Oral Contraceptive Preparations Research Articles

Effect of Contraceptives on the Adhesion of Escherichia coli to Uroepithelial Cells

We studied the effect of female ovarian hormones present in contraceptive preparations on six strains of Escherichia coli isolated from patients with urinary tract infections. These strains had variable attachment potential. To study this effect in vivo, we gave a woman an oral contraceptive preparation and then compared the amount of attachment to her uroepithelial cells before and after hormone administration. To study the in vitro effect, we exposed uroepithelial cells from this same woman to different hormone concentrations for up to 18 hr and noticed any alteration in adhesion. We observed that in vivo as well as in vitro exposure of uroepithelial cells to hormones enhanced the adhesion of all E. coli strains.

Side effects and compliance with low- and conventional-dose oral contraceptives among adolescents

Oral contraceptives are the most popular birth control method for teenagers, yet many teens discontinue use of these contraceptives prematurely. The need to minimize any potential long-term medical complications from the use of contraceptive hormones must be balanced with the desirability of increasing acceptance of contraceptives by adolescents. There has been concern that the use of socalled “low-dose” estrogen preparations, although decreasing the likelihood of complications, may lead to side effects that make compliance less certain. The present study comparing two commonly used oral contraceptive preparations, one low dose, one conventional dose, tests the hypothesis that among adolescents an association exists between oral contraceptive side effects and compliance. Using a double-blind crossover method, 55 sexually active adolescent females received two months each of a preparation containing 35 μg ethinyl estradiol and 0.5 mg norethindrone and another containing 50 μg mestranol and 1.0 mg norethindrone. The 50-μg preparation was associated with fewer side effects when administered during the first two months. No differences in side effects were noted in the latter two months, but there was a slight increase in weight gain when compared with the 35-μg preparation. The most common side effect was intermenstrual bleeding with the 35-μg pill. There was no documented relationship between the occurrence of side effects and compliance.

Transfer of norethisterone(NET) and levonorgestrel(LNG) from a singie tablet into the infant's circulation through the mother's milk

A single tablet of either of the three different types of oral contraceptive preparations, viz. “Gynovlar” containing 3000 ug norethisterone (NET) and 50 ug ethinyl estradiol (EE 2) or “Ovral” containing 250 ug levonorgestrel (LNG) and 50 ug EE 2, or a daily progestogen only type — “Minipill” containing 30 ug of LNG only, were administered to 40 normal lactating women on a random basis. The sampling schedule in all the three body fluids, i.e. the maternal sera, breast milk and the infant's sera, was kept in such a manner that the peak levels of the contraceptive steroids would be expected to be present in these fluids. The results of this study indicate that the transfer ratio of LNG or NET from the maternal sera to her breast milk was approximately 10% (6–34%) for Gynovlar, 9% (5–18%) for Ovral and 6% (2–34%) for Minipill. However, it was interesting to observe that whereas the transfer ratio of NET or LNG from breast milk to infant's sera was similar for combination pills — 8% (3–23%) for Gynovlar and 12% (3–42%) for Ovral, it was significantly higher for progestogen only Minipills — 38% (13–92%) for LNG. The precise reason for the higher transfer ratio of LNG from breast milk to infant's serum in Minipill users cannot be explained.

Effect of seven low-dose combined oral contraceptive preparations on carbohyrate metabolism

The effect of seven low-dose oral contraceptive preparations on carbohydrate metabolism was investigated in groups of 10 healthy volunteers. All preparations contained a similar amount of ethinyl estradiol but differed in the content and type of progestogen. The following progestogens were used: levonorgestrel (monophasic and triphasic), norethisterone (monophasic), cyproterone acetate (monophasic), desogestrel (monophasic and biphasic) and gestodene (triphasic). An oral glucose tolerance test was performed before and after 6 months of treatment; glucose disappearance and insulin response curve were determined. Long-term glucose homeostasis was assessed by the estimation of the extent of glycosylation of plasma proteins and hemoglobin A1. The area under the curve for insulin and glucose did not change during treatment with any of the preparations. In addition the representative variables for long-term glucose control did not increase for any of the preparations during treatment. We conclude from these results that the low-dose pills investigated in this study do not have any adverse effects on glucose metabolism after treatment for 6 months.

The effect of triphasic and biphasic oral contraceptive preparations on HDL-cholesterol and LDL-cholesterol in young women

Lipid changes were measured during two consecutive studies on efficacy, side effects, and metabolic changes of oral contraceptive (OC) preparations. The mean lipid values of women on OCs at the start of the two studies were compared to those of women who had not taken OCs for at least 3 months. It was found that LDL-cholesterol (LDL-C) mean values of the women on OCs were higher than the mean values of women who had not taken OCs for at least 3 months. In study #1, women received the OC preparation Triphasil † . In study #2, women were randomised to one of 3 OC perparations (Triphasil, Ortho † 777 or Ortho † 10/11). HDL-cholesterol (HDL-C) and LDL-C were measured over time at six months and at 12 months after receiving the study medications. The results show that HDL-C increased in women on Ortho 777 and 10/11 and decreased in women on Triphasil at six months, and these changes were not found at 12 months. The results showed change over time for the LDL-C mean values, in that women not on OCs at the start of the studies had increased LDL-C mean values, and women on OCs at the start of the studies had decreased LDL-C mean values. Further the LDL-C mean values in women not on OCs at the start of the studies who received Triphasil (containing the gonane progestin dl-norgestrel) increased over time, whereas the combined mean values of those who received Ortho 777 and Ortho 10/11 (containing the estrane progestin norethindrone) did not increase over time. The significance of these results is discussed. † for the steroid content of these preparations see footnote Table II. Since blood samples were taken at random during the menstrual cycle, analyses were performed to determine if this variable would have confounded the results. A weak negative correlation was found with LDL-C values in women after 6 months on the study medication. No other significant correlation was detected for this variable in the data.

The Triphasics. Insights for Effective Clinical Use

Three triphasic oral contraceptive preparations are currently being widely used in the United States. These are Ortho-Novum 7/7/7 (Ortho Pharmaceutical), Tri-Norinyl (Syntex) and Triphasil (Wyeth). The hormone manipulation in these formulations more closely mimics the normal menstrual cycle and decreases the total amount of hormone delivered. These drugs were formulated to decrease menstrual irregularities and nuisance side effects and increase menstrual control, while maintaining efficacy and safety. This article describes these products, their mechanisms of action, efficacy and selected areas of concern for clinical practice in relation to side effects, safety and menstrual control. Findings and suggestions related to the therapeutic administration, patient use, counseling and management of these newer oral contraceptives will assist the nurse practitioner in providing optimum care to the consumer.

Belgian Trial of an Oral Contraceptive Containing 0.150 mg Desogestrel and 0.020 mg Ethinylestradiol

Abstract. The efficacy and cycle control of and tolerance to a new oral contraceptive combination containing 0.150 mg desogestrel + 0.020 mg ethinylestradiol was investigated by seven Belgian investigators in a total of 295 women (7257 cycles). The trial was set up as a part of a larger European open multi‐center study. This very low estrogen‐dose combination was found to be a highly effective oral contraceptive preparation with a good cycle control. Only one pregnancy occurred (not a product failure). The frequency of absence of withdrawal bleeding was low (generally less than 6% during the initial treatment cycles, gradually decreasing to less than 3% after 20 cycles) and in most women the amount and duration of withdrawal bleeding showed no change or a slight decrease in comparison with those of the menstrual bleeding before treatment. The incidence of irregular bleeding (spotting and breakthrough bleeding) rapidly decreased over the subsequent treatment cycles, from 11.7% after 3 cycles to 8.8% after 6 cycles and less than 5% after 12 or more cycles. The preparation was well tolerated. There were no serious side effects and only 8 (2.7%) women dropped out because of minor side effects.

Metabolic effects of a biphasic oral contraceptive preparation containing ethinyloestradiol and desogestrel on serum lipoproteins and apolipoproteins.

The effect of the administration of a biphasic oral contraceptive containing ethinyloestradiol and desogestrel on the distribution and composition of serum lipoproteins was studied in a group of 17 healthy female volunteers. The women were treated for a period of 6 months and compared with a control group of ten untreated volunteers. The serum lipoproteins were fractionated by density gradient ultracentrifugation into very low density lipoproteins (VLDL), low density lipoproteins (LDL), and into the high density lipoprotein (HDL) subfractions 2 and 3 (HDL2, HDL3). Lipids and apolipoproteins were assayed in the various fractions. No modification of either the lipid or apolipoprotein concentrations was observed in the control group. In the treated group, sex hormone-binding globulin (SHBG) and cortisol-binding globulin (CBG), and the serum content of cholesterol, triglycerides, HDL-cholesterol, apolipoprotein A-I (apo A-I) and apolipoprotein A-II (apo A-II) increased significantly after 3 and 6 months. The cholesterol and apolipoprotein B (apo B) content of VLDL increased significantly after 3 and 6 months, but remained unchanged in LDL. High density lipoprotein subfraction 2 (HDL2)-cholesterol was significantly increased after 3 and 6 months but apo A-I only after 6 months. Since apo A-II did not change, the apo A-I/A-II ratio increased significantly after 6 months of treatment. In the HDL3 fraction, the apo A-I increase was significant after 3 and 6 months, while the increase of apo A-II was significant after 6 months. The apo A-I/A-II ratio remained constant.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative effects of monophasic desogestrel plus ethinyloestradiol and triphasic levonorgestrel plus ethinyloestradiol on lipid metabolism

The effects of the monophasic oral contraceptive preparation desogestrel plus ethinyloestradiol (EE) and triphasic levonorgestrel plus EE on lipid metabolism were compared. Sixteen young healthy female volunteers received monophasic desogestrel plus EE ( 21 × 150 30 ), whereas eighteen women received triphasic levonorgestrel plus EE ( 6 × 50 30 + 5 × 75 40 + 10 × 125 30 ) for six consecutive cycles. The lipid composition of the various lipoprotein fractions was estimated after separation in a density gradient by ultracentrifugation. In addition, the apolipoproteins A-I and B were assessed. HDL-cholesterol (precipitation method), HDL-2 cholesterol, HDL-2 phospholipids and the ratio apolipoprotein A-I to apolipoprotein B were significantly higher in the monophasic desogestrel group than in the triphasic levonorgestrel group after three and six treatment cycles. HDL-cholesterol (gradient), HDL-phospholipids (gradient), HDL-3 phospholipids and apolipoprotein A-I were only significantly higher after six treatment cycles. No differences between the groups were observed for the other lipid variables studied including triglycerides and VLDL-triglycerides.

Pharmacokinetics of oral contraceptive steroids in Egyptian women: Studies with ovral, nordette and norminest

Plasma concentration profiles and pharmacokinetic parameters have been obtained following single dos administration of three commonly used oral contraceptive steroid preparations, Ovral, Nordette and Norminest to Egyptian women. The constituents of the preparations are as follows: Ovral (50μg ethinyloestradiol, EE 2 and 500 μg levonorgestrel, LNG); Nordette (30μg EE 2 and 150μg LNG); and Norminest (35μg EE 2 and 500 μg norethisterone, NOR). Peak plasma concentrations of EE 2 ranged between 116–160 pg ml −1 for Ovral, 55–78 pg ml −1 for Norminest and 30–70 pg ml −1 for Nordette. There was no significant difference in half-life ( t 1 2 ), oral clearance (CL) or apparent volume of distribution (Vd). The relative values of the area under the plasma concentration-time curve (AUC) reflected well the different amounts of oestrogen in each preparation. There was no significant difference in ( t 1 2 ), CL or Vd for LNG in the 2 preparations containing this progestogen. The mean AUC following Nordette (150 μg LNG) was 40% of that following Ovral (500 μg LNG; p ⩽ 0.001). Comparing pharmacokinetic parameters for the same dose of LNG (Ovral) and NOR (Norminest) showed the AUC to be decreased and CL and Vd increased in the latter group. The study indicates that the kinetic profile of the OCS in healthy Egyptian women are similar to other ethnic populations.

The effect of cyclical hormonal changes on erythrocyte electrolyte transport mechanisms

Electrolyte transport characteristics were examined in erythrocytes from 13 normal men and from two groups of women: taking combined oral contraceptive preparations (O/C, n = 10), and ovulatory women (non-O/C, n = 10) pre- and post-ovulation, at the same time intervals (days 7-10 and days 15-18) during a menstrual cycle. With rubidium (86Rb+) used as a potassium analogue, co-transport (ouabain-resistant, frusemide-sensitive 86Rb+ influx) values were found to be lowest in non-O/C women (28 +/- SE 2.5 nmol h-1 10(-9) cells) and highest in men (56 +/- 5.7, P less than 0.001), with results between the two in women taking O/C (42 +/- 4.2, P less than 0.05 vs men, P less than 0.01 vs non-O/C). Passive 86Rb leak (frusemide-and ouabain-resistant) was significantly lower in men (13 +/- 1.6 nmol h-1 10(-9) cells) than in both groups of women (non-O/C 29 +/- 1.8, P less than 0.001; O/C 25 +/- 1.2, P less than 0.001). There was no cyclical variation within either group of women. Maximum ouabain binding (number of NA+,K+-ATPase units) was the same in all groups. Na+,K+-ATPase activity, as determined by ouabain-sensitive 86Rb influx, was the same in men and non-O/C groups, but was significantly suppressed in O/C compared with both men (P less than 0.01) and non-O/C women (P less than 0.05). The differences found were not due to alterations in either progesterone or aldosterone, but could represent an androgenic effect in vivo of the 19-nortestosterone derivatives in combined oral contraceptive preparations.

Drug interactions with oral contraceptive preparations.

Oral contraceptives (OCs) should be used with additional caution in combination with other drugs in certain disease states. This discussion focuses on only those interactions which are due to identifiable pharmacokinetic processes. Pharmacological interactions between OCs and other compounds may be of 2 kinds: drugs may impair the effectiveness of the OCs to cause breakthrough bleeding or to allow pregnancy to occur; and OCs may interfere with the metabolism of other componds. In general interactions of the 1st kind are due to interference with the absorption metabolism or excretion of estrogens and interactions of the 2nd kind are due to competition for metabolic pathways. It is difficult to obtain estimates of the frequency of interactions but it seems likely that as low-dose preparations become more widely used interactions of the 1st type will become more common and those of the 2nd type less common. Although it is probably only those women with low plasma hormone concentrations who are at risk that other drugs may interfere with contraceptive efficacy and women with high plasma concentrations of estrogen who are at risk of side-effects and that OCs may interfere with other drugs there is no way of detecting women in either category. Consequently it is safer for the present to assuume that all women who take OCs might be at risk of some form of interaction. Significant drug interactions in which contraceptive efficacy is reduced are more likely to occur in the early part of the cycle when circulating hormone concentrations are of critical importance. It is well known that infective diarrhea can induce OC failure by increasing gastrointestinal motility and reducing hormone absorption. Thus any drug which reduces gut transit time and causes diarrhea is potentially likely to reduce circulating concentrations of OCs. The sulphation of ethinl-estradiol in the gastrointestinal wall has been shown to be a site of interaction for the enhancement of the activity of OCs. Ascorbic acid also undergoes sulphate conjugation in the gut wall and acts as a competitive inhibitor for sulphation of estrogens. The most clinically significant group of interactions occurs with other drugs that are metabolized by the same hepatic microsomal pathways as is estrogen. Most of the anticonvulsant drugs are inducers of microsomal enzymes. Rifampicin is known to be a potent inducer of hepatic microsomal enzymes and has been shown to increase the rate of metabolism of both estrogeens and progestogens. A recent report has suggested that the antifugal drug griseofulvin may cause a clinically important interaction with OCs. There are numerous well documented clinical reports of women who have taken OCs without missing a dose who have become pregnant while taking a variety of antibiotic agents such as ampicllin and tetracycline. Estrogens are inhibitors of hepatic microsomal enzymes. In this way they may show the metabolsim of other drugs thus increasing their plasma and tissue concentrations and increasing the risk of side-effects. These interactions might be expected to become less common as the concentration of estrogen in OCS decreases.

The bioavailability of ethinyloestradiol and levonorgestrel in patients with an ileostomy

The bioavailability of ethinyloestradiol and levonorgestrel has been studied in 5 young women with an ileostoray following surgery for ulcerative colitis and compared to that in 5 control subjects. Single i.v. and oral doses of both drugs were administered and the bioavailability calculated from the ratio of the two areas under the plasma concentration versus time curve for the two drugs. The mean bioavailability of ethinyloestradiol in the patients with an ileostomy was 55.4 ± 10.9% (± S.D.) compared to a control value of 45.0 ± 6.1% (p > 0.1). The mean bioavailability of levonorgestrel in the ileostomy patients was 85.2 ± 13.1% compared to 104.6 ± 22.3% in the controls (p 0.1). Women who have an ileostomy following lower bowel surgery can rely on their oral contraceptive preparations being absorbed in the normal way.

Effect of Oral Contraceptive Preparations Containing Different Progestogens on the Fibrinolytic System

Effect of Oral Contraceptive Preparations Containing Different Progestogens on the Fibrinolytic System

Synphase - another triphasic oral contraceptive

There are now six oral contraceptive (OC) preparations available in which the doses of the constituents vary through the cycle. All such “phased” formulations contain an oestrogen and a progestogen. In one (BiNovum), the cycle comprises two formulations (biphasic) with a single pill change after the 7th day. The remainder (Logynon, Logynon ED, Synphase, Trinordiol and TriNovum) are all triphasic with changes in formulation on or around the 6th and 12th days. In the original triphasic preparations (Logynon or Trinordiol)1 the progestogen content increases through the cycle: for the first 6 days each pill contains 50μg levonorgestrel, for the next 5 days 75μg, and in the last 10 days 125μg. This is also the pattern for TriNovum but norethisterone replaces levonorgestrel.

A randomized double-blind study of the effects of two low-dose combined oral contraceptives on biochemical aspects Report from a seven-centred study: WHO special programme of research, development and research training in human reproduction Task Force on Oral Contraceptives

A comparative study of the metabolic effects of two combined oral contraceptive preparations was undertaken in seven WHO Collaborating Centres for Research in Human Reproduction. A total of 847 subjects were randomly allocated to one of two pill groups — norethisterone 1mg/ethinyl estradiol 35ug (NET/EE) or levonorgestrel 150ug/ethinyl estradiol 30ug (LNG/EE). An additional 195 women using an IUD served as a comparison group. Blood samples were taken on admission, and at 3 and 12 months thereafter. Both pills induced changes in fasting and 2-hour glucose, triglycerides, total cholesterol, HDL-cholesterol, bilirubin, alkaline phosphatase, albumin, and total protein, but not aspartate aminotransferase. The most dramatic and probably most clinically important changes were an increase in triglycerides and a decrease in HDL-cholesterol. The NET/EE preparation appeared to induce a greater increase in triglycerides, but no significant difference was found between the two pill preparations with respect to HDL-cholesterol changes.

The measurement of arterial smooth muscle cell mitogens in the blood of oral contraceptive users

We have previously shown that serum from young women receiving the same combined mestranol-norethindrone containing oral contraceptive (OC) preparation accelerated the proliferation of arterial smooth muscle cells (SMC) in tissue culture, and this in vitro effect was not a direct action of either of its estrogenic or progestagenic constituents. To identify the substance(s) which might contribute to this potentially atherogenic action, blood was obtained from 20 OC users and control women for the measurement of growth hormone, insulin, somatomedins (insulin-like growth factor IGF-I and IGF-II), and the platelet α-granule constituents platelet-derived growth factor (PDGF), β-thromboglobulin, and platelet factor 4 (PF4). No difference was demonstrable between OC users and controls in the levels of any of these growth-promoting hormones, nor in plasma concentrations of any of the platelet α-granule proteins. These studies indicate that the enhanced mitogenicity found in OC sera is probably not attributable directly to these hormones or PDGF, and may instead result from an in vivo OC-induced alteration in other as yet unidentified mediators of cellular growth.

Cutaneous malignant melanoma in women: exogenous sex hormones and reproductive factors.

The roles of exogenous sex hormones and reproductive factors in the causation of malignant melanoma of the skin in women were examined in a case-control study of 276 patients and 276 matched controls in Western Australia. There was no consistent evidence of a relationship between the incidence rates of different histogenetic types of melanoma and age at menarche, duration of menstrual life, degree of obesity, number of pregnancies more than 20 weeks in duration or use of oral contraceptive preparations (OCP). Exposure to OCP was examined separately for different age periods and in different intervals of time before diagnosis; no consistent trend emerged. There was borderline evidence of an association of superficial spreading melanoma with duration of use of unopposed oestrogens. On the basis of seven studies of the relationship of melanoma to OCP published to date, we estimate that the total incidence rate of melanoma in OCP ever-users is unlikely to be increased by more than one third the rate in never-users.

Metabolic effects of two triphasic formulations containing ethinyl estradiol and dl-norgestrel

The metabolic effects of two triphasic oral contraceptive (OC) preparations containing dl-norgestrel(dlN) and ethinyl estradiol(EE) were studied in young women. The marked difference in the two preparations was in the progestogen content, allowing the study of the metabolic effects of high and low progestogen in oral contraception. The results suggest that high progestogen increases serum sodium, potassium, blood urea nitrogen, creatinine, total protein, albumen, and lactic dehydrogenase. An increase in aspartate transaminase and a decrease in alkaline phosphatase were probably estrogen-related. High progestogen significantly reduced the fasting blood glucose levels (p < .001). Both preparations significantly increased the levels of cholesterol and triglycerides in women who had not taken OCs for 3 or more months, and with the low progestogen preparation these increases are dissimilar to the effects reported in the triphasic preparations containing levonorgestrel.

Agreement between women's histories of oral contraceptive use and physician records.

The histories of oral contraceptive (OC) use provided by women participating in a study of hepatocellular adenoma (HCA) were compared with records obtained from their physicians. In the HCA study two memory aids were used to assist women in their recall: a calendar of significant events during a woman's lifetime to which she might relate her use of OCs and a book of colour photographs of the 90 OC preparations available up to the time of the study. Using the number of months of a woman's history which could be checked against physician records (mean for all women of 33 months) as the denominator, the highest proportion of concordance was for month-specific duration of OC use (90%) with lower agreement for duration and brand (62%) and duration, brand, and dose (54%). Agreement was better for cases than for controls.