Impairment of prednisolone disposition in women taking oral contraceptives or conjugated estrogens.

Companion studies were designed to determine the effects of oral contraceptives and conjugated estrogens on the pharmacokinetics of prednisolone. Twenty-four normal women entered the studies, including six young women taking oral contraceptives and six age-matched control women, and six postmenopausal women receiving conjugated estrogens and six age-matched postmenopausal women. All received 0.53 mg/kg prednisolone phosphate, iv. Significant decreases (P less than 0.05) in the clearance and volume of distribution and significant increases in the half-life were found for both total and unbound prednisolone in the women taking oral contraceptives compared to values in the young control women. A significant decrease in the unbound clearance and increases in the total and unbound half-lives of prednisolone were found in the women receiving conjugated estrogens compared to values in the postmenopausal control women. Total clearance and volume of distribution were unchanged by conjugated estrogen therapy. Administration of prednisolone to women receiving estrogen-containing oral contraceptives or conjugated estrogens results in exposure of these women to increased concentrations of unbound prednisolone for increased periods of time. Increases in the pharmacological and toxic effects of prednisolone might be expected in these women.

Existence of multiple peaks in plasma ethinyl estradiol and norethindrone after oral administration of a contraceptive pill.

Previous measurements of plasma ethinyl estradiol (EE2) and norethindrone (NE) over 24 h after oral administration of a contraceptive pill have demonstrated a single steroid peak occurring 1-2 h after pill ingestion, with a gradual decline over the next 22 h. In the present study plasma concentrations of EE2 and NE were measured 0, 0.5, 0.75, 1, 2, 4, 12, and 24 h after oral ingestion of a contraceptive pill containing 35 micrograms EE2 and 1 mg NE at 0, 3, 6, and 9 months of use in 58 normal healthy women. Contrary to previous reports, analysis of the 464 steroid curves (58 subjects x 4 time periods x 2 steroids) revealed the presence of multiple hormone peaks. Two peaks of EE2 were identified in 44.8% of women during the first pill cycle and in 75.9%, 55.2%, and 67.2% of women after 3, 6, and 9 months of pill use. Two hormone peaks of NE were observed in 29.3% of women during the first cycle and in 36.2%, 50%, and 44.8% at 3, 6, and 9 months, respectively. Existence of these multiple peaks at the frequency observed has not previously been reported. Further quantification of the frequency and magnitude of these peaks could be helpful in explaining differences in biological responses associated with pill use.

Effects of a new oral contraceptive containing an antimineralocorticoid progestogen, drospirenone, on the renin-aldosterone system, body weight, blood pressure, glucose tolerance, and lipid metabolism.

Combined hormonal oral contraceptives (OCs) may lead to a mild rise in blood pressure and body weight. In rare instances, large increments in blood pressure are measured. We investigated the effect of a combination of ethinyl estradiol (EE) plus a progestogen with antimineralocorticoid, i.e. natriuretic, properties [Drospirenone (DRSP)] on body weight, blood pressure, the renin-aldosterone system, atrial natriuretic factor, plasma lipids, and glucose tolerance. It is anticipated that this will lead to the development of an OC that does not raise body weight or blood pressure. Four groups of 20 women each received 30 micrograms EE plus 3 mg DRSP (group A), 20 micrograms EE plus 3 mg DRSP (group B), 15 micrograms EE plus 3 mg DRSP (group C), and, as a control OC, 30 micrograms EE plus 150 micrograms levonorgestrel (Microgynon, Schering; group D) for 6 months. During the OC-free control cycles before and after treatment and throughout treatment, the target parameters were measured. Between the pretreatment cycle and the sixth treatment cycle, mean body weight fell by 0.8 to 1.7 kg in groups A, B, and C (P < 0.05 vs. D), whereas it rose by 0.7 kg in group D. Systolic and diastolic blood pressures fell by 1-4 mm Hg in groups A, B, and C (significant for A and C vs. D) and increased by 1-2 mm Hg in group D. Renin substrate rose equally in all groups (P < 0.05), whereas PRA and plasma aldosterone rose significantly only in the DRSP groups, presumably due to sodium loss. In the DRSP groups, high density lipoprotein cholesterol rose (P < 0.05), in contrast to group D. Low density lipoprotein cholesterol fell slightly (P > 0.05), whereas triglyceride levels showed a stronger increase in the DRSP groups (P < 0.05) than in group D. All groups attained good cycle control; group A had the best. Side-effects were minimal. To our knowledge, this is the first report on a combined OC that leads to a small decrease in body weight and blood pressure. It may be especially beneficial for women susceptible for a gain in weight and a rise in blood pressure.

PIP: The potential of a new oral contraceptive (OC) containing drospirenone (DRSP) to avert the moderate increases in body weight and blood pressure often associated with use of existing combined OCs was investigated in a study of four groups of 20 German women each. Group A received 30 mcg of ethinyl estradiol (EE) and 3 mg of DRSP, Group B was administered 20 mcg of EE and 3 mg of DRSP, Group C received 15 mcg of EE and 3 mg of DRSP, and Group D was given a standard OC containing 30 mcg of EE and 150 mcg of levonorgestrel. Between the pretreatment cycle and the last (sixth) treatment cycle, mean body weight fell by 0.8-1.7 kg in Groups A, B, and C, but rose by 0.7 kg in Group D. Systolic and diastolic blood pressures fell by 1-4 mm Hg in Groups A, B, and C and rose by 1-2 mm Hg in Group D. Renin substrate rose equally in all four groups, while plasma renin activity, plasma aldosterone, and high density lipoprotein cholesterol rose significantly only in the three DRSP groups and serum triglyceride levels were significantly higher in Group D than in the three DRSP groups. Glucose tolerance increases were similar in all four groups. Finally, all groups--but especially Group A--experienced good cycle control and there were no serious side effects. These findings suggest that a combined OC containing DRSP may be especially beneficial for women who have a tendency to gain weight or experience a rise in blood pressure while taking OCs.

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.

Inhibition of antipyrine metabolism by low-dose contraceptives with gestodene and desogestrel.

To examine the effects of the two newest monophasic oral contraceptives on liver microsomal drug metabolism, plasma kinetics and urinary metabolite excretion of antipyrine, a model substrate for liver microsomes, were evaluated. Plasma lipid and lipoprotein levels, and in particular the high-density lipoprotein subfractions, were also monitored in view of their apparent regulation by a P450-dependent system. Ten healthy volunteers were treated with each contraceptive for a period of 3 months in a crossover trial. Both contraceptives significantly reduced antipyrine clearance by 34.6% (gestodene) and 43.3% (desogestrel) by impairing the oxidative metabolism, particularly to the 4-hydroxy and 3-hydroxymethyl metabolites, with little difference between the two associations. In addition, with both a comparable highly significant rise of plasma triglyceride levels, apolipoproteins A-I and A-II and the high-density lipoprotein-3 subfraction was observed. Treatment with these new monophasic contraceptives may reduce the metabolism of concomitantly given drugs undergoing oxidative transformations.

Influence of sex and oral contraceptive steroids on antipyrine metabolite formation.

Our study was undertaken to determine the influence of sex and the use of oral contraceptive steroids on antipyrine clearance and metabolite formation. Our subjects were eight men (M), eight women (F), and eight women who had been using oral contraceptive steroids (OC) for at least 6 mo; all were healthy. The groups were matched for age and smoking and drinking habits. Antipyrine elimination half-life (t1/2) was longer in the OC than in the F group (12.9 +/- 2.0 and 9.7 +/- 1.7 hr) and clearance was lower (2.0 +/- 0.1 and 2.8 +/- 0.5 l/hr), while volume of distribution (Vd) was essentially the same (37.1 +/- 5.7 and 38.5 +/- 4.6 l). The M group had longer t1/2s than the F (11.8 +/- 1.2 and 9.7 +/- 1.7 hr) and greater Vds (47.1 +/- 5.4 and 38.5 +/- 4.6 l), but clearance values were the same (2.8 +/- 0.5 and 2.8 +/- 0.5 l/hr) in the two groups. Compared to the F, the three metabolic pathways of antipyrine appeared to be inhibited in the OC group. Partial clearances for production for the F and OC groups were (l/hr); norantipyrine (NORA) 0.70 +/- 0.13 and 0.42 +/- 0.12, 4-hydroxyantipyrine (OHA) 1.19 +/- 0.37 and 0.83 +/- 0.25, and 3-hydroxymethylantipyrine (HMA) 0.45 +/- 0.10 and 0.33 +/- 0.09. Partial clearance for production in the F group was higher than in the M for OHA (1.19 +/- 0.37 and 0.78 +/- 0.15 l/hr) and NORA (0.07 +/- 0.13 and 0.56 +/- 0.13 l/hr), but not for HMA (0.45 +/- 0.10 and 0.40 +/- 0.05 l/hr). In the F group, total metabolite recovery was higher than the M. We conclude that sex and OC steroids have differential effect on the several metabolic pathways of antipyrine.

Imipramine disposition in users of oral contraceptive steroids.

Ten women on long-term, low-dose estrogen oral contraceptive steroids (OCS) and eight age-matched drug-free female controls received an intravenous infusion of 12.5 mg imipramine. Eleven (six OCS users and five controls) also took a 50-mg oral dose of imipramine on another occasion. After intravenous injection, volume of distribution was much the same in the OCS and control groups and clearance was of the same order (899 and 975 ml/min). Elimination t1/2 was prolonged in OCS users after intravenous doses (17.8 vs 25.5 hr) but did not change after oral doses (18.4 vs 19.1 hr). Imipramine plasma protein binding was of the same order in both groups. Absolute bioavailability increased in OCS users (from 27.1% vs 44.1%), which resulted in a trend toward decreased apparent oral clearance (from 4649 vs 2322 ml/min). Women who used OCS regularly show little change in imipramine kinetics after intravenous dosing. After oral dosing absolute systemic bioavailability increased, resulting in decreased apparent oral clearance in the absence of any change in oral elimination t1/2. Imipramine (with high first-pass hepatic extraction) is nonrestrictively cleared, with drug elimination predominantly a function of hepatic blood flow. These data are consistent with OCS inhibition of hepatic imipramine oxidation with no alteration in hepatic blood flow resulting from chronic OCS use.

PIP: 10 women on longterm, low dose estrogen oral contraceptives (OCs) and 8 age matched drug free female controls received an intravenous infusion of 12.5 mg imipramine. 11 (6 OC users and 5 controls) also took a 50 mg oral dose of imipramine on another occasion. After intravenous injection, volume of distribution was much the same in the OC and control groups and clearance wa of the same order (899 and 975 ml/minute). Elimination 1/2-life was prolonged in OC users after intravenous doses (17.8 vs 25.5 hours) but did not change after oral doses (18.4 vs 19.1 hours). Imipramine plasma protein binding was of the same order in both groups. Absolute bioavailability increased in OC users (from 27.1% vs 44.1%), which resulted in a trend towards decreased apparent oral clearance (from 4649 vs 2322 ml/minute). Women who used OCs regularly showed little change in imipramine kinetics after intravenous dosing. After oral dosing, absolute systemic bioavailability increased, resulting in decreased apparent oralclearance in the absence of any change in oral elimination 1/2-life. Imipramine (with high 1st pass hepatic extraction) is nonrestrictively cleared, with drug elimination predominantly a function of hepatic blood flow. These date are consistent with OC inhibition of hepatic imipramine oxidation with no alteration in hepatic blood flow resulting from chronic OC use.

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.

Pharmacokinetics of single and multiple doses of ethinyl estradiol and levonorgestrel in relation to smoking.

The effects of tobacco and oral contraceptive (OC) use (Ovral) on the pharmacokinetics of levonorgestrel (0.25 mg) and ethinyl estradiol (50 micrograms) were examined. Young women (n = 27) were grouped as follows: I: non-OC users/nonsmokers; II: OC users/nonsmokers; III: non-OC users/smokers; and IV: OC users/smokers. The apparent clearance of levonorgestrel in group I was 80.9 +/- 15.6 ml/hr/kg and the half-life was 19.3 hours. A significant decrease in levonorgestrel clearance was seen in the chronic OC users (groups II and IV). The apparent oral clearance of ethinyl estradiol was 1002 +/- 398 ml/hr/kg in group I and the half-life averaged 7.7 hours. Groups II and III showed decreased (not significant) clearance of ethinyl estradiol. Tobacco use had no effect on steroid pharmacokinetics in the non-OC users. Although chronic OC use did not affect ethinyl estradiol clearance, a joint effect of tobacco/OC use on enhancing clearance of ethinyl estradiol appeared to occur. A linear relationship was found between 24-hour trough serum concentrations and AUC values of both steroids that may facilitate population monitoring studies of OC exposure.

PIP: The effects of combined cigarette smoking and oral contraceptive (OC) use on the pharmacokinetics of the pill's major components were examined in 27 white female volunteers grouped as follows: Group 1, non-OC user, nonsmoker; Group 2, OC user, nonsmoker; Group 3, non-OC user, smoker; Group 4, OC user, smoker. The 11 OC users in the study had been taking the pill for over 6 months; 5 were taking Ovral (50 mcg of ethinyl estradiol, 0.5 mg of norgestrel) and the remaining 6 switched to Ovral for the 1-month cycle before the study period. The non-OC users took 1 study dose of Ovral. The clearance of levonorgestrel was significantly lower in chronic OC users (mean elimination half-life of 30 hours) than in single-dose subjects (mean elimination half-life of 23 hours). The mean elimination half-life of ethinyl estradiol was approximately 12 hours for both chronic and acute OC use, although there was a nonsignificant tendency for lower ethinyl estradiol clearances in chronic OC users. Chronic tobacco use as a single factor did not influence the pharmacokinetics of levonorgestrel; however, a joint effect from chronic OC use and tobacco use was seen for ethinyl estradiol. Tobacco use had no effect on steroid pharmacokinetics in the non-OC users. Finally, a linear relationship was found between 24-hour trough serum concentrations and area-under-curve values of both steroids that may facilitate population monitoring studies of OC exposure.

Oxidative status and oral contraceptive. Its relevance to platelet abnormalities and cardiovascular risk.

Oral contraceptive (OC) use is a risk for thrombogenic events. This paper reviews effects of OC on oxidative status, coagulation, and platelet activity. Complicating effects of cardiovascular risk factors such as smoking, diabetes, hyperpidemia, and hypertension, are discussed. From these data we conclude that: 1. OC use modifies slightly but significantly the oxidative status in women and in animals by decreasing in plasma and blood cells the antioxidant defenses (vitamins and enzymes). 2. The changes in the oxidative status are related to an increase in plasma lipid peroxides apparently responsible for the hyperaggregability and possibly the imbalance in clotting factors associated with the OC-induced prethrombotic state. 3. These effects of OC appear to be increased by a high intake of polyunsaturated fat and counteracted by supplements of vitamin E. 4. The risk factors acting synergistically with OC, have all been shown to increase platelet reactivity. In addition, smoking, diabetes, and, to some extent, dyslipidemia are associated with an increased level of lipid peroxides and concomitant changes in the antioxidant defenses that can be additive to those induced by OC. Thus, free radicals and lipid peroxidation could be the underlying mechanism in the predisposition to thrombosis induced by most risk factors in OC users. 5. Results of epidemiologic and experimental studies in this field will be concordant only when diet and natural antioxidants will be systematically taken into consideration.

PIP: Although any cardiovascular complications of combined oral contraceptive (OC) use have dramatically increased in the past decade, both as a result of lower dosages (under 50 mcg) of estrogen in newer OCs and the recommendation that this method be used only by nonsmokers under 35 years of age, there remains a need to deepen understanding of the mechanisms involved. The increased levels of estrogen in OCs, associated with free radical generation, lead to a disruption in oxidative status. Further deterioration occurs when other risk factors (smoking, diabetes, or nutritional insufficiency) that also induce the production of free radicals and promote lipid peroxidation are present. The increase in plasma lipid peroxides appears to be responsible for the hyperaggregability and imbalance in clotting factors associated with the OC-induces thrombotic state. This hyperaggregability is modulated in OC users by the intake of polyunsaturated fan and antioxidants. Key to the avoidance of thrombotic events in OC users is the screening out of potential acceptors with risk factors such as smoking that act synergistically with OCs. Determination of platelet reactivity should be considered in questionable cases. Since vitamin E has been shown to improve platelet reactivity and oxidative status in OC users, its addition directly to the pill should be considered as a preventive measure. Now that the link between thrombogenic mechanisms and lipid peroxidation has been established, research should be undertaken to separate the estrogenic from the free radical-inducing properties of OCs.

Gabapentin does not interact with a contraceptive regimen of norethindrone acetate and ethinyl estradiol.

Anticonvulsants that induce hepatic metabolism increase clearance of oral contraceptive hormones and thereby cause contraceptive failure. Gabapentin is not metabolized in humans and has little liability for causing metabolic-based drug-drug interactions. In healthy women receiving 2.5 mg norethindrone acetate and 50 microg ethinyl estradiol daily for three consecutive menstrual cycles, concurrent gabapentin administration did not alter the steady-state pharmacokinetics of either hormone. Thus, gabapentin is unlikely to cause contraceptive failure.

PIP: Anticonvulsants that induce hepatic metabolism increase the clearance of synthetic estrogens and progestogens used in oral contraceptives (OCs), thereby potentiating contraceptive failure. In contrast, the anticonvulsant drug gabapentin is not metabolized in humans and has little liability for metabolic-based drug interactions. The present study sought to confirm whether concurrent administration of gabapentin would alter the pharmacokinetics of norethindrone acetate (2.5 mg) and ethinyl estradiol (50 mcg) in healthy US women. A total of 13 women were enrolled for three menstrual cycles each. Pharmacokinetic values did not change appreciably as a result of the addition of gabapentin. The rate and extent of absorption of both hormones were unaffected by the anticonvulsant. Gabapentin plasma concentration time profiles and pharmacokinetic values from this study were similar to historical values after administration of gabapentin alone. The observed lack of interaction between gabapentin and norethindrone acetate or ethinyl estradiol is consistent with the fact that gabapentin is not metabolized, is not an inducer or inhibitor of hepatic drug metabolizing enzymes, is absorbed via a specific transport system for amino acids, and is not bound to plasma proteins. Anticonvulsant drugs that do not interact with OCs should be considered for the treatment of epileptic women of childbearing age who are using this method of fertility control.

Blood changes in sex steroid hormone users. Circulating immune complexes induced by estrogens and progestogens and their relation to vascular thrombosis.

Oral contraceptives (OC) have been shown to induce in some women antiethinylestradiol antibodies which may be detected as circulating immune complexes by precipitation in ammonium sulphate at 25% saturation (CIC.AS). A reevaluation of the presence of CIC.AS in 644 women either receiving sex steroid hormones or not was made, and the respective role of estrogens and progestogens investigated, together with the influence of the dose. The study confirmed that CIC.AS levels were significantly different in controls (442 +/- 246 micrograms/ml serum), healthy gonadal hormone users (754 +/- 700 micrograms) and users with thrombosis (1331 +/- 1099 micrograms/ml). These results indicated that: 1. CIC.AS could be induced by synthetic estrogens as well as progestogens, but not by non-synthetic hormones; 2. the induction of CIC.AS seemed poorly dose-related, and 3. was not correlated with the duration of use; 4. in reactive women, high CIC.AS levels occurred as soon as 3 weeks after the beginning of synthetic gonadal hormones use, persisted throughout treatment and decreased slowly when discontinued; 5. in women with thrombosis CIC.AS were more frequently detected (64.7%) than in healthy users (32.2%) P less than 0.001. The importance of the immunologic changes as a risk factor in thrombosis in OC users was evaluated in comparison with other predisposing factors and tobacco smoking.

PIP: Oral contraceptives (OCs) have been shown to induce antiethinyl estradiol antibodies in some women which may be detected as circulating immune complexes by precipitation in ammonium sulphate at 25% saturation (CIC.AS). A reevaluation of the presence of CIC.AS in 644 women either receiving sex steroid hormones or not was made, and the respective role of estrogens and progestogens investigated, together with the influence of the dose. The study confirmed that CIC.AS levels were significantly different in controls (442 +or- 246 mcg/ml serum), healthy gonadal hormone users (754 +or- 700 mcg) and users with thrombosis (1331 +or- 1099 mcg/ml). These results indicated that: 1) CIC.AS could be induced by synthetic estrogens as well as progestogens but not by nonsynthetic hormones; 2) the induction of CIC.AS seemed poorly dose-related; and 3) the induction was not correlated with the duration of use; 4) high CIC.AS levels occurred as soon as 3 weeks after the beginning of synthetic gonadal hormone use in reactive women and persisted throughout treatment and decreased slowly when discontinued; and 5) CIC.AS was detected more frequently (64.7%) in women with thrombosis than in healthy users (32.2%), P0.001. The importance of the immunologic changes as a risk factor in thrombosis in OC users was evaluated in comparison with other predisposing factors and tobacco smoking.

Blood pressure rhythm and endocrine functions in normotensive women on oral contraceptives.

DESIGN AND METHODS: Twenty-four hour blood pressure profiles were determined by non-invasive ambulatory blood pressure measurements in young normotensive women during the follicular and luteal phases of the menstrual cycle. Forty women participated, 20 of whom were on oral contraceptives (ethinyl-ethylestradiol 0.03 mg + levonorgestrel 0.15 mg) and 20 of whom were age- and weight-matched control individuals not on oral contraceptives. Data on systolic and diastolic blood pressure and heart rate were analyzed in each case by linear and rhythm analysis. Urine was collected day and night on each occasion on which ambulatory blood pressure measurements were recorded. RESULTS AND CONCLUSION: Daytime, night-time, and 24 h mean systolic and diastolic blood pressure and heart rate did not depend on the cycle phase. The nocturnal fall in blood pressure was preserved in both groups and during both phases. Rhythm analysis by partial Fourier series showed that, of 240 individual 24 h blood pressure profiles, only 12 (5%) did not exhibit a significant circadian rhythm. Linear and rhythm analyses revealed that during both phases of the menstrual cycle systolic and diastolic blood pressure were significantly higher throughout the 24 h, especially during the night, in women taking oral contraceptives. During both phases of the menstrual cycle urinary aldosterone excretion was significantly higher in women taking oral contraceptives. This increase could contribute to the night-time blood pressure elevations caused by oral contraceptives. The results suggest a modulating influence of sex steroids on the circadian blood pressure profile even in normotensive healthy volunteers.

PIP: Noninvasive ambulatory blood pressure monitoring has shown that blood pressure exhibits a pronounced circadian variation in both normotensive volunteers and patients with essential hypertension, with a daytime peak and a nocturnal fall. To investigate the effect of oral contraceptives (OCs) on the 24-hour blood pressure profile during the follicular and luteal phases of the menstrual cycle, a case-control study was conducted involving 20 users of OCs (0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel) and 20 age- and weight-matched healthy controls. Linear and rhythm analyses revealed that both systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly higher in OC users than in controls throughout the 24-hour observation period. The 24-hour, daytime, and nighttime means of SBP and DBP were not dependent on menstrual cycle phase. In both groups, peak SBP values occurred around 15-17 hours, trough values at 4-5 hours at night, and maximum slopes between 8-10 in the morning. Of the 240 individual 24-hour blood pressure profiles analyzed, only 12 (5%) did not exhibit a significant circadian rhythm. Finally, urinary aldosterone excretion was significantly higher among OC users in both phases of the menstrual cycle.

Drugs and folate metabolism.

Folates are a group of compounds which are required in the diet and are important in DNA, amino acids and possibly also amine metabolism. The biologically active folates are in the tetrahydro form. Tetrahydrofolates are produced from unreduced dietary folates by the enzyme dihydrofolate reductase. A number of drugs such as aminopterin, methotrexate (amethopterin), pyrimethamine, trimethoprim and triamterene act as folate antagonists and produce folate deficiency by inhibiting this enzyme. With other drugs which produce low serum and tissue concentrations of folate such as anticonvulsants, antituberculosis drugs, alcohol and oral contraceptives, the mechanism of this effect is uncertain. Possible mechanism include reduced absorption, prevention of release of folate from tissue stores, altered plasma protein binding, or increased folate metabolism in the liver. Treatment with folic acid antagonists such as methotrexate readily causes megaloblastic anaemia; this can be prevented by therapy with folinic acid (5-formyltetrahydrofolate). The role of other drugs in producing megaloblastic anaemia is less certain, e.g. it occurs in less than 0.75% of patients receiving anticonvulsants. The possible neurological and psychiatric effects of folate deficiency are also uncertain. However, in patients with folate deficiency who have neuropsychiatric symptoms, neuropathy or myelopathy, and normal vitamin B12 levels, it may be of value to try therapy with folic or folinic acid.

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

Interactions of contraceptive steroids with binding proteins and the clinical implications.

PIP: There are various complex interactions between combined oral contraceptives (COCs) containing the estrogen, ethinyl estradiol, and a synthetic gestagen and sex hormone binding globulin (SHBG). 1 interaction is that the magnitude of effect of the COC on hepatic synthesis, and thus serum concentration of SHBG, depends on the relative doses of the estrogen and gestagen and on the nature of the gestagen. Next, the interaction between the COC and the SHBG affects the biological activity of the synthetic steroids and influences the binding and the biological activity of the sex hormones produced by the body. The extent of this effect is based on the relative doses of the estrogen and gestagen, on the nature of the gestagen, and the concentration of endogenous sex hormones present. In addition, since women take the COC once/day, serum concentrations of the synthetic estrogen and gestagen fluctuate. Therefore the equilibrium between the synthetic hormones and the endogenous sex hormones also changes. Finally, a broad variation exists in serum concentrations of the synthetic estrogen and gestagen between females using the same COC. Therefore large intersubject variations between SHBG and the endogenous and exogenous hormones are expected.^ieng

Effects of oral contraceptives on free fatty acid metabolism in women.

These studies examined whether women using oral contraceptives have abnormalities in free fatty acid (FFA) metabolism compared with women not using oral contraceptives. Plasma palmitate kinetics ([3H]palmitate) were measured at rest, following glucose ingestion, and during epinephrine infusion in 13 oral contraceptive users and 13 matched women not using oral contraceptives. Oral contraceptive users had significantly greater plasma triglyceride concentrations and glucose responses to oral glucose tolerance testing. No differences in basal (2.1 +/- 0.1 v 1.8 +/- 0.2 micromol x kg fat-free mass x FFM(-1) x min[-1]), glucose-suppressed (0.6 +/- 0.1 v 0.5 +/- 0.1 micromol x kg FFM(-1) x min[-1]), or epinephrine-stimulated (3.3 +/- 0.1 v 3.6 +/- 0.2 micromol x kg FFM(-1) x min[-1]) palmitate flux were detected between women using and not using oral contraceptives. The respiratory quotient (RQ) also was not different between groups. We conclude that the increase in plasma triglycerides and the mild glucose intolerance seen with oral contraceptive use is not associated with significant abnormalities of FFA metabolism.

PIP: Some researchers have reported differences in plasma free fatty acid (FFA) concentrations between oral contraceptive (OC) users and nonusers, suggesting an influence of the pill on adipose tissue lipolysis. To confirm this finding, the present study examined FFA flux in 13 OC users and 13 controls matched for age, weight, and body composition under overnight postabsorptive conditions, after glucose ingestion to suppress FFA release, and during an epinephrine infusion to simulate lipolysis. No significant differences in FFA kinetics were observed between OC users and nonusers under any of these three conditions. In addition, the respiratory quotient under all three conditions was comparable in the two groups of women, suggesting no effect of OCs on fatty acid oxidation. The results suggest that the hypertriglyceridemia and slightly greater plasma glucose response to glucose tolerance testing seen in OC users are not associated with significant abnormalities of effective adipose tissue lipolysis.

Management of sexually assaulted females.

PIP: The victim of sexual assault has 5 needs: 1) care of injuries, 2) prevention of venereal disease, 3) prevention/alleviation of psychologic damage, 4) medicolegal examination with documentation for law enforcement authorities, and 5) prevention of pregnancy. The staff of Philadelphia General Hospital, in a program designed to meet these needs, treated 480 (24.6 per 100,000 population) victims of sexual assault in 1968. 70% were ages 14-44, 24% below 14 years of age. In this program, serologic testing and cultures are followed by intramuscular injection of penicillin, 2,400,000 units. Both pediatric and adult victims are treated with reassurance, close follow-up and psychiatric referral as indicated. Detection of motile spermatozoa by examination of vaginal aspirate by a qualified experienced laboratory technician is of utmost importance. Postcoital contraceptive therapy revealed a high incidence of gastrointestinal side effects and 4 pregnancies were established in the treated cycle.^ieng

Immediate postpartum oral contraception.

PIP: Oral contraceptives were administered on Postpartum Day 5 to 363 patients, 83 of whom were breast-feeding, to determine if bleeding quantity could be reduced and menstrual periods established earlier in the puerperium, to evaluate the effect on lactation, and to note if side effects could be minimized by initiating pill usage earlier postpartum; 245 patients, of whom 91 were breast-feeding, served as controls. All of the women were patients at the U.S. Air Force Hospital in Wiesbaden, West Germany. 54% of the lactating mothers on the pill were successfully breast-feeding at 6 weeks compared with 59% of the controls. 87% of the patients taking pills had their 1st menstrual period before 6 weeks postpartum compared with 23% of the controls. No significant decrease in quantity of bleeding was noted. Patients taking the pill did report a weight gain. The uterus returned to normal size sooner in the group taking the pill and there was less breast tenderness. 65% of the multigravida mothers taking the pill thought they had a more favorable postpartum course, 24% saw no difference, and 11% thought their postpartum experience was less favorable. Patient acceptance was excellent and no major porblems were encountered.^ieng

Contraceptive mechanism of microdose norethindrone.

PIP: To determine how microdose progestogens exert their contraceptive mechanism, 5 normal 20-40 year old women (each acting as her own control) were studied during a normal menstral cycle followed by a cycle in which each received orrally 350 mcg norethindrone per day beginning on Cycle Day 1 for 30 days. Results indicated that all control cycles were ovulatory. In the treated cycle, endometrial morphology was altered. There was also significant suppression of preovulatory FSH and LH peaks, alteration of urinary estrogens (either increase or decrease), and marked suppression of progesterone production during the luteal phase. Cervical mucus properties and sperm penetration were inhibited during the treatment cycle. These findings suggest that at least 3 different factors were involved in the contraceptive mechanism of microdose norethindrone: 1) alteration of ovulation and progesterone production by the corpus luteum, 2) cervical mucus changes and inhibition of sperm transport, and 3) endometrial changes.^ieng