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PubMed1991

Oral contraceptives stimulate the excretion of clofibric acid glucuronide in women and female rats.

1. Glucuronidation of clofibric acid, the pharmacologically active form of the hypolipidemic drug clofibrate was investigated in a human population, either in vitro with liver homogenates from biopsies, or after ingestion of the drug and determination of the urinary metabolite. No difference in the glucuronidation rate according to age of the patients was observed. Bilirubin but not clofibric acid glucuronidation was significantly higher in women (106% increase), when expressed per gram of tissue. 2. The excretion of clofibryl glucuronide in women who took oral contraceptives was significantly enhanced by 25%. 3. In female rats, treatment with the contraceptive agent norethindrone also stimulated by 48% the formation of clofibrylglucuronide in liver microsomes.

Adult↗
PubMed1991

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.

Animals↗
PubMedDate not supplied

Mechanism-based inactivation of human liver microsomal cytochrome P-450 IIIA4 by gestodene.

A series of 17 alpha-acetylenic steroids was examined with regard to ability to inactivate human liver microsomal cytochrome P-450 (P-450) IIA4, an enzyme involved in the oxidation of a number of drugs, carcinogens, and steroids, including estrogens and progestogens. Of the eight compounds tested, gestodene was found to be particularly active as a mechanism-based inactivator of P-450 IIIA4. Inhibition of both microsomal nifedipine oxidation and 17 alpha-ethynylestradiol (EE) 2-hydroxylation was dependent upon NADPH and gestodene concentration. Rates of inactivation were pseudo first order-values of kinactivation = 0.4 min-1 and Ki = 46 microM and a partition ratio of 9 were calculated. The kinactivation is approximately 50-fold greater than estimated for EE and is one of the highest reported for P-450 mechanism-based inactivators. Spectrally detectable P-450 was also destroyed in microsomes, but several experiments indicate that little covalent binding to amino acid residues of P-450 IIIA4 occurs. Microsomal inactivation of P-450 could be blocked by the presence of other P-450 IIIA4 substrates, and several activities catalyzed by other P-450s were not inhibited under conditions in which greater than 90% of P-450 IIIA4 was inactivated. Consideration of structure/activity relationships among the 17 alpha-acetylenic steroids examined indicates that the delta 15 double bond is critical but is not in itself sufficient for the inactivation process, which is postulated to result from attack of P-450 on the substituted acetylenic carbon and lead to porphyrin N-alkylation. The effectiveness of this mechanism-based inactivator may account for reports of increased estrogen and steroid levels in some women using gestodene in oral contraceptives.

Contraceptives, Oral↗
PubMed1991

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.

Adult↗
PubMed1992

Concentration of fat, protein, lactose and energy in milk of mothers using hormonal contraceptives.

Energy, protein, lactose and fat were studied in the milk of mothers who were using different types of contraceptives. One hundred and eleven mothers made up the following groups. C: control (barrier and natural methods, or sterilization), n = 22; combined pill: LDP (low dose pill (levonorgestrel 0.15 mg + ethinylestradiol 0.03 mg)), n = 12 and MDP (medium dose pill (levonorgestrel 0.25 mg + ethinylestradiol 0.05 mg)), n = 13; MP (minipill (norethindrone 0.35 mg)), n = 37; DMPA (injectable progesterone (depot medroxiprogesterone acetate 150 mg)), n = 17; and IUD (plastic or copper intrauterine device), n = 10. The mean stages of lactation were, respectively, 15, 17, 5, 9, 5 and 9 weeks. The mean duration of observation for the study groups ranged from 2 to 4 weeks. Milk samples were collected before and after initiation of treatment (mean = 20 days; range = 14-103 days). The stage of lactation and the interval of nursing before sampling were recorded so that statistical account could be taken of these uncontrollable sources of variability. When incorporated as covariates, they showed that no significant differences existed between the groups tested, either before or after treatment.

Adult↗
PubMed1992

Contact factor proteases and the complexes formed with alpha 2-macroglobulin can interfere in protein C assays by cleaving amidolytic substrates.

Plasma from women taking combined oral contraceptives and cold-activated plasma contain proteases which cleave chromogenic substrates in protein C assays in the absence of protein C activators such as Protac. This spontaneous activity makes a background substraction necessary and makes protein C (PC) assays less accurate. We investigated two commonly used substrates < Glu-Pro-Arg-pNA (S-2366) and 2AcOH.H-D-Lys(Cbo)-Pro-Arg-pNA (PC substrate) and found that cold-activated normal and protein C-deficient plasmas gave absorbance values up to 300 times higher than buffer blanks. FXIa cleaves these substrates but activity was not blocked by corn or lima bean trypsin inhibitors, soy bean trypsin inhibitor (SBTI), hirudin or epsilon-amino-n-caproic acid (EACA). Kaolin activation of normal, FXI, FIX, FVIII, FVII and protein C-deficient, but not of FXII or prekallikrein (PKK)-deficient plasmas led to cleavage of chromogenic substrate for protein C. The protein C substrates were cleaved by purified kallikrein and alpha- and beta-FXIIa. Immunoabsorption with alpha 2-macroglobulin (alpha 2M) antibodies removed 60% of the alpha 2M and 70% of the activity on PC Substrate. Gel filtration of normal plasma on Sephadex G-150 gave a single peak of protein C activity and antigen in the included volume. After cold activation of the fractions, a second protein C-like peak appeared in the void volume, but with no detectable protein C antigen. This peak coincided with alpha 2M (chromogenic and ELISA) and plasma kallikrein (S-2302), but FXII (measured with a substrate insensitive to kallikrein) eluted separately.(ABSTRACT TRUNCATED AT 250 WORDS)

Amides↗
PubMed1990

The interaction of phenytoin and carbamazepine with combined oral contraceptive steroids.

Patients taking oral contraceptive steroids (OCS) are known to suffer contraceptive failure while taking anticonvulsants such as phenobarbitone, phenytoin and carbamazepine. We have studied the single dose kinetics of ethinyloestradiol (EE2); 50 micrograms, and levonorgestrel (Ng); 250 micrograms in groups of women before and 8-12 weeks after starting therapy with phenytoin (n = 6) and carbamazepine (n = 4). The area under the plasma concentration-time curve (AUC) was measured over a 24 h period for each steroid and significant reductions were seen with both anticonvulsants. Phenytoin reduced the AUC for EE2 from 806 +/- 50 (mean +/- s.d.) to 411 +/- 132 pg ml-1 h (P less than 0.05) and for Ng from 33.6 +/- 7.8 to 19.5 +/- 3.8 ng ml-1 h (P less than 0.05). Carbamazepine reduced the AUC for EE2 from 1163 +/- 466 to 672 +/- 211 pg ml-1 h (P less than 0.05) and for Ng from 22.9 +/- 9.4 to 13.8 +/- 5.8 ng ml-1 h (P less than 0.05). These changes are compatible with the known enzyme inducing effects of phenytoin and carbamazepine. Patients taking these anticonvulsants will need to be given increased doses of OCS (equivalent to 50-100 micrograms EE2 daily) to achieve adequate contraceptive effects.

Adolescent↗
PubMed1991

Lack of effect of oral contraceptive use on the pharmacokinetics of quinine.

The pharmacokinetics of quinine after a single 600 mg oral dose of quinine sulphate were studied in seven female subjects who used oral contraceptives and in seven age-matched female controls who did not. There were no significant differences (P greater than 0.05) in the maximum plasma concentration (Cmax) and the time of peak concentration (tmax) between the subjects who used oral contraceptives (Cmax = 5.3 +/- 1.0 (s.d.) mg l-1; tmax = 1.4 +/- 0.7 h) and the control subjects (Cmax = 5.6 +/- 0.9 mg l-1; tmax = 2.1 +/- 0.9 h). The mean elimination half-life of quinine in the oral contraceptives user group (12.5 +/- 1.9 h) was similar (P greater than 0.05) to that in the control group (11.8 +/- 2.7 h). The oral clearance of quinine in the oral contraceptive user group was 0.133 +/- 0.055 l h-1 kg-1 (range 0.073-0.233) and was not significantly different (P greater than 0.05) from that observed in the control group (0.125 +/- 0.025 l h-1 kg-1, range 0.075-0.148).

Adult↗
PubMed1990

The pill and cancer: a review of the literature. A case of swings and roundabouts?

The literature review has been carried out to determine the effects of the contraceptive pill in relation to the development of certain cancers. Current research findings are presented, in an attempt to evaluate the risks and benefits associated with oral contraceptive use. Particular attention is paid to the findings of a recent United Kingdom National Study, which supports the controversial link between the pill and breast cancer. The actions of the combined oral contraceptive pill and the progesterone-only pill are explored regarding their influence on the ovarian, breast, endometrial and cervical cancers. A background to the incidence and risk factors associated with these cancers is given. Included is a brief analysis of long and short-term use, dose variability and chemistry of the pill. It emerges through the literature that the pill clearly has a protective function in relation to cancers of the ovary and the endometrium. However, its influence on the development of breast cancer and cervical cancer remains irresolute pending further research. In the absence of firm guidelines for advice to clients concerning the sensible use of oral contraceptives, proposals are included for a more reasoned approach to choice.

Clinical Trials as Topic↗
PubMed1992

The induction of amenorrhoea.

A survey has shown that many women favour eliminating menstruation and it has been suggested that therapeutic induction of amenorrhoea might be an advantage in female personnel mobilised for war. The traditional method has been to take the oral contraceptive pill continuously. This produces weight gain and other side-effects; spotting and breakthrough bleeding can be a problem initially. The method is however cheap. The Gonadotrophin Releasing Hormone (GnRH) analogue, goserelin, is extremely effective, produces less side-effects, but it is very expensive. Two synthetic steroids, danazol and gestrinone, are moderately effective, have a variety of prominent side-effects and are also quite expensive. With all these drugs normal menstruation resumes in the cycle after they are discontinued. Although goserelin has many advantages over the continuously taken contraceptive pill, its cost precludes it from consideration as a means of eliminating menstruation.

Amenorrhea↗
PubMed1975

Effect of selective lesioning of brain serotonin or catecholamine-containing neurons on the activity of oral steroid contraceptives in rats.

The effect of different dosage combinations of lynoestrenol and mestranol were studied in rats that have been subjected to selective lesioning of brain serotonin or catecholamine-containing neurons. Lesions of the midbrain raphe, which cause a marked decrease of serotonin in the forebrain, were without any effect on the estrus cycle, fertility and activity of the steroids under study. An intraventricular injection of 6-hydroxydopamine, which causes a selective decrease of noradrenaline and dopamine in the forebrain, produced a transient effect only on the estrus cycle but did not significantly change the fertility or the activity of the substances investigated. The data indicate that the integrity of monoaminergic neurons in the brain is not an essential condition for the aspects investigated in the present study.

Animals↗
PubMed1991

Pharmacokinetics of levonorgestrel in 18 women after 1 month of treatment with a triphasic oral contraceptive.

A triphasic levonorgestrel (LNG)- and ethinylestradiol-containing oral contraceptive was administered to 18 women. Plasma samples were obtained throughout a treatment cycle just before drug administration and on the last treatment day (day 21), several plasma samples were collected from each individual up to 48 h postadministration. LNG was determined by radioimmunoassay in all plasma samples. In addition, the concentration of sex-hormone-binding globulin (SHBG) was determined in plasma samples collected from the same subjects during treatment, as well as during a pre- and a posttreatment cycle. During the treatment cycle, plasma levels of LNG determined just before drug administration increased and reached steady state at about day 16. This increase was due to an increased dose of LNG according to the triphasic dose regimen, a concomitantly ethinylestradiol-induced increase in SHBG and due to pharmacokinetic accumulation, since LNG had a terminal half-life of approximately 28.5 h and the dosing interval was 24 h. Steady-state levels and pharmacokinetic parameters of LNG determined on the last day of treatment were in good accordance with previously published results.

Adolescent↗
PubMed1979

High-dose medroxyprogesterone acetate (MPA) treatment in advanced breast cancer. A review.

Medroxyprogesterone acetate (MPA) when employed at high doses (greater than or equal to 500 greater than or equal to 1000 mg/day i.m.) can produce objective remission with improved survival in about 30% of postmenopausal women with advanced breast cancer resistant to cytotoxic drugs and endocrine therapies. When administered to women not previously treated with chemotherapy, the objective remission response rate reached 40%. From available evidence, high dose MPA can be considered a useful agent in the treatment of advanced breast cancer in postmenopausal women with soft tissue, pulmonary, pleural or osseous involvement even when patients have become refractory to prior hormone and cytotoxic therapies. Early results suggest that the response rate can be increased in patients with estrogen and/or progesterone-positive receptors. It is note worthy that in a study conducted on postmenopausal women resistant to cytotoxic and/or hormonal drugs, the median duration of survival was 13.5 months, while CRs plus PRs did not reach the median at 24 months after starting MPA treatment. High dose MPA is essentially devoid of major side effects. Relief of pain, increase in appetite and body weight, and sense of well being are characteristic features of the improved quality of life under MPA treatment. However, a gluteal abscess (from 2% to 20% dose related) is the most frequent side effect. A promising area for future studies is combined therapy using hormonal and cytotoxic agents or alternating sequential combinations. Well-designed studies are needed to develop means for increasing the complete response rate and therefore survival. Recent studies of combined chemo- and hormonal (MPA) therapy have yielded objective tumor regressions of 53 to 80% with an increased rate of complete remissions and duration of response.

Animals↗