6 months compared with an increase of 23.4% for the same period in the IUD group. In the TP group there was a significant decrease in serum total cholesterol without changes in HDL-cholesterol and triglycerides level. We conclude that even low-dose triphasic oral contraceptive pills can cause glucose intolerance in women with previous gestational diabetes mellitus.

PIP: The glucose and lipid metabolism in a group of 20 women with a previous history of gestational diabetes were evaluated before and after 6 months of treatment with a low-dose triphasic oral contraceptive (OC). Another group of 5 women, also with a history of gestational diabetes but who were given an IUD, served as controls. 26.7% of the women in the triphasic OC group developed impaired glucose tolerance; however, values reverted to normal in all but 1 woman after OC discontinuation. The IUD group showed no change in glucose tolerance. The integrated insulin response to a 75 gm oral glucose tolerance test increased by 48.3% at 6 months in the OC group compared with an increase of 23.4% for the same period in the control group. Also recorded in the OC group but not among controls was a significant increase in serum total cholesterol without changes in high density lipoprotein-cholesterol and triglyceride levels. It was concluded that even low-dose triphasic OCs can cause glucose intolerance in women with previous gestational diabetes mellitus. Thus, the theoretical risk of precipitating permanent diabetes should be weighed against the risk of pregnancy. In cases where OCs are the only reliable method possible, careful and frequent monitoring of carbohydrate metabolism should be performed. Older, heavier women with a family history of diabetes are in particular need of close surveillance and constant monitoring of their glucose and lipid metabolism.

Ovarian activity during regular oral contraceptive use.

The aim of this study was to assess whether during regular OC use ovarian activity might lead to ovulation, as assessed by ultrasound (US) evaluation of follicular growth and blood levels of 17-beta-estradiol and progesterone. A total of 51 healthy women with normal menstrual cycles (28 +/- 3 days) and no gynecological symptoms were recruited. A total of 22 patients were given a triphasic OC pill containing 35 mg ethinyl estradiol (EE) and 50 mg desogestrel (DSG) in the first seven tablets; 30 mg EE and 100 mg DSG in tablets 8 to 14, and 30 mg EE and 150 mg DSG in tablets 15 to 21; 29 patients received one of two OC pills, both containing 20 mg EE plus 150 mg DSG (15 patients) or 75 mg of gestodene (14 patients). A total of 86 cycles were monitored: 51 during the 3rd-4th cycle and 35 during the 6th-8th cycle of OC treatment. Follicular-like structures were observed in nine patients. The frequency of follicular-like structures was similar during the 3rd-4th cycle (9%) and during the 6th-8th cycle (11%). There was no relationship between follicular growth and blood levels of E2 and progesterone, which always appeared suppressed. In conclusion, the results of this study suggest that during OC use (even with low dose of ethinyl estradiol), a little ovarian activity may be present without ovulation.

PIP: Several studies have described a 10-20% incidence of folliculogenesis during low-dose oral contraceptive (OC) use. This study used ultrasound evaluation of follicular growth and blood levels of 17-beta-estradiol and progesterone to determine whether OC-induced ovarian activity led to ovulation in 51 healthy women with regular menstrual cycles. Subjects were given a new triphasic OC containing 35 mg ethinyl estradiol (EE) and 50 mg desogestrel (DSG) in the first 7 tablets, 30 mg EE and 100 mg DSG in tablets 8-14, and 30 mg EE and 150 mg DSG in tablets 15-21 (22 women); an OC containing 20 mg EE and 150 mg DSG (15 women); or an OC comprised of 20 mg EE and 75 mg gestodene (14 women). A total of 86 cycles were monitored: 51 during the third and fourth cycles and 35 during the sixth through eighth cycles of treatment. Follicular-like structures were observed in 9 patients. Follicular growth occurred in 4 cycles (11%) in the triphasic group, 3 (13%) in the EE-DSG group, and 2 (7%) in the EE-gestodene group. The frequency of follicular-like structures was similar during the third-fourth cycle (9%) and the sixth-eighth cycle (11%). There was no association between follicular growth and blood levels of estradiol and progesterone. These results are compromised by the fact that only 35 of the 51 subjects completed 2 cycles. Nonetheless, they tend to confirm the observation that even a low dose of ethinyl estradiol can produce some ovarian activity without ovulation.

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.

The effect of deliberate omission of Trinordiol or Microgynon on the hypothalamo-pituitary-ovarian axis.

The effect of deliberate omission of a phased formulation pill, Trinordiol (ethinyl estradiol 30 micrograms + levonorgestrel 50 micrograms: 6 tablets; ethinyl estradiol 40 micrograms + levonorgestrel 75 micrograms: 5 tablets; ethinyl estradiol 30 micrograms + levonorgestrel 125 micrograms: 10 tablets) or a low-dose, combined, oral contraceptive pill, Microgynon (ethinyl estradiol 30 micrograms + levonorgestrel 150 micrograms: 21 tablets) on the hypothalamo-pituitary-ovarian axis were studied. Thirty-six women were recruited to the study and divided equally between the two types of pill. Medication was begun on the 8th pill-free day of the cycle and continued for 7 days (Group 1), 14 days (Group 2) or 21 days (Group 3). Levels of FSH, LH, estradiol (E2) and progesterone (P) were measured in plasma on alternate days during the final week of pill therapy, and daily for the 7 days after stopping the pill. For the first 2 weeks of pill therapy, follicular activity, as judged by plasma levels of E2, was greater in women taking Trinordiol than in those taking Microgynon, but was similar in both groups by the third week of pill treatment. Five women taking Trinordiol (2 in Group 1 and 3 in Group 2) had plasma levels of E2 in excess of 500 pmol/l whilst taking the pills, and only 1 patient achieved this degree of follicular activity after stopping the tablets. One woman who had taken 7 days of Trinordiol (Group 1) showed a rise of plasma levels of P to 6.8 nmol/l, but luteinization did not occur in any of the remaining 35 women who took Trinordiol or Microgynon. These findings suggest that follicular activity is less completely suppressed by Trinordiol than Microgynon, at least in the first 2 weeks of pill therapy, but that normal ovulation is still a rare event in the week after cessation of either of these pills, even if only 7 days of medication have been taken.

PIP: The effect of deliberate omission of a phased formulation pill, Trinordiol (ethinyl estradiol 30 microgram + levonorgestrel 50 microgram: 6 tablets; ethinyl estradiol 40 microgram + levonorgestrel 75 microgram: 5 tablets; ethinyl estradiol 30 microgram + levonorgestrel 125 microgram: 10 tablets) or a low-dose, combined, oral contraceptive pill, Microgynon (ethinyl estradiol 30 microgram + levonorgestrel 150 microgram: 21 tablets) on the hypothalamo-pituitary-ovarian axis were studied. 36 women were recruited to the study and divided equally between the 2 types of pill. Medication was begun on the 8th pill-free day of the cycle and continued for 7 days (Group 1), 14 days (Group 2) or 21 days (Group 3). Levels of FSH, LH, estradiol (E2) and progesterone (P) were measured in plasma on alternate days during the final week of pill therapy, and daily for the 7 days after stopping the pill. For the 1st 2 weeks of pill therapy, follicular activity, as judged by plasma levels of E2, was greater in women taking Trinordiol than in those taking Microgynon, but was similar in both groups by the 3rd week of pill treatment. 5 women taking Trinordiol (2 in Group 1 and 3 in Group 2) had plasma levels of E2 in excess of 500 pmol/l whilst taking the pills, but this level of follicular activity was maintained in only 3 of these women in the 7 "pill-free" days. None of the women taking Microgynon had levels of E2 above 500 pmol/l whilst taking the pills and only 1 patient achieved this degree of follicular activity after stopping the tablets. 1 woman who had taken 7 days of Trinordiol (Group 1) showed a rise of plasma levels of P to 6.8 nmol/l, but luteinization did not occur in any of the remaining 35 women who took Trinordiol or Microgynon. These findings suggest that follicular activity is less completely suppressed by Trinordiol than Microgynon, at least in the 1st 2 weeks of pill therapy, but that normal ovulation is still a rare event in the week after cessation of either of these pills, even if only 7 days of medication have been taken.

The relative bioavailability of levonorgestrel and ethinyl estradiol administered as a low-dose combination oral contraceptive.

The relative bioavailability of levonorgestrel (LNG) and ethinyl estradiol (EE) administered concomitantly both as an oral tablet and as a solution was assessed in a randomized two-period crossover study in 24 healthy women. Serum concentrations were monitored for 96 h after each administration. The relative bioavailability (Fr) of LNG in the tablet with respect to the solution was 107%; thus the two formulations were bioequivalent with respect to LNG. The relative bioavailability of EE, however, was significantly lower for the tablet (Fr 83%) compared to the solution. This difference may have been due to either decreased absorption or enhanced presystemic elimination of EE from the tablet formulation.

PIP: The relative bioavailability of levonorgestrel (LNG) and ethinyl estradiol (EE) administered concomitantly both as an oral tablet and as a solution was assessed in a randomized 2-period crossover study in 24 healthy women. Serum concentrations were monitored for 96 hours after each administration. The relative bioavailability of LNG in the tablet with respect to the solution was 107%; thus the 2 formulat6ions were bioequivalent with respect to LNG. The relative bioavailability of EE, howevedr, was significantly lower for the table compared to the solution. This difference may have been due to either decreased absorption or enhanced presystemic elimination of EE from the tablet formulation.

Effects of low and high dose oral contraceptives on blood coagulation and thrombogenesis induced by vascular subendothelium exposed to flowing human blood.

We investigated the effect of oral contraceptives with low and high estrogen concentration on blood coagulation and thrombogenesis, induced by vascular subendothelium of rabbit aorta exposed to flowing human blood. Twenty healthy women intending to take oral contraceptives were studied [1] before drug ingestion (control), and subsequently during the intake of oral contraceptives with [2] low estrogen content (20 micrograms ethinyl estradiol and 150 micrograms desogestrel per day) and [3] high estrogen content (50 micrograms ethinyl estradiol and 125 micrograms desogestrel per day). All experiments were performed between day 17 and 21 of the menstrual cycle and drug effects were studied during the third tablet cycle. Deposition of fibrin, platelets and platelet thrombi on vascular subendothelium was tested at a defined blood flow and wall shear rate (10 ml/min, 650 s-1) and was quantified by morphometrical techniques. Treatment with the low and high dose contraceptive increased the plasma levels of ethinyl estradiol (728 +/- 139 and 1438 +/- 212 vs. 0 fmol/l [low and high dose vs. control], means +/- SEM, P less than 0.001) and fibrinogen (2.3 +/- 0.1 and 2.6 +/- 0.1 vs. 2.0 +/- 0.1 g/l, P less than 0.05); and decreased antithrombin III activity (95 +/- 3 and 92 +/- 3 vs. 101 +/- 3 %, P less than 0.05). Fibrin deposition on vascular subendothelium was enhanced by the high dose contraceptive only (47 +/- 4 vs. 35 +/- 4 % coverage of the subendothelial surface with fibrin, high dose vs. control, P less than 0.05). The subendothelial deposition of platelets and platelet thrombi was not changed by contraceptive treatment. These results indicate that treatment with high dose contraceptives leads to an increase of fibrin-subendothelial interactions, whereas low dose contraceptives do not significantly alter the blood-subendothelium interactions. observed in this ex vivo model of thrombogenesis.

A comparative randomized trial on the impact of two low-dose oral contraceptives on ovarian activity, cervical permeability, and endometrial receptivity.

In a double-blind randomized study, the suppression of ovarian activity and anti-conceptive effects on the cervix and endometrium were assessed during administration of two low-dose monophasic oral contraceptives (20 micrograms ethinyl estradiol [EE], 500 micrograms norethisterone--Eve 20 [Grünenthal, Aachen, Germany]; 20 micrograms EE, 150 micrograms desogestrel --Lovelle [Organon, Munich, Germany]). One hundred eighteen healthy women (ages: 18-35 years) were studied in 10 investigation centers during medication with either Eve 20 (n = 59) or Lovelle (n = 59). During three treatment cycles, ovarian activity was evaluated by sonographic determination of follicle-like structures (FLS) and by simultaneous assessment of serum endocrine profiles (gonadotropins LH and FSH, ovarian steroids estradiol [E2] and progesterone [P]). While on either treatment, no ovarian activity (as judged by no FLS and/or reduced sex steroid levels) was found in 90.8% (Eve 20) and 97.2% (Lovelle) of all investigated cycles. Follicular activity or cyst formation were detected in 18 of 173 cycles (Eve 20) and in 5 of 175 cycles (Lovelle), respectively. Gonadotropin levels were suppressed (LH < 6 IU/L, FSH < 8 IU/L) in most treatment cycles (Eve 20 76.6% vs. Lovelle: 84.8%). Serum E2 concentrations exceeding 0.1 nmol/L indicated residual follicular activity in 19.3% (Eve 20) versus 12.2% (Lovelle) of all cycles. An estimated by serum P levels over 5 nmol/L, ovulation had presumably occurred in 4.1% (Eve 20) versus 2.9% (Lovelle) of treatment cycles. However, when the sonographical and endocrinological data were combined, no ovulation was documented in any pill cycle. The quality and quantity of the cervical mucus was found to be minimal in the majority of women. Moreover, the endometrial layer was determined to be low by ultrasound during most pill cycles, indicating equally strong suppressive effects on endometrial receptivity by the two contraceptives. These observations suggest that ovarian activity is suppressed in the majority of cycles during use of low-dose contraceptives. This effect may mainly be medicated by pronounced suppression of serum gonadotropin levels. Strong anti-conceptive effects of these formulations on both cervical permeability and endometrial receptivity are additional factors ensuring the contraceptive efficacy of these formulations.

PIP: The impact of two low-dose monophasic oral contraceptives (OCs) on suppression of ovarian activity, cervical permeability, and endometrial receptivity was investigated in a randomized double-blind study involving 118 healthy women 18-35 years of age recruited from 10 study centers in Germany. 59 women received Eve (20 mcg of ethinyl estradiol and 500 mcg of norethisterone) and 59 were given Lovelle (20 mcg of ethinyl estradiol and 150 mcg of desogestrel) for a total of 3 cycles. No ovarian activity, as assessed by sonographic determinations of follicle-like structures and serum endocrine profiles, was detected in 90.8% of cycles of Eve users and 97.2% of cycles in the Lovelle group. Follicular activity or cyst formation was found in 18 of 173 cycles of Eve users and 5 of 175 cycles of Lovelle users. Gonadotropin levels were suppressed (luteinizing hormone under 6 IU/L and follicle-stimulating hormone less than 8 IU/L) in 76.6% of treatment cycles in the Eve group and 84.8% of cycles in the Lovelle group. Serum estradiol concentrations exceeding 0.1 nmol/L, indicative of follicular activity, were recorded in 19.3% of cycles of Eve users and 12.2% of cycles in the Lovelle group. Although serum progesterone levels were over 5 nmol/L in 4.1% of cycles in the Eve group and 2.9% of those in the Lovelle group, consolidation of sonographic and endocrinologic data failed to document ovulation in any treatment cycles. The quantity and quality of cervical mucus was minimal in most women in both groups. Finally, the endometrial layer was determined to be low by ultrasonography during most pill cycles, confirming the OCs' equally strong suppressive effects on endometrial receptivity.

Formulation and noncontraceptive uses of the new, low-dose oral contraceptive.

Although contraceptive efficacy is the major reason for using oral contraceptives (OCs), other physiologic changes occur with them that can be beneficial to patients. The new, low-dose OCs are of particular interest in this regard.

PIP: Whether the differences in progestin-estrogen formulations of oral contraceptives (OCs) lead to any clinically significant differences is an important question, even though the concept of "tailoring the pill to the patient" has assumed less importance as the hormonal dosages have decreased. Each component can be evaluated individually, but it is often difficult to predict the result of their combined action. All of the new low-dose formulations contain the same estrogen, ethinyl estradiol (EE). Although the type of progestin in low-dose OCs is probably of little significance for efficacy and cycle control, it may be more important in regard to lipid and carbohydrate metabolism. Combined OC therapy acts simultaneously at various levels of the reproductive system, and contraceptive efficacy of pills with less than 50 mcg of estrogen probably results from these combined actions. The action of estrogen and progesterone is synergistic: the sustained estrogen component exerts negative feedback on gonadotropin secretion, provides stability to the endometrium, and increases the potency of the progestational agent, while progestin can influence only estrogen-primed tissue. The progestin suppresses luteinizing hormone secretion; in addition, progestational influence dominates estrogenic influence in affecting the remainder of the reproductive system. Previous OC usage may delay pregnancy by several months but does not impair longterm fertility potential or increase congenital anomalies or abortions if conception occurs subsequent to the 1st post-pill cycle. Breakthrough bleeding, which occurs in 15% of users, is the single most frequent cause of pill discontinuation but appears to be of no medical consequence. Breakthrough bleeding and amenorrhea may be controlled by changing the pill formulation. Depression has been reported in 5% of OC users, but pill use appears to alleviate premenstrual tension. The individual patient's risk-benefit ratio must be considered when noncontraceptive uses of the pill are contemplated. OC use has been cited as a cure for dysmenorrhea, although the mechanism is uncertain. The possible preservation of fertility or prevention of progression of endometriosis with cyclic pill use should be investigated. The controlled sloughing of a uniformily thinning endometrium prevents and controls dysfunctional uterine bleeding, endometrial hyperplasia, and the anemia that results. Use of OCs has been recommended in treatment of hirsutism to suppress ovarian function when the hypersecretion of androgens is documented. Since both adrenal and ovarian androgens are often involved in hirsutism, the combined suppressive actions of OCs frequently are beneficial. Estrogens also decrease sebum production and often result in indirect acne improvement. Cyclic estrogen-progesterone therapy is recommended for inducing sexual maturation in primary amenorrhea secondary to gonadal failure.

Planned Parenthood experience with triphasil.

Triphasil, a low-dose combination oral contraceptive containing levonorgestrel and ethinyl estradiol, was tested in four Planned Parenthood clinics on 317 women between 18 and 34 years of age (mean, 23) for a total of 4,692 cycles, or 361 woman-years of usage. Approximately half these volunteers (165) were nulligravidas, and 309 (97.5%) were white. Despite instructions on proper tablet usage, there were 416 cycles (8.9%) in which one or more tablets were missed. Only one pregnancy occurred, in a cycle in which a total of four tablets was missed, for an uncorrected Pearl index of 0.28 pregnancies per 100 woman-years of usage. No pregnancy resulted from method failure, indicating a 100% efficacy rate for Triphasil when taken properly. The mean length of the menstrual cycle with Triphasil was 27.9 days; the mean length of menses, 4.4 days; and the mean latency period, 2.1 days. Menstrual flow was average in 64.1% of the subjects, light in 34.1%, heavy in 1.3% and variable in 0.5%. Amenorrhea during the tablet-free interval occurred in only 0.6% of the 4,692 cycles in which Triphasil was used. Breakthrough bleeding occurred in 6.9% of first cycles and 3.2% of total cycles; spotting, in 10.7% of first cycles and 4.4% of total cycles. Other symptoms that occurred with an incidence of greater than or equal to 1% were acne (1.0%), appetite increase (1.2%), breast discomfort (2.8%), breast enlargement (1.3%), gastrointestinal symptoms (1.7%), simple headache (1.4%) and nausea (1.1%). A total of 44 women (13.9%) discontinued treatment for medical reasons.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in the plasma levels of proteins C and S in young women on low-dose oestrogen oral contraceptives.

The physiological importance of proteins C and S as natural anticoagulants is demonstrated by the increased risk of thromboembolic disease among subjects with hereditary deficiency of both proteins. In the present study the effects were evaluated of low-dose oestrogen oral contraceptives (OC) on the plasma levels of immunological protein S, as free (PS-f), and in reversible complex with C4b-binding protein as well as functional protein C (PC) in a homogeneous group of 20 young healthy women. The participants were randomly given either gestodene (75 micrograms) or desogestrel (150 micrograms) in combination with ethinyl oestradiol (30 micrograms). Blood samples were taken prior to the initiation of the treatment and at the end of the sixth 21-day treatment cycle. The mean concentration of both free and bound PS fell significantly, the decrease still being within the reference range. Conversely, the plasma values for PC rose to a statistically significant extent. There were no significant differences between the two OCs. Hypothetically, the changes in PS-f (active fraction) might be conducive to a procoagulant state, which the increased PC may compensate. The reverse effect of two OCs on the activity of the protein C-protein S anticoagulant system might suggest a different regulation of their synthesis.

PIP: The influence of low-dose oral contraceptives (OCs) on plasma levels of proteins C and S was investigated i 20 healthy women. These proteins, along with antithrombin III, are the most significant inhibitors of coagulation. Blood samples were collected after 6 months of treatment with an OC containing 30 mcg of ethinyl estradiol and either 150 mcg of desogestrel or 75 mcg of gestodene. A significant increase in functional protein C concentrations (from 55.70 + or - 9.84 to 117.48 + or - 21.29 in the desogestrel group and 68.80 + or - 19.11 to 135.60 + or - 28.66 in the gestodene group) was recorded between baseline and the 6-month measurement. There was a corresponding decrease in plasma concentrations of free protein S (from 98.48 + or - 9.64 to 73.96 + or - 12.07 in the desogestrel group and 104.79 + or - 31.52 to 83.14 + or - 18.28 in the gestodene group). Although these OC-induced changes were statistically significant, all values remained within the normal range. The differences between the 2 OC formulations were not significant. It is hypothesized that the changes in the active fraction of protein S recorded in OC users produce a procoagulant state and increases in protein C reflect an effort to compensate for this change. The findings that OC use increases protein C and decreases protein S values suggests that the two proteins differ in the regulation of their synthesis.

Plasma rifampicin levels during oral contraception.

PIP: Researchers conducted a study on the effect of oral contraceptives (OCs) on rifampicin plasma levels in 6 healthy women between 19-38 years old. These women's weight ranged between 40-60 kg an their height between 150-160 cms. All hemoglobin levels were 10 g. They had not used OCs for 3 months before the research began. As a control, the volunteers 1st did not receive an OC and had a menstrual cycle. Blood samples were collected between days 15-28 of the menstrual cycle. They took a daily low dose OC containing 1 mg norethisterone acetate and 30 mcg ethinyl estradiol in the next cycle. Before and after the 2nd OC cycle, they took 450 mg of rifampicin while the stomach was void and laboratory personnel estimated plasma levels of rifampicin by microbiological assay at 0, 1, 2, 4, 6 and 8 hours. When the women were taking no OC, peak plasma levels of rifampicin ranged between 8.2-36 mcg/ml, while they varied between 11.25-29 mcg/dl during the 2nd OC cycle. Further, the time of peak concentration of rifampicin when the women did not use an OC occurred between 2-4 hours in 5 women and at 6 hours for the other woman. During OC administration, all the women's peak concentration was 2 or 4 hours. The area under curve (AUC) of rifampicin while no OC was used extended from 29.85-176 + or - 22.1 mcg/ml/hour and 61.9-157.7 + or - 14.9 mcg/ml/hour while the women took the OC. No significant difference existed between before and during OC use plasma levels of rifampicin and AUC. Even though studies show that rifampicin treatment reduces plasma levels of OCs, these results demonstrate that a low dose OC does not change rifampicin levels.^ieng

[Residual function in the ovary during low-dose oral contraceptive treatment]. / Residualfunktionen i ovariet ved lavdoseret p-pillebehandling.

Development in oral contraceptives during the past 20 years has involved continued reduction in the total quantity of hormone and alterations in the oestrogen/gestagen ratio and in the steroid structure for the gestagens employed. These changes have been undertaken primarily to counteract metabolic side effects and influence on the haemostatic system. Inhibition of the mechanism of ovulation is, however, also dependent on the steroid dosage and in cases where low-dosage oral contraception is employed, ultrasound investigations have demonstrated a risk of continued ripening of follicles during treatment. Correspondingly, hormone measurements during the pill-free week have demonstrated increase in the follicle-stimulating hormone, luteinizing hormone and the oestrogen concentration. The permissible margin of error in employing oral contraception has therefore diminished and is more dependent on the dosage and potency, particularly of gestagens. As the critical phase for failure of treatment is the first week of intake of oral contraceptives, it is important that treatment is commenced at the correct time not only at the commencement of treatment but also after the pill-free periods. If a pill is forgotten during the preovulatory oestrogen level and two pills are then taken, this may be interpreted by the organism as a positive oestrogen feed-back and, theoretically, this may result in increased gonadotropin production and thus further increase the risk of ovulation. In cases with the risk of malabsorption on account of gastro-intestinal disease and in cases with interaction with other medicaments, employment of alternative forms of contraception is recommended.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: Developments in oral contraceptives (OCS) over the last 20 years have involved continued reduction in the total quantity of hormone and alterations in the estrogen/gestagen ratio and in the steroid structure for the gestagens employed. These changes have been made primarily to counteract metabolic side effects and influence on the hemostatic system. Inhibition of the mechanism of ovulation is, however, also dependent on the steroid dosage and in cases where low dose OCs are employer, ultrasound investigations have demonstrated a risk of continued ripening of follicles during treatment. Correspondingly, hormone measurements during the pill-free week have demonstrated the increase in follicle stimulating hormone, luteinizing hormone, and estrogen concentration. The permissible margin of error in employing OCs has therefore diminished and is more dependent on the dosage and potency, particularly of gestagens. As the critical phase for treatment failure is the 1st week of OC intake, it is important that treatment be commenced at the correct time, both after the pill-free periods as well as at the beginning of treatment. If a pill is omitted during the preovulatory estrogen level and 2 pills are then taken, this may be interpreted by the organism as a positive estrogen feedback and, theoretically, this may result in increased gonadotropin production and thus further increase the risk of ovulation. In cases where there is malabsorption risk due to gastrointestinal disease and in cases where there is interaction with other medication, use of alternative forms of contraception is recommended. Whether the residual function in the ovaries during low dose OC use increases the risk of cyst formation as compared with traditional preparations is still uncertain until results of further investigations are available. (author's modified)

Oral contraceptives in 1984.

PIP: Low dose estrogen tablets, containing less than 50 mcg of ethinyl estradiol, were formulated because of the recognized dose response relationship with the steroid content of the tablet and side effects. These new oral contraceptives (OCs) are as effective as the older high-dose OCs, and available evidence reports fewer side effects. This discussion reviews pharmacology of these new OCs, the mechanism of action, contraindications, side effects, and problems with the low-dose estrogen OC. Ethinyl estradiol is the only estrogen used in the low-dose combination OC. There are several synthetic progestins: norethindrone, norethindrone acetate, norgestrel, levonorgestrel, and ethynodiol diacetate. These progestins have different potencies so the pharmacologic activity cannot be accurately predicted based on the amount present in the tablet. The synthetic steroids in OCs are absorbed in the small intestine, metabolized in the liver, excreted in the bile and feces with a half-life of 24 hours. The low-dose estrogen combination preparation is taken 3 out of every 4 weeks. Its contraceptive effect is primarily a result of hypothalamic mediated gonadotropin suppression with subsequent inhibition of ovulation. Contraindications to taking the low-dose OC are the same as for the higher dose OC: thromboembolic or cardiovascular disease, estrogen dependent neoplasia, markedly impaired liver function, undiagnosed genital bleeding, congenital hyperlipidemia, pregnancy, and women over age 30 who smoke. Relative contraindications include hypertension, diabetes mellitus, migraine headaches, uterine myomas, and epilepsy. The often quoted 2-5-fold increased incidence of thromboembolic disease, myocardial infarction, and stroke is based on large epidemiologic studies involving patients taking the older higher dose OCs. Current data from patients taking the newer low-dose medication demonstrate minimal if any increased incidence of these problems in young women who do not smoke. The low-dose estrogen OCs have minimal effect on lipid levels. Early reports of patients using the low-dose OC have shown little if any increased incidence of hypertension. The low-dose contraceptives have little effect on glucose tolerance, and there is no evidence to show an increased incidence of overt diabetes in OC users. There is no evidence that use of the combination OC causes an increase in cancer of the cervix, uterus, or ovaries. Clinical complaints of nausea, breast discomfort, chloasma, weight changes, and depression are reduced with the low-dose estrogen preparation. Hypomenorrhea while taking the OC occasionally occurs because the lower dose of estrogen is insufficient to stimulate the endometrial growth in face of the predominant progestin-atrophy effect.^ieng

Effect of low estrogen combination oral contraceptive on metabolism of aspirin and phenylbutazone.

Plasma levels of aspirin and phenylbutazone were estimated before and during administration of low estrogen combination type oral contraceptive for two menstrual cycles in ten and seven female volunteers, respectively. Aspirin was administered at doses of 300 and 600 mg, while phenylbutazone was administered at a dose of 400 mg. Blood samples were collected at intervals of 1, 2, 4, 6, and 8 h for aspirin and 2, 4, 6, 8, 24, 48, 72, and 80 h for phenylbutazone. Plasma levels, plasma half-life (t1/2), as well as area under curve (AUC) for aspirin after use of oral contraceptive revealed lower values. Phenylbutazone levels were not affected. Repeat studies of plasma t1/2 and AUC for aspirin after discontinuation of oral contraceptive showed values similar to basal levels.

PIP: Plasma levels of aspirin and phenylbutazone were estimated before and during the administration of low estrogen combination type oral contraceptive (OC) for 2 menstrual cycles in 10 and 7 female volunteers, respectively. Aspirin was administered at doses of 300 and 600 mg.; phenylbutazone was administered at a dose of 400 mg. Blood samples were collected at intervals of 1, 2, 4, 6, and 8 hours for aspirin and 2, 4, 6, 8, 24, 48, 72, and 80 hours for phenylbutazone. Plasma levels, area under curve (AUC), and plasma half life (t1/2) of aspirin were significantly lower during OC use as compared with predrug data. This was applicable to both doses of aspirin. Plasma levels of phenylbutazone did not show significant differences. Since there were significant alterations in plasma levels of aspirin during OC use, the study was repeated after a drug free interval of 3-5 months. A rise in plasma levels and t1/2 was observed after discontinuation of OC. Tmax for aspirin was not consistently altered during OC use, but the Pmax was reduced in all cases during OC use and was found to recover in all the 7 subjects studied after discontinuation of OC. Salicylate levels in 5 women using OC for more than 2 years were similar to the levels before administration of OC.

The effect of oral contraceptives in Malaysians: 1. iron metabolism and erythropoiesis.

PIP: Previous studies have suggested the possible involvement of oral contraceptives (OC) in enhanced red blood cell production (erythropoiesis). The present study attmepts to determine the effect of OC use on iron storage, as measured by serum ferritin, and on erythropoeitic activity in Malaysians. Health women of the 3 major Malaysian ethnic groups (Malays, Chinese, and Indians), all of whom were low-dose OC users, served as the study group. The findings confirm previous reports that serum iron levels are significantly increased in women taking OCs. Serum ferritin, a better measure of total body iron stores, dropped during the 1st 1-12 months of OC therapy. The drop was most pronounced at 4-6 months. However, by 1 or 2 years, the serum ferritin levels were comparable to those of the control group. Coinciding with the drop in serum ferritin was an increase in hemoglobin synthesis and erythropoiesis. These findings suggest that the initial drop in serum ferritin may be attributed to increased mobilization and utilization of iron as a result of increased erythropoiesis. This enhanced red blood cell production appears to be a consequence of OC therapy. After the 1st year, a new equilibrium is reached, at which the mean hemoglobin level, as well as total white blood cell and platelet count, is higher in OC users than in controls. Such changes have been shown to affect the flow properties of blood; further studies are needed to determine if these factors bear on the thromboembolic complications of OC use.^ieng