Oral Contraceptive Steroids Research Articles

Effects of oral contraceptive steroids on the thickness of human cornea.

Twenty-three women of childbearing age were monitored for a period of 3 months to evaluate the effect of oral contraceptive steroids on central corneal thickness. Eight of these women acted as the control group and 15 were first-time users of oral contraceptive steroids. Two males were also studied to investigate the possible existence of cyclic change of corneal thickness in females vs males. The results obtained from the control group of females indicated a definite cyclic variation in corneal thickness, females showing minimum thickness just before ovulation. The cornea seemed to be thickest either at the beginning or the end of the menstrual cycle. The males showed no specific pattern. The variation seen in females is hypothesized to be related to the ovarian and gonadotropin hormones. Of the experimental group, the females who were using the higher progesterone concentration pill showed stabilization starting almost immediately and by the 3rd month their corneal thickness showed very little variation during the cycle. The women on lower dosage pills also stabilized but took longer to do so.

The interaction of phenobarbital and other anticonvulsants with oral contraceptive steroid therapy

In a group of 5 women on long-term anticonvulsant and oral contraceptive therapy, the plasma ethynylestradiol (EE) concentration on 50 μg EE daily was 11.1 ± 4.5 pg/ml. These values were at the lower end of the range found in normal women in this laboratory taking 30 μg EE daily (6–190 pg/ml). Four women have been studied prospectively for 3 months, over 1 cycle before and 2 cycles during phenobarbital 30 mg b.i.d. therapy. Significant falls in the plasma EE concentration were seen in two women (from 104.8 ± 13.4 to 37.7 ± 2.0 pg/ml and from 125.6 ± 23.8 to 34.8 ± 6.7 pg/ml p < 0.01) and breakthrough bleeding was seen in both women. No changes in plasma concentrations of follicle stimulating hormone, progesterone, norethindrone or norgestrel were seen. There was a significant increase in the sex hormone binding globulin capacity from 100.7 ± 5.8 to 133.3 ± 1.2 nmoles/1 (p < 0.05). These changes are consistent with the known microsomal enzyme inducing effect of phenobarbital.

Effects of contraceptive agents on the biochemical and protein composition of human endometrium

An analysis of the nucleic acid and protein composition of endometrial tissue was undertaken in normal women and in patients using either steroidal oral contraceptives or intrauterine contraceptive devices (IUCD). In the presence of an IUCD, endometrial RNA/DNA and protein/DNA ratios were elevated in the secretory phase of the menstrual cycle compared to values obtained in normal women. In the oral contraceptive group, endometrial RNA/DNA and protein/DNA ratios were below the normal range in the late proliferative phase of the cycle. Typical electrophoretic profiles in the oral contraceptive group were similar to the control group, although a quantitative analysis revealed that the concentrations of certain characteristic uterine proteins were reduced. In the IUCD group, there was a preferential appearance of two proteins with approximate molecular weights of 36,000 and 26,000 daltons. Another protein with a molecular weight of 48,000 daltons, which demonstrated a cyclic change during the normal menstrual cycle, was reduced in both study groups. The results suggest that both agents studied induce changes in the macromolecular composition of the human endometrium which may relate to their contraceptive effect.

Effect of contraceptive steroids on γ-aminobutyric acid metabolism and pyridoxal kinase activity in rat brain

Adult female albino rats were administered oral contraceptive steroids daily for 3 months and γ-aminobutyric acid (GABA) content as well as the GABA metabolizing enzyme(s) activity were assayed. GABA content of the brain was found to be elevated in both estrogenic and progestogenic hormone-treated animals. However, no significant change was observed either in glutamic acid decarboxylase (EC 4.1.1.15) activity or in γ-aminobutyric acid transminase (EC 2.6.1.19) activity of brain tissue in hormone-treated animals. Interestingly, parallel to the increase of GABA content, a concomitant elevation of pyridoxal kinase (PL-kinase) (EC 2.7.1.35) activity was observed. It seems that the increase in the GABA concentration by the contraceptive steroids might have been mediated through an elevated pyridoxal kinase activity of the brain. The possible mechanism and interrelationship between the metabolic activities is discussed.

Role of angiotensin II in oral contraceptive hypertension in anesthetized rats

Rats fed a diet containing an oral contraceptive estrogen-progestogen mixture (Enovid) for 26 weeks developed a significant (P<0.01) elevation in mean arterial pressure (145 ± 6 mm Hg) when compared to a control group of rats fed the same diet without oral contraceptive steroids (mean arterial pressure averaged 117 ± 6 mm Hg). Infusion of [Sar 1, Ala 8] angiotensin II, a competitive antagonist of angiotensin II, reduced the mean arterial pressure (P<0.01) in the oral contraceptive-treated rats to 117 ± 9 mm Hg, while infusion of this angiotensin II analogue into the control rats did not lower the arterial pressure. These studies provided evidence that angiotensin II may be involved in the hypertension produced by Enovid treatment in rats.

Drug interaction with oral contraceptive steroids.

Drug interaction with oral contraceptive steroids.

Phenobarbitone interaction with oral contraceptive steroids in the rabbit and rat.

1 The effect of phenobarbitone on the single dose pharmacokinetics of the synthetic steroids, ethinyloestradiol (EE2) and norethisterone, has been studied in the rabbit and rat. 2 EE2 is subject to an extensive first pass effect (96%). The plasma clearance of EE2 approaches total hepatic blood flow. It is suggested that a secondary peak in EE2 plasma concentration time curves at 5 h is due to enterohepatic recycling. Phenobarbitone had no effect on plasma EE2 concentrations following intravenous administration and produced a variable decrease after oral administration. 3 In phenobarbitone-treated rabbits, following intravenous administration of norethisterone there was no significant change in the area under the curve (AUC) compared to controls. In contrast, following oral administration of norethisterone to treated rabbits, the AUC was 20% and the peak plasma concentration 17% of that in controls. 4 The data in rabbits are consistent with drugs which are highly extracted by the liver. 5 In rats, phenobarbitone had no effect on plasma norethisterone concentrations following intravenous or hepatic portal (bolus) administration, but caused a decrease in systemic availability after both infusion into the portal vein (over a period of 5 min) and oral administration. 6 It is concluded that the rate of delivery of norethisterone to the liver is important in determining whether or not enzyme induction will cause an increased first pass effect. 7 Phenobarbitone caused an increase in conjugation of norethisterone in the gastrointestinal tract of rats.

Malignant Mammary Tumors in Beagle Dogs Dosed With Investigational Oral Contraceptive Steroids&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;

Of 172 beagle dogs administered investigational oral contraceptive steroids for 2.4-5.2 years, 9 developed malignant mammary tumors. At necropsy their ages varied from 41 to 70 months, with a mean age of 4.9 years. The malignant tumors were observed in 1 dog that received ethynerone plus mestranol at 1.05 mg/kg/day and in 4 dogs that received chlorethynyl norgestrel plus mestranol at 1.05 mg/kg/day. Also, 4 dogs that received anagestone acetate plus mestranol at either 0.44 or 1.10 mg/kg/day developed malignant mammary tumors. Malignant tumors were not seen in 33 dogs administered mestranol at 0.02 and 0.05 mg/kg/day for 7 years or in 18 dogs given ethynerone without mestranol at 1.00 mg/kg/day for 5 years. No malignant tumors were observed in 18 control dogs maintained for 7 years without treatment. Three dogs had single malignant mammary nodules, 3 dogs had 2 malignant nodules, 2 dogs had 4-6 malignant nodules, and 1 dog in the treatment group given high dosages of ethynerone plus mestranol had 14 mammary nodules composed of fibrosarcoma. The malignant tumors were histologically classified as 5 anaplastic carcinomas, 2 solid carcinomas, 1 tubular adenocarcinoma, 1 squamous cell carcinoma, and 1 fibrosarcoma. Most dogs had only 1 histologic type of cancer (8/9 dogs); however, 1 dog had carcinomas of both solid and anaplastic types involving different glands. Metastases were present in 5 dogs and most often involved regional lymph nodes and lung.

Oral contraceptive steroids: effects on iron and zinc levels and on tryptophan pyrrolase and alkaline phosphatase activities in tissues of iron-deficient anemic rats

Weanling Wistar-strain female rats were fed a normal or an iron-deficient diet for 8 weeks and oral contraceptive steroids (OCS) were added for the last 4 weeks. Hemoglobin content, serum iron and zinc levels, liver iron levels, and tryptophan pyrrolase activities, and liver, kidney, and brain zinc levels and alkaline phosphatase activities were determined. Compared to control rats given the normal diet (N group), elevated liver zinc levels and tryptophan pyrrolase activity were found in rats fed the normal diet containing OCS ( + S group), but other parameters did not alter. In rats fed the iron-deficient diet alone (D group), only liver zinc levels were significantly higher, while other parameters were in general lower than those in the N group. In rats fed the iron-deficient diet containing OCS (D + S group), all hematological values, tissue mineral contents with the exception of liver zinc levels, and liver tryptophan pyrrolase and kidney alkaline phosphatase activities were lowered, compared to the N or N + S group. However, compared to the D group, the values of most parameters in the D + S group did not differ significantly, apart from an increase in serum zinc levels. These observations suggest that OCS does not greatly influence the various changes caused by iron-deficient anemia.

Pituitary and ovarian responsiveness to a graded gonadotropin releasing factor stimulation test in women using a low-estrogen or a regular type of oral contraceptive

The hypothalamic-pituitary-ovarian axis was evaluated in 47 women who were using mechanical contraception (MC) (N = 20), standard oral contraceptives containing 50 micrograms (μg) or more of estrogen (SOC) (N = 17), and a low-estrogen oral contraceptive containing 35 μg of ethinyl estradiol (LEOC) (N = 10). In the last half of their cycles, measurements were made of basal blood levels of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH), prolactin, estradiol, progesterone, testosterone, and dihydrotestosterone. The SOC group had significantly lower concentrations of basal LH, FSH, estradiol, progesterone, and testosterone. The LEOC group showed only decrease in estradiol. In addition, the women were all evaluated with a sequentially administered intravenous gonadotropin-releasing factor (GNRF) test in which 10 samples of blood were drawn over 4.5 hours for analysis of FSH and LH, and in which GNRF was administered as a 0.5 μg, 5.0 μg, and 50.0 μg bolus. There was a significantly suppressed response for both gonadotropins in the SOC group. The women using the low-estrogen oral contraceptive had no suppression of the FSH response, and the LH response was suppressed only after the maximal GNRF stimulation (50.0 μg). The gonadotropin responses to all GNRF injections were significantly different between the SOC and LEOC subgroups. These data suggest that some of the physiologic effects of oral contraceptive steroids, such as pituitary gonadotropin suppression, are dose-related, and that, therefore, the low-estrogen type of oral contraceptives have potentially fewer adverse effects and, presumably, may produce amenorrhea less often.

Influence of environmental chemicals on drug therapy in humans: studies with contraceptive steroids.

The effects have been studied of various environmental factors on the variability in response to oral contraceptive steroid therapy in women. Ten- to thirty-fold variations in plasma concentrations of norethisterone, L-norgestrel and ethinyloestradiol have been shown in samples taken 12 h after administration of oral contraceptives in mid-menstrual cycle. Factors shown to be responsible for this variation include passage into the enterohepatic circulation, a variable first-pass effect, and changes in metabolism in the gut wall or liver due to diet, disease, smoking or administration of drugs. Phenobarbitone and the antibiotic rifampicin increase both oestrogen and progestogen metabolism in women and in experimental animals by increasing hepatic and gut wall metabolism. In animals, other antibiotics (ampicillin, neomycin and lincomycin) suppress the gut flora that normally hydrolyse steroid conjugates excreted in bile; enterohepatic circulation or oral contraceptive steroids is thus reduced and their plasma concentrations lowered by up to 90%. In the human, ampicillin has a variable but less dramatic effect on elimination of oral contraceptives. Samples of gut wall mucosa obtained from patients with coeliac disease are defective in their ability to metabolize oral contraceptives. Cigarette smokers eliminate ethinyloestradiol more rapidly than non-smokers; an increased production of reactive steroid metabolites may thus be a cause of vascular disease in women who smoke and take contraceptive steroids.

The effect of oral contraceptive steroids and enzyme inducing drugs on sex hormone binding globulin capacity in women [proceedings

An improved assay for sex hormone binding globulin (SHBG) was used to confirm previously published results on the accumulation of SHBG in a group of 3 women starting oral contraceptive therapy with Minovlar. In all 3 women both SHBG and norethisterone concentrations increased 2-3 fold during the first cycle and in a woman studied for 3 months levels were stable by the end of the second cycle. A positive correlation was found between SHBG capacity and norethisterone concentration in all women. An animal model was also developed in which ethinyl estradiol was given orally to rabbits (50 mcg/kg) and goats (500 mcg) for 19 days with blood sample collections on alternate days. No increase in SHBG capactiy in either species was observed. 11 women were investigated to determine the effects of known enzyme-inducing drugs in women taking long-term oral contraception. Long-term therapy with phenobarbitone primidone phenytoin and carbamazepine was combined with an oral contraceptive of either 30 or 50 mcg of ethinyl estradiol. In women taking 30 mcg the SHBG capacity was significantly higher than in controls receiving only the oral contraceptives (P < .05). Similar results occurred in women taking 50 mcg of ethinyl estradiol. 8 women on long-term rifampicin therapy for tuberculosis and who were not on oral contraceptives had SHBG capacity measured 1 month before cessation of therapy and 1 month after stopping rifampicin and the capacity was significantly higher during rifampicin intake (P < .0005). SHBG capacity appears to be increased by drugs known to be enzyme-inducing agents.

Clinical pharmacology of oral contraceptive steroids: drug interactions

Clinical pharmacology of oral contraceptive steroids: drug interactions

Benign Liver Tumors and Oral Contraceptive Therapy

Clinical data obtained from 1972–1978 on 107 cases of oral-contraceptive-steroid-associated hepatic adenomas is presented in tabular form. Although a cause-and-effect relationship has not been definitively established, experimental evidence that supports an etiological role of contraceptive steroids in the production of benign liver tumors is described. Based on metabolic and toxicity studies, a mechanism is postulated whereby contraceptive steroid therapy may result in induced activities of drug metabolizing enzymes. In certain circumstances, increased levels of activated metabolites may irreversibly bind to hepatic macromolecules and produce altered cell growth. The possible promoter role of oral contraceptive steroids in tumor formation is discussed.

Plasma Xa inhibitory activities and plasma concentrations of norgestrel and ethinyloestradiol in women on oral contraceptive steroids.

British Journal of Clinical PharmacologyVolume 8, Issue 5 p. 505-506 Free Access Plasma Xa inhibitory activities and plasma concentrations of norgestrel and ethinyloestradiol in women on oral contraceptive steroids. DJ Back, DJ BackSearch for more papers by this authorM Bates, M BatesSearch for more papers by this authorMW Burke, MW BurkeSearch for more papers by this authorAM Breckenridge, AM BreckenridgeSearch for more papers by this authorFE Crawford, FE CrawfordSearch for more papers by this authorM MacIver, M MacIverSearch for more papers by this authorML Orme, ML OrmeSearch for more papers by this authorPH Rowe, PH RoweSearch for more papers by this authorE Smith, E SmithSearch for more papers by this authorS Webster, S WebsterSearch for more papers by this author DJ Back, DJ BackSearch for more papers by this authorM Bates, M BatesSearch for more papers by this authorMW Burke, MW BurkeSearch for more papers by this authorAM Breckenridge, AM BreckenridgeSearch for more papers by this authorFE Crawford, FE CrawfordSearch for more papers by this authorM MacIver, M MacIverSearch for more papers by this authorML Orme, ML OrmeSearch for more papers by this authorPH Rowe, PH RoweSearch for more papers by this authorE Smith, E SmithSearch for more papers by this authorS Webster, S WebsterSearch for more papers by this author First published: November 1979 https://doi.org/10.1111/j.1365-2125.1979.tb01034.xCitations: 10AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References BACK, D.J., BRECKENRIDGE, A.M., CRAWFORD, F.E., MacIVER, M., ORME, M.L'E., ROWE, P.H. & WATTS, M.J. (1979). An investigation of the pharmacokinetics of ethinyl-oestradiol in women using radioimmunoassay. Contraception (in press). BIGGS, R., DENSON, K.W.E., AKMAN, N., BARRETT, R. & HUDDEN, M. (1970). Antithrombin III, Antifactor Xa and Heparin. Br. J. Haematol., 19, 283– 305. ORAL CONTRACEPTIVES AND HEALTH (1974). Royal College of General Practitioners Report, London. SAGAR, S., STAMATAKIS, J.D., THOMAS, D.P. & KAKKAR, V.V. (1976). Oral contraceptives, antithrombin III activity and post operative deep venous thrombosis. Lancet, i, 509– 511. VESSEY, MP., DOLL, R., FAIRBAIRN, A.S. & GLOBER, G. (1970). Post-operative thromboembolism and the use of oral contraceptives. Br. med. J., 3, 123– 126. VON KAULLA, E. & VON KAULLA, K.N. (1970). Oral contraception and low Antithrombin III activity. Lancet, i, 36. WESSLER, S., GITEL, S.N., WAN, L.S. & PASTERNAK, B.S. (1976). Estrogen containing oral contraceptives. A basis for their thrombogenicity. J. Am. med. Ass., 236, 2179– 2182. YIN, E.T. (1974). Effect of heparin on the neutralization of Factor Xa and thrombin by the plasma alpha-2 globulin inhibitor. Thrombos. Diathes. Haemorrh., 33, 43– 50. Citing Literature Volume8, Issue5November 1979Pages 505-506 ReferencesRelatedInformation

Benign Liver Tumors and Oral Contraceptive Therapy

Clinical data obtained from 1972–1978 on 107 cases of oral-contraceptive-steroid-associated hepatic adenomas is presented in tabular form. Although a cause-and-effect relationship has not been definitively established, experimental evidence that supports an etiological role of contraceptive steroids in the production of benign liver tumors is described. Based on metabolic and toxicity studies, a mechanism is postulated whereby contraceptive steroid therapy may result in induced activities of drug metabolizing enzymes. In certain circumstances, increased levels of activated metabolites may irreversibly bind to hepatic macromolecules and produce altered cell growth. The possible promoter role of oral contraceptive steroids in tumor formation is discussed.

Leber und Ovulationshemmer

Since introduction of oral contraceptive steroids a variety of physiologic-adaptive and toxic side effects have been reported. A review is given. The study reports also four cases of hepatic vein thrombosis (Budd-Chiari-Syndrome-Venoocclusive disease) and three cases of benign hepatic tumors (liver cell adenoma and focal nodular hyperplasia) in young women following 2- to 5-year treatment with oral contraceptive steroids.

Plasma Levels of Adrenocorticotropin and Cortisol in Women Receiving Oral Contraceptive Steroid Treatment*

The secretion rate and plasma concentration of the adrenocortical steroid cortisol is modified in subjects treated with estrogenic and/or progestational steroids. The effects of contraceptive steroids on the secretion of ACTH are poorly documented, however, In the current investigation, we found that concentrations of ACTH and cortisol in plasma obtained at 0800--0900 h from a group of women with normal cyclic menses (n = 4) ranged from 78--120 pg/ml and 77--137 ng/ml, respectively. Although significant cyclic changes in the plasma levels of LH, FSH, 17 beta-estradiol, and progesterone occurred during the ovarian cycle, no obvious cyclic fluctuations in plasma levels of ACTH or cortisol were observed. In women treated with Norinyl 1 + 80 (1.0 mg norethindrone plus 0.08 mg mestranol), plasma concentrations of LH, FSH, 17 beta-estradiol, and progesterone were significantly lower (P less than 0.001) than plasma levels of these hormones in normal women during the ovarian cycle. The mean daily plasma concentrations of ACTH were significantly lower (P less than 0.001), whereas plasma cortisol levels were significantly higher (P less than 0.001) in women treated with oral contraceptive steroids compared to the levels of these hormones in the untreated ovulatory women.

Human hexosaminidase isozymes: IV. Effects of oral contraceptive steroids on serum hexosaminidase activity

Data from a mass screening program for identification of persons who are heterozygous for Tay-Sachs disease have been analyzed for the effects of oral contraceptive steroids on the activity in serum of hexosaminidase (hex) and the various hex isozymes. Women using oral contraceptives show a significantly higher total serum hex activity, reflecting mainly an increase in the heat-stable hex isozyme (hex I), and a smaller increase in the heat-labile hex A than do women using no medications. The changes in women using oral contraceptives are qualitatively similar to those observed during pregnancy. The distribution of responses to oral contraceptives is unimodal, and some of the variations may be related to differences in amount of steroid ingested. In addition, underlying genetic variation may contribute to the observed differences in enzyme activities.

Disposition of chlordiazepoxide: Sex differences and effects of oral contraceptives

There is considerable interspecies and interdrug variability in the effect of sex differences and oral contraceptive (OC) steroids on hepatic drug elimination. Their influence on the disposition of chlordiazepoxide has been studied in 11 healthy young men (29 +/- 5 yr), 11 healthy young women (28 +/- 5 yr), and 7 healthy women receiving OC steroids (27 +/- 2 yr) for more than 6 months. The elimination half-life (t1/2(beta)) was longer (from 14.8 +/- 5.9 hr to 8.9 +/- 2.5 hr) and protein binding less (95.5 +/- 1.4% and 97.0 +/- 1.2%) in women than in men. Weight-normalized plasma clearances of total drug did not differ, but the clearance of unbound drug was significantly less in women (8.7 +/- 5.0 ml/min/kg) than in men (15.6 +/- 5.3 ml/min/kg). Women on OC steroids had a lower plasma binding (from 93.6 +/- 1.5% to 95.5 +/- 1.4%) and a higher volume of distribution (from 0.62 +-/ 0.23 l/kg to 0.40 +/- 0.14 l/kg) than women not on OC steroids. The elimination t1/2 was longer (from 24.3 +/- 12 hr to 14.8 +/- 5.9 hr) and the clearance of unbound drug lower (from 5.7 +/- 3.0 ml/min/kg to 8.7 +/- 5.0 ml/min/kg) in women on OC steroids than in those not using them, but these differences were not statistically significant.