Evidence that treatment with monophasic oral contraceptive formulations containing ethinylestradiol plus gestodene reduces bone resorption in young women.

The aim of the study was to evaluate if a pill containing the same dose of the same type of progestin compound (gestodene, GES, 75 microg) but different doses of ethinylestradiol (EE2) (20 or 30 microg) differently influences specific markers of bone resorption (urinary levels of pyridinoline (PYR) and dexoxypyridinoline (D-PYR)). During the 12 months of the study a significant decrease of urinary levels of PYR and D-PYR was found in 2 groups of young post-adolescent women taking the pills with 20 and 30 microg of EE2 in comparison with control women (subjects of the same age group with normal menstrual cycle who did not use contraception). In women taking pills with 20 or 30 microg EE2, the levels of sex hormone-binding globulin (SHBG) significantly increased during treatment in comparison with baseline, whereas in the same time period no changes occurred in control women. These findings suggest that similar to the pill containing 30 microg EE2, the lower dosage of the EE2 pill (20 microg) is also capable of reducing bone resorption. Twenty and 30 microg EE2 pills exert the same biological estrogenic effect. In fact, SHBG levels significantly increased with both pills. However, an additional effect of the progestin compound that could act directly on progestin or estrogen receptors of bone cannot be excluded. Since contraception with a pill containing the lowest estrogen dose is associated with the lowest incidence of side effects, these findings further suggest a pill containing 20 microg EE2 for young post-adolescent women would be the best choice.

PIP: The aim of this study was to evaluate if a pill containing the same dose of the same type of progestin compound (gestodene, GES, 75 mcg) but different doses of ethinyl estradiol (EE2) (20 or 30 mcg) differently influences specific markers of bone resorption (urinary levels of pyridinoline (PYR) and dexoxypyridinoline (D-PYR). During the 12 months of the study a significant decrease of urinary levels of PYR and D-PYR was found in 2 groups of young postadolescent women taking the pills with 20 or 30 mcg EE2 in comparison with control women (subjects of the same age group with normal menstrual cycles who did not use contraception). In women taking pills with 20 or 30 mcg EE2, the levels of sex hormone-binding globulin (SHBG) significantly increased during treatment in comparison with baseline, whereas in the same time period no changes occurred in control women. These findings suggest that similar to the pill containing 30 mcg EE2, the lower dosage of the EE2 pill (20 mcg) is also capable of reducing bone resorption. 20 and 30 mcg EE2 pills exert the same biological estrogenic effect. In fact, SHBG levels significantly increased with both pills. However, an additional effect of the progestin compound that could act directly on progestin or estrogen receptors of bone cannot be excluded. Since contraception with a pill containing the lowest estrogen dose is associated with the lowest incidence of side effects, these findings further suggest that a pill containing 20 mcg EE2 would be the best choice for young postadolescent women.

Comparative study on the acceptability of two modern monophasic oral contraceptive preparations: 30 microgram ethinyl estradiol combined with 150 microgram desogestrel or 75 microgram gestodene.

Cycle control and tolerability of two monophasic oral contraceptive pills containing 30 microg ethinyl estradiol (EE) with either 150 microg desogestrel (DSG) or 75 microg gestodene (GSD) were compared in women starting oral contraception. A minimum of 200 healthy women at risk for pregnancy were to be treated for a total of 6 cycles per patient in a prospective, randomized open parallel-group multicenter trial. Two hundred and forty-one subjects were randomized, 115 to DSG/EE and 126 to GSD/EE. Compliance to the study preparation was high (around 95%) in both groups and no pregnancies occurred during the study. Cycle control was excellent; there were no differences between the two groups with regard to incidence of spotting and breakthrough bleeding or duration and intensity of withdrawal bleeding. Side-effects were mild and in general comparable in the two groups. Both at baseline and during treatment, a higher proportion of women taking GSD/EE complained about breast tenderness. This resulted in more early withdrawals because of breast tenderness in the GSD/EE group. It was concluded that monophasic DSG/EE and GSD/EE are equally effective, have similar cycle control and both are generally well tolerated.

[Current monophasic hormonal contraception]. / Suvremennata monofazna khormonalna kontratseptsiia.

Data are presented from an investigation of the use of monophasic contraceptive pills chosen by different age groups. Analyses are made of the data obtained from the Bulgarian Association for Family Planning (BAFP) card index for the last two years. Information is given on the number of observed cycles, type of applied contraceptive pill, aims of their application (contraception, treatment of acne, menstrual disturbances etc.), age of patients, as well as any possible adverse effects--change in blood pressure, bodyweight changes, intermenstrual bleeding, hairiness, breast problems, paraclinical changes, etc. The observed cycles show a very small percentage of adverse effects with hormonal contraception, mainly during the first 2 or 3 cycles, with predominance of intermenstrual bleeding. No bodyweight changes or increased hairiness were observed.

PIP: The data for this analysis were obtained from the records of the Bulgarian Association for Family Planning (BAFP); the data covered a period of 3 years and were for 593 women with a total menstrual cycle of 3132. The most frequently used monophasic oral contraceptives were Cilest (containing norgestimate and ethinyl estradiol), used by 233 women, Marvelon (containing desogestrel and ethinyl estradiol), used by 154 women, Microgynon FE, used by 117 women, and Nordette (containing levonorgestrel and ethinyl estradiol), used by 89 women. The preparations were used mainly for contraception, but some women used them for menstrual regulation (27 women used Nordette for this purpose and so did 25 women use Marvelon for such a purpose), and a small percentage of the women used them for used dysmenorrhea. 103 (43.2%) women who used Cilest were in the 14-19 age group, while 106 (45.4%) of them were in the 20-25 age group. In the 14-19 age group 20 (17.2%) used Microgynon, 18 (20.2%) used Nordette, and 60 (38.8%) relied on Marvelon. In the 20-25 age group the respective figures were 79 (67.2%) for Microgynon, 40 (44.9%) for Nordette, and 67 (42.5%) for Marvelon. Some of the unfavorable metabolic effects of oral contraceptives included the increase of LDL and the reduction of HDL levels and androgenic effects. The most frequent side effect was intermenstrual bleeding, of which there were 19 cases for Cilest, 7 for Microgynon, 5 for Nordette, and 11 for Marvelon. Menstruation was prolonged in 4 women using Cilest and in 5 using Marvelon. 5 women using Cilest, 2 using Microgynon, and 2 using Nordette had headache. Other adverse effects included episodes of galactorrhea, discomfort, mastopathy, and bloating in the stomach. These effects did not pose a risk to general or reproductive health and did not justify discontinuation of use for these preparations.

A randomized cross-over study on various hormonal parameters of two triphasic oral contraceptives.

The effect of two triphasic oral contraceptives (Triquilar [TRQ] and Trisiston [TRS]) containing ethinyl estradiol (EE) and levonorgestrel (LNG) on various hormonal parameters was investigated in 26 women during a cross-over study. TRS consisted of 0.03 mg EE + 0.05 mg LNG (six tablets), 0.04 mg EE + 0.075 mg LNG (six tablets), and 0.03 mg EE + 0.15 mg LNG (nine tablets), whereas TRQ was different in the second phase (five tablets) and third phase (10 tablets). Blood samples were taken on days 6, 11, 21, and 28 of the control and washout cycles and the third treatment cycle. Both formulations inhibited ovulation reliably and decreased the serum levels of gonadotropins, free testosterone, and dehydroepiandosterone sulfate in a time-dependent manner, whereas estradiol and testosterone were already suppressed on day 6, indicating a direct suppressive effect on ovarian steroid synthesis. Prolactin, which rose sporadically in some women, was not significantly changed. In contrast, the levels of sex hormone binding globulin, corticosteroid binding globulin, and cortisol were significantly elevated by 100%. During the hormone-free interval of 7 days, all parameters returned at least partly to baseline. There was no significant difference between the effects of both formulations. The results suggest the possibility of a direct inhibitory effect of contraceptive steroids on ovarian steroid synthesis.

PIP: A randomized crossover study involving 26 women in Germany investigated the effect of two triphasic oral contraceptives (OCs) on selected hormonal parameters. The first triphasic, Trisiston, contained 0.03 mg of ethinyl estradiol (EE) and 0.05 mg of levonorgestrel (LNG) (6 tablets), 0.04 mg EE and 0.075 mg LNG (6 tablets), and 0.03 mg EE and 0.15 mg LNG (9 tablets). The second, Triquilar, differed from the first in the second (5 tablets) and third (10 tablets) phases. Serum samples were collected on days 6, 11, 21, and 28 of the control and washout cycles and the third treatment cycle. There were no significant differences in the hormonal effects of the two formulations. Both triphasics inhibited ovulation reliably and decreased serum levels of gonadotropins, free testosterone, and dehydroepiandrosterone sulfate in a time-dependent manner. Estradiol and testosterone were already suppressed on day 6. Prolactin rose sporadically in some women, but was not significantly changed. In contrast, levels of sex hormone binding globulin, corticosteroid binding globulin, and cortisol were significantly elevated by 100%. During the 7-day hormone-free interval, all parameters returned at least partly to baseline. These findings suggest a direct inhibitory effect of OC steroids on ovarian steroid synthesis.

Weight change with oral contraceptive use and during the menstrual cycle. Results of daily measurements.

Although weight gain is among the most common complaints of women using oral contraceptives (OC) and a frequent reason for discontinuation, studies demonstrate little basis for this perception. We explored this issue by analyzing the daily weights of 128 women during four cycles of triphasic OC use. The mean weight at the end of the fourth cycle of use was the same as baseline weight (average weight change, 0.0 pounds). The largest proportion of women, 52%, remained within 2 pounds (0.9 kg) of their starting weight, and 72% of women had either no weight change or a loss. Over each menstrual cycle, regular but minor weight shifts were observed, with the mean weight rising by one-half pound (0.2 kg) during the first weeks of each cycle and falling by the same amount during the last few days. These results emphasize the lack of association of OC use with weight gain but OC may be blamed at least in part, based on cyclic fluctuations. Counseling should emphasize weight gain as a misperception and stress the fact that a highly effective and safe form of contraception should not be ruled out or discontinued because of concern about weight.

PIP: Although weight gain has been identified as the most common single reason for discontinuing oral contraceptive (OC) use, the few studies that have addressed this issue have found little or no OC-related weight change. The present study analyzed the daily weights of 128 US women, 18-35 years of age, over the course of 4 cycles of use of a triphasic OC (Tri-Norinyl). The mean weight change between study start and completion was 0.0 pounds. 52% of study participants experienced no weight change (defined as remaining within 2 pounds of their starting weight) and an additional 33% experienced a gain or loss of less than 5 pounds. Overall, 72% of subjects had either no weight gain or lost weight. These results did not differ for the various age, race, and parity groupings. Analysis of daily weight measurements indicated that women tended to gain a small amount of weight (about one-half pound) during the first few weeks of each treatment cycle and to lose approximately the same amount during menstruation. Thus, at least some change in weight blamed on OC use may be attributable to normal cyclic fluctuations. Contraceptive counseling should stress the fact that the empirical research has failed to document weight gain as a side effect of OC use.

The cardiovascular safety of triphasic contraceptive steroids.

It was hypothesized that estrogen-induced cardioprotection is mediated by up-regulation and down-regulation of expression of nitric oxide (NO) and P-selectin, respectively. Published data on circulating levels of the vasodilator NO, atherogenic glycoprotein P-selectin, and lipoprotein-a [Lp(a)] in users of triphasic contraceptive steroids are lacking. A total of 30 healthy women (nonusers, controls) and 82 women using oral triphasic contraceptive steroids (ethinyl estradiol and levonorgestrel: Triovlar, Schering AG) for 18 to 24 cycles participated in this study. Fasting blood samples were obtained from users and nonusers for the determination of P-selectin and Lp(a) by enzyme immunoassay and NO by a colorimetric method. The serum Lp(a) levels in OC users were significantly higher than those of nonusers. On the other hand, the serum NO levels in OC users were significantly elevated when compared to nonusers. Plasma P-selectin was significantly lowered in OC users p < 0.005. These results demonstrate the beneficial effects of ethinyl estradiol in the triphasic contraceptive regimen. Ethinyl estradiol may afford a degree of anti-atherogenic-cardioprotective effect by up-regulation of the expression of the vasodilator NO and down-regulation of the expression of the atherogenic P-selectin. This may outweigh the cardiovascular risk of the increased atherogenic Lp(a). This study may explain the very low rate of mortality from venous thromboembolism in OC users, which compares favorably with the risks that many people accept in daily life.

Effectiveness of norgestimate and ethinyl estradiol in treating moderate acne vulgaris.

BACKGROUND: An excess of androgen is believed to contribute to development of acne in some patients. Because oral contraceptives (OCs) may reduce the active androgen level, hormonal therapy with OCs has been used successfully to treat patients with acne, although this treatment has previously not been studied in placebo-controlled trials. OBJECTIVE: Our purpose was to evaluate the efficacy of a triphasic, combination OC (ORTHO TRI-CYCLEN [Ortho-McNeil Pharmaceutical, Raritan, N.J.], norgestimate/ethinyl estradiol) compared with placebo in the treatment of moderate acne vulgaris. METHODS: Two hundred fifty-seven healthy female subjects, 15 to 49 years of age with moderate acne vulgaris, were enrolled in a multicenter, randomized, double-blind, placebo-controlled clinical trial. Each month for 6 months, subjects received either 3 consecutive weeks of the OC (i.e., tablets containing a fixed dose of ethinyl estradiol [0.035 mg] and increasing doses of norgestimate [0.180 mg, 0.215 mg, 0.250 mg]) followed by 7 days of inactive drug or placebo (color-matched tablets). Efficacy was assessed by facial acne lesion counts, an investigator's global assessment, a subject's self-assessment, and an analysis of within-cycle variation (cycle 6) in lesion counts. RESULTS: Of the 160 subjects in whom efficacy could be evaluated, the OC group showed a statistically significantly greater improvement than the placebo group for all primary efficacy measures. The mean decrease in inflammatory lesion count from baseline to cycle 6 was 11.8 (62.0%) versus 7.6 (38.6%) (p = 0.0001), and the mean decrease in total lesion count was 29.1 (53.1%) versus 14.1 (26.8%) (p = 0.0001) in the OC and placebo groups, respectively. In the investigator's global assessment, 93.7% of the active treatment group versus 65.4% of the placebo group were rated as improved at the end of the study (p < 0.001). Six of the seven secondary efficacy measures (total comedones, open comedones, closed comedones, papules, pustules, and the subject's self-assessment of study treatment) were also significantly more favorable in the OC group compared with the placebo group. CONCLUSION: An OC containing 0.035 mg of ethinyl estradiol combined with the triphasic regimen of norgestimate is a safe and effective treatment of moderate acne vulgaris in women with no known contraindication to OC therapy.

PIP: To evaluate the efficacy of a triphasic combined oral contraceptive (OC) in the treatment of moderate acne vulgaris, 231 healthy US volunteers 15-49 years of age with this dermatologic condition were enrolled in a phase III, multicenter, double-blind, placebo-controlled clinical trial. Each month for 6 months, subjects (n = 110) received either 3 consecutive weeks of Ortho Tri-Cyclen (containing a fixed dose of 0.035 mg of ethinyl estradiol and 0.180, 0.215, and 0.250 mg of norgestimate) followed by 7 days of inactive drug or placebo. The OC group showed significantly greater improvement than controls on all efficacy measures. The mean decrease in inflammatory lesion count from baseline to the sixth cycle was 11.8 (62.0%) among cases and 7.6 (38.6%) in controls, while the mean decrease in total lesion count was 29.1 (53.1%) versus 14.1 (26.8%) in the OC and placebo groups, respectively. In the investigator's global assessment, 93.7% of women in the treatment group and 65.4% of controls were rated as improved at the end of the study. Similarly, more cases than controls considered their acne "improved" at the study's end and expressed a preference for this therapy over other forms of acne treatment. These findings indicate that treatment of moderate acne vulgaris with a low-dose triphasic OC is safe and effective in women with no contraindications to OC use.

Increased levels of activated factor VII and decreased plasma protein S activity and circulating thrombomodulin during use of oral contraceptives.

In the present study the effect of oral contraceptive (OC) treatment on selected factors involved in the activation, i.e. circulating activated factor VII (cFVIIa), and in the inhibition of blood coagulation, i.e. plasma protein S activity and circulating thrombomodulin (cTM), were for the first time measured in OC users in a prospective study. Beside other coagulation variables, these parameters were measured during treatment with three low estrogen formulations containing different gestagen components (norgestimate, gestodene). During OC treatment increases in the activation markers prothrombin fragment F1 + 2 and D-Dimer were found, suggesting an increased activation of blood coagulation and fibrinolysis. Along with elevated plasma levels of FVII antigen, cFVIIa was also found increased in all three treatment groups, while inhibitory components of blood coagulation, plasma protein S activity and cTM, significantly and similarly decreased during treatment in all three treatment groups. We conclude that low dose estrogen pills induce similar changes in the plasma levels of main regulatory components of blood coagulation, despite differences in their gestagen components. Increased levels of activators and decreased activities of inhibitors may contribute to arterial and venous thrombotic complications seen in predisposed OC users.

PIP: The effect of oral contraceptive (OC) treatment on selected factors involved in the activation and inhibition of blood coagulation was measured in a prospectively randomized parallel-group centralized-center study. These were circulating activated factor VII (cFVIIa) as well as plasma protein S activity and circulating thrombomodulin (cTM). In addition to other coagulation variables these parameters were measured during treatment with 3 low-estrogen formulations containing different gestagen components (norgestimate, gestodene). 60 healthy women 19-37 years old were included. The women in Group I used Cileste tablets containing 35 mcg ethinyl estradiol (EE) and 250 mcg norgestimate (NG). Group II women used the 3-phase preparation Tri-Cileste containing EE and different doses of NG; and Group II women used the 3-phase preparation Triodena containing different doses of EE and gestodene (GS). 21 days on treatment were followed by 7 days off of treatment before the next cycle was started. Participants were treated for 6 cycles. Blood samples were obtained during the luteal phase before treatment and on days 18-22 of the 3rd and 6th treatment cycle. The plasma levels of various coagulation parameters, such as fibrinogen (Cileste, Tri-Cileste p 0.05; Triodena p 0.0005); fibrin-split product D-Dimer (Cileste p 0.05; Tri-Cileste, Triodena p 0.005), prothrombin fragment F1+2 (Cileste p 0.0005); Tri-Cileste, Triodena p 0.05); Factor VII antigen (Cileste, Triodena p 0.0005; Tri-Cileste p 0.005); FVII clotting activity (Cileste p 0.0005; Tri-Cileste p 0.05; Triodena p 0.005), and activated factor VII (Cileste p 0.0005; Tri-Cileste p 0.05; Triodena p 0.005) were significantly higher during the 3rd treatment cycle compared with the pretreatment values. A significant decrease was also found in the plasma levels of total and free protein S antigen (total protein S: Cileste p 0.05; Tri-Cileste, Triodena p 0.005; free protein S: Cileste, Tri-Cileste p 0.0005; Triodena p 0.05) and circulating thrombomodulin (Cileste p 0.05; Tri-Cileste p 0.0005; Triodena p 0.005).

No influence of proinsulin and insulin on plasma levels of plasminogen activator inhibitor type 1 and tissue plasminogen activator in young women before and during intake of contraceptive steroids.

Clinical observations in patients predisposed to cardiovascular disorders and recent experimental observations suggest that proinsulin and insulin participate in the regulation of fibrinolysis in vivo. In the present study, we examined if proinsulin and insulin affect the constitutive (fasting) secretion of plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA) in young healthy women (N = 17). We also measured the antigen concentrations of PAI-1 and t-PA during slow and fast changes in proinsulin and insulin levels induced by oral (OGTT) and intravenous (IVGTT) glucose tolerance tests. The assessments were performed before and after 6 months of treatment with contraceptive steroids, which have a well-defined influence on the fibrinolytic variables. We observed no consistent correlations between fasting values of proinsulin, insulin, PAI-1, and t-PA either before or during hormonal treatment. Before hormonal treatment, PAI-1 and t-PA antigen levels decreased (P < .05) during the hyperproinsulinemia and hyperinsulinemia induced by the OGTT and IVGTT. After hormonal intake for 6 months, a decrease only in t-PA concentrations during the OGTT was observed despite similar proinsulin and insulin responses to the glucose loads. Our findings suggest that proinsulin and insulin have no influence on the regulation of plasma levels of PAI-1 and t-PA in young healthy women, irrespective of intake of contraceptive steroids.

PIP: In Denmark, clinicians conducted clinical and metabolic evaluations on 17 healthy women, 21-26 years old, within the last 10 days of their menstrual cycle preceding intake with a triphasic oral contraceptive (OC) (ethinyl estradiol + norgestimate) and during the last 7 days of the sixth period of OC treatment. They aimed to examine the effect of proinsulin and insulin on fasting secretion of plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA). OCs have a well-defined effect on plasma levels of PAI-1 and t-PA. The clinical researchers also studied the antigen concentrations of PAI-1 and t-PA during slow and fast changes in proinsulin and insulin levels induced by oral and intravenous glucose tolerance tests. They did not find consistent correlations between fasting values of proinsulin, insulin, PAI-1, and t-PA either before or during OC treatment. During the glucose tolerance test induced hyperproinsulinemia and hyperinsulinemia and before OC treatment, PAI-1 and t-PA antigen levels fell (p 0.05). After 6 months of OC treatment, t-PA levels fell only during the oral glucose tolerance test (p 0.05) even though proinsulin and insulin responded similarly to the glucose loads. These findings suggest that neither proinsulin nor insulin regulate plasma levels of PAI-1 and t-PA in young healthy women regardless of OC use status.

Laboratory criteria for menopause in women using oral contraceptives.

OBJECTIVE: To evaluate laboratory criteria for menopause in women talking oral contraceptives (OC). DESIGN: Prospective, uncontrolled pilot study. SETTING: San Francisco General Hospital, San Francisco, California, and Magee-Womens Hospital, Pittsburgh, Pennsylvania. PATIENTS: Twenty-eight menopausal women. INTERVENTIONS: Fourteen menopausal women received triphasic 35 micrograms ethinyl E2 and 180-215-250 micrograms norgestimate, and 14 menopausal women received monophasic 30 micrograms ethinyl E2-150 micrograms desogestrel. MAIN OUTCOME MEASURES: Serum FSH, LH, and E2 levels were evaluated on days 14 and 28 (day 7 of the pill-free interval) of the third cycle of pills. RESULTS: Twelve women in each group completed the study. Fifteen (62.5%) subjects still had a serum FSH < 30 mIU/mL (30 IU/L) on the 7th day of the pill-free interval of the third pill package. All subjects had a serum FSH:LH ratio > 1 and 20 of 21 (95%) subjects had E2 < 20 pg/mL (73 pmol/L) at the end of the pill-free interval of the third cycle. CONCLUSIONS: Measuring FSH on the 7th day of the pill-free interval is not a sensitive test for menopause. Serum FSH:LH ratio > 1 or E2 < 20 pg/mL (73 pmol/L) on the 7th day of the pill-free interval may be a more appropriate marker of menopause in women using OC in the later reproductive years.

PIP: Health workers recruited 28 women aged 35-65 attending San Francisco General Hospital in California or Magee-Women's Hospital in Pittsburgh, Pennsylvania, for a prospective study designed to evaluate the laboratory criteria for menopause in women using oral contraceptives (OCs). The first 14 women received three cycles of a triphasic OC containing 35 mcg ethinyl estradiol and 180, 215, and 250 mcg norgestimate (Orth Tri-Cyclen-28). They comprised group 1. The remaining 14 women received three cycles of a monophasic OC containing 30 mcg ethinyl estradiol and 150 mcg desogestrel (Ortho-Cept-28). They comprised group 2. 12 women in each group completed the study. The mid-cycle luteinizing hormone (LH) level was much higher in group 1 than in group 2 (8.8 vs. 3.6 mIU/ml; p = 0.02). The serum follicle stimulating hormone (FSH) level of 62.5% of the women was still less than 30 mIU/ml on day 28 of the third pill package. All the women had an FSH:LH ratio of 1 at baseline and on day 28 of the third OC package, indicative of menopause. This ratio was significantly higher on day 7 of the pill-free interval than at baseline or mid-cycle (2.82 vs. 1.99 and 2.26, respectively; p 0.0001). The proportion of women with estradiol levels of 25 pg/ml was 90% at baseline and in the middle of the third cycle and 95% at the end of the pill-free interval of the third cycle. These findings suggest that the mid-cycle FSH:LH ratio and measuring FSH on the seventh day of the pill-free interval are not reliable indicators of menopause. Instead, a serum FSH:LH ratio of 1 or an estradiol level of 20 pg/ml on the seventh day of the pill-free interval may be a more reliable indicator of menopause in women using OCs in their later reproductive years.

The role of triphasic levonorgestrel in oral contraception: a review of metabolic and hemostatic effects.

Epidemiological studies suggesting a possible association between the use of combined oral contraceptives and an increased risk of cardiovascular disease have led to extensive investigations into the effect of oral contraceptives on lipid and carbohydrate metabolism, and on hemostasis. Since this association was originally suggested, the steroid dose in oral contraceptives has been significantly reduced and new progestogens have been developed. Also, triphasic formulations have been introduced which offer a well-balanced estrogen/progestogen ratio, allowing a further reduction in the progestogen dose per cycle, and thus helping to minimize unwanted metabolic and hemostatic effects. The metabolic interactions of triphasic levonorgestrel, the first triphasic formulation to be introduced, have received particular attention. Lipid metabolism appears to be largely unaffected by triphasic levonorgestrel, most studies reporting no significant change in high- (HDL-C) or low-density lipoprotein-cholesterol (LDL-C) levels. Several studies have reported a decrease in the lipoprotein subfraction HDL2-C levels, but in most cases measurements of the LDL-C/HDL-C and apolipoprotein A-1/B ratios reveal no clinically significant effects. Concerning lipids, most studies suggest that triphasic levonorgestrel has less metabolic impact than the monophasic formulation. In common with all currently available oral contraceptives, triphasic levonorgestrel appears to have some effect on carbohydrate metabolism. The study results vary, however; some investigators have found an impairment of glucose tolerance, whereas others have not detected any significant effect. Compared with lipid and carbohydrate metabolism, fewer studies have investigated the effect of triphasic levonorgestrel on hemostasis. In common with all estrogen-containing oral contraceptives, levonorgestrel appears to stimulate some procoagulant activity, elevating the levels of factors VII and X, and fibrinogen. However, the effect of triphasic levonorgestrel appears to be balanced, with most studies reporting a corresponding increase in anti-coagulant-fibrinolytic activity. Although most of the studies reviewed here reported some statistically significant metabolic interactions, many authors comment that the changes are probably not clinically relevant in terms of an altered risk of cardiovascular disease. The true risk of vascular disease associated with modern low-dose oral contraceptives remains to be confirmed when sufficient epidemiological data eventually become available.

PIP: This review of studies published since 1985 on the metabolic effects of triphasic levonorgestrel in oral contraceptives (OCs) reveals that triphasic levonorgestrel tends not to affect lipid metabolism. Specifically, it does not significantly change the level of the lipids associated with increased vascular risk (low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), and lipid ratios). Overall, triphasic levonorgestrel OCs do not affect triglycerides, while other OCs increase the level of triglycerides. They also have a lower effect on lipid metabolism than do monophasic levonorgestrel OCs. About 50% of the studies suggest that triphasic levonorgestrel OCs do not affect carbohydrate metabolism, while the remaining studies suggest that they cause a significant increase in carbohydrates. Some studies found that triphasic levonorgestrel OCs impair glucose tolerance. Studies on the effect of triphasic levonorgestrel on hemostasis are less numerous than those on lipid and carbohydrate metabolism. Unlike all combined monophasic OCs, triphasic levonorgestrel OCs appear to have a balanced effect on hemostasis. In fact, they stimulate both the coagulant and anti-coagulant-fibrinolytic pathways. Many of the researchers who found statistically significant metabolic interactions found that the changes fell within the normal clinical range and therefore did not increase the risk of cardiovascular disease. Triphasic levonorgestrel OCs tend to have less of a metabolic effect than its monophasic counterpart and a metabolic effect similar to other low-dose OCs.

Oral contraceptive effects on methylprednisolone pharmacokinetics and pharmacodynamics.

OBJECTIVE: Oral contraceptive (OC) steroids alter the disposition of numerous drugs, including corticosteroids. We investigated the pharmacokinetics and pharmacodynamics of methylprednisolone. METHODS: Twelve women (six women used OC steroids and six women did not) received intravenous methylprednisolone (0.6 mg/kg ideal body weight). Methylprednisolone disposition was assessed from plasma concentrations. Pharmacodynamic parameters measured were plasma cortisol, whole blood histamine (reflecting basophils), and blood helper T lymphocytes. RESULTS: Methylprednisolone clearance was significantly decreased in the women who used OC steroids (0.298 versus 0.447 L/hr/kg), resulting in a longer elimination half-life (2.20 versus 1.72 hours). With use of indirect response models, significant differences were observed with the cortisol and basophil responses. A larger value for the concentration that inhibits the zero-order production rate by 50% (0.37 versus 0.11 ng/ml) was observed in the women who used OC steroids for suppression of cortisol secretion, indicating less sensitivity to the suppressive effects of methylprednisolone. Greater net suppression of basophils was observed in the users of OC steroids (area under the response curve, 694 versus 401 ng x hr/ml). No differences were observed for helper T-cell responses. CONCLUSION: OC steroids appear to inhibit methylprednisolone metabolism. However, mixed changes in several responses occur, indicating that women can probably receive similar doses of methylprednisolone irrespective of OC steroid use.

PIP: At the Buffalo General Hospital in New York, researchers randomly assigned 6 healthy, nonobese women, 30-36 years old and using a triphasic oral contraceptive (OC) (Triphasil 28, Wyeth-Ayerst Laboratories), to either the baseline phase group or the group receiving an intravenous bolus of methylprednisolone sodium succinate at a dose of 0.6 mg/kg ideal body weight during the 2-week period after ovulation (i.e., luteal phase). These women were compared with 6 other women who did not use OCs but did receive the same dose of methylprednisolone. The purpose was to determine whether the adrenosuppressive, anti-inflammatory, and immunosuppressive effects of methylprednisolone differ in OC users. OC users experienced slower clearance of methylprednisolone (33% slower) than controls. This slower clearance rate contributed to a longer elimination half-life for methylprednisolone (2.2 vs. 1.72 hours; p 0.05). OC users also had a rate of slower elimination of cortisol than controls (0.180 vs. 0.276 hr-1; p 0.05). They had higher mean cortisol levels than controls (136 vs. 65 ng/ml). Women who used OCs for suppression of cortisol secretion had a larger value for the concentration of cortisol that suppresses the zero-order production rate by 50% (0.37 vs. 0.11 ng/ml; p 0.05), suggesting a decreased sensitivity to the effects of methylprednisolone on cortisol suppression. OC users experienced a greater net suppression of basophils at drug effect than at baseline. Methylprednisolone appeared to have no effect on helper T-cell responses. These findings suggest that OCs inhibit methylprednisolone metabolism. Since there were inconsistent changes in several responses, women can likely receive similar doses of methylprednisolone irrespective of OC use.

Effects of oral contraceptives on plasma neutral amino acids and cholesterol during a menstrual cycle.

OBJECTIVE: Concentrations of plasma neutral amino acids, i.e. threonine, serine, asparagine, glycine, alanine, citrulline, alpha-aminobutyric acid, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine, and tryptophan, and serum cholesterol, were determined at the follicular (Day 4), mid-cycle (Day 16) and luteal (Day 25) phases of the menstrual cycle in 15 users of the new generation of combined oral contraceptives (OC), 11 on multiphase combined OC, and 17 controls. RESULTS: The controls showed a decrease in the sum of amino acids to 95% at mid-cycle and 90% in the luteal phase relative to the follicular phase, and a significant decrease in the tyrosine level at the luteal relative to the follicular phase. Since there was no significant difference between the two OC subgroups in the levels of the specified variables at either of the phases, the two groups were considered together. The sum of amino acids in the OC group decreased to 89% at mid-cycle and 91% at the luteal phase relative to the follicular phase, indicating less metabolic effect than reported for older OC formulations. Compared to the controls, the OC group showed significant increased threonine level at the luteal phase, decreased glycine levels at mid-cycle and the luteal phases, decreased citrulline level at mid-cycle, and markedly decreased tyrosine levels at the mid-cycle and luteal phases. Neither total nor high density lipoprotein (HDL) cholesterol differed significantly between the control and OC groups. CONCLUSION: The results suggest that the metabolic effects of the new generation combined OC on neutral amino acids and cholesterol are only modest to slight, except for the effect on tyrosine, the brain noradrenaline precursor, which may cause disturbances of various noradrenaline-mediated central functions in susceptible subjects.

PIP: Concentrations of plasma neutral amino acids and serum cholesterol were determined at the follicular (day 4), mid-cycle (day 16), and luteal (day 25) phases of the menstrual cycle in 15 users of the new generation of combined oral contraceptives (OCs), 11 on multiphase combined OCs, and 17 controls. The controls showed a decrease in the sum of amino acids to 95% at mid-cycle and 90% in the luteal phase relative to the follicular phase and a significant decrease in the tyrosine level in the luteal relative to the follicular phase. Since there was no significant difference between the two OC subgroups in the levels of the specified variables at either of the phases, the two groups were considered together. The sum of amino acids in the OC group decreased to 89% at mid-cycle and 91% in the luteal phase relative to the follicular phase, indicating less metabolic effect than reported for older OC formulations. Compared to the controls, the OC group showed significant increased threonine levels in the luteal phase, decreased glycine levels at mid-cycle and in the luteal phase, decreased citrulline levels at mid-cycle, and markedly decreased tyrosine levels at mid-cycle and in the luteal phase. Neither total nor high-density lipoprotein (HDL) cholesterol differed significantly between the control and OC groups. The results suggest that the metabolic effects of the new generation combined OCs on neutral amino acids and cholesterol are only modest to slight, except for the effect on tyrosine, the brain noradrenaline precursor, which may cause disturbances of various noradrenaline-mediated central functions in susceptible individuals.

Effect of low-dose oral triphasic contraceptives on blood viscosity, coagulation and lipid metabolism.

The purpose of the study was to determine the relationship between hemorheological profile, i.e. blood viscosity, and other risk factors for cardiovascular and thrombotic diseases in women taking oral contraceptives and if blood viscosity may be considered a marker of cardiovascular risk in OC users. Plasma levels of coagulation parameters, serum lipids, blood viscosity and RBC deformability were determined in a group of 10 women taking OC vs. 10 controls. The blood parameters were evaluated before OC use and thereafter at 3 and 6 months. A significant change in the partial thromboplastin time, fibrinogen, HDL and apolipoprotein A-I was observed, while the other parameters remained unchanged. Plasma viscosity was significantly increased during OC treatment; whole blood viscosity and RBC deformability remained unchanged. However, although some parameters were significantly modified during OC treatment, all alterations remained within the normal range of laboratory values. The data confirm that low-dose triphasic OC therapy does not affect significantly the coagulation system, serum lipid metabolism and blood viscosity. Plasma viscosity measurement may be considered as a marker for monitoring women using OC because it is apparently the most sensitive parameter.

PIP: Previous studies have documented an association between blood viscosity and risk factors for cardiovascular and thromboembolic disease. The present study assessed the impact of use of a low-dose, triphasic oral contraceptive (OC) containing ethinyl estradiol in combination with gestodene on the coagulation system, serum lipid metabolism, and blood viscosity. Enrolled were 10 OC users with no history of OC use before the study and 10 non-users. At 3 and 6 months after initiation of OC use, significant changes were recorded in partial thromboplastin time, fibrinogen, high density lipoprotein, and apolipoprotein A-1. Plasma viscosity was significantly increased during OC use, while whole blood viscosity and erythrocyte deformability remained unchanged. All alterations associated with OC treatment remained within the normal range of laboratory values, however. Thus, these findings suggest an absence of any significant OC effects on the hemostatic balance or lipid metabolism that might represent a risk factor for cardiovascular disease. Moreover, the measurement of blood viscosity may be a promising marker for monitoring thrombotic risk in women taking OCs given its apparent high sensitivity.

Effect of two oral contraceptives containing ethinylestradiol and gestodene or norgestimate upon androgen parameters and serum binding proteins.

The effect of a triphasic oral contraceptive containing ethinylestradiol and gestodene (EE/GSD) on various serum hormonal parameters was compared with that of a monophasic formulation containing 35 micrograms ethinylestradiol and 250 micrograms norgestimate (EE/NGM). Blood samples were collected from 46 women on days 2, 11, and 21 of the preceding control cycle and of the third, sixth and twelfth treatment cycle. There was no significant difference in the influence on any hormonal parameter between both formulations. Both EE/GSD and EE/NGM caused a time-dependent suppression of serum dehydroepiandrosterone sulphate (DHEA-S) by 20-30% (p < 0.01) and a reduction of 5 alpha-androstane-3 alpha, 17 beta-diol glucuronide by 50-60% (p < 0.01) during each treatment cycle, while androstenedione levels were reduced by 25% (p < 0.01). There was also a significant decrease in the levels of total testosterone by 30-35% (p < 0.01) and free testosterone by 60% (p < 0.01), while sex hormone-binding globulin (SHBG) was increased by 200-240% on days 11 and 21 (p < 0.01). During the pill-free interval the SHBG levels were reduced to a certain degree but remained elevated by 100% as compared to the pretreatment values. The serum levels of corticosteroid-binding globulin (CBG) which is known to be influenced only by the estrogenic component of combination pills, increased significantly by 170% (p < 0.01) during each treatment cycle. During the pill-free interval of 7 days, the CBG levels decreased but were still elevated by 90-100% as compared to the control cycle. Similarly, the serum levels of cortisol were significantly elevated by 110-140% (p < 0.01) during treatment with both preparations. The results demonstrate a profound suppression of androgen levels and peripheral androgen metabolism.

PIP: At the J. W. Goethe University Hospital in Frankfurt am Main, Germany, researchers randomly allocated 46 women to use either the triphasic oral contraceptive (OC) containing 30 mcg ethinyl estradiol (EE) and 50 mcg gestodene or the monophasic OC containing 35 mcg EE and 250 mcg norgestimate. They wanted to compare the effects of the two OCs on different serum hormonal parameters and serum binding proteins. Health workers took blood samples from the women on days 2, 11, and 21 of the cycle before OC use and of treatment cycles 3, 6, and 12. The two groups had similar hormonal parameters. Both OCs suppressed serum levels of dehydroepiandrosterone sulphate (DHEA-S) by 20-30% (p 0.01). They reduced 5alpha-androstane-3alpha, 17beta-diol glucuronide by 50-60% (p 0.01) during each treatment cycle. Both OCs also reduced androstenedione serum levels by 25% (p 0.01). Both OCs reduced serum levels of total testosterone by about 30% and of free testosterone by 60% (p 0.01-0.05 and p 0.01, respectively). The 200% increase of serum levels of sex hormone binding globulin (SHBG) on days 11 and 21 of each cycle in both groups (p 0.01) caused the more pronounced decrease of serum levels of free testosterone. Suppression of ovarian androgen synthesis also contributed to the more pronounced decrease of free testosterone. SHBG levels fell during the pill-free interval but remained 100% higher than pretreatment values. Serum levels of corticosteroid binding globulin (CBG) increased by 170% during each treatment cycle (p 0.01). CBG levels fell during the pill-free interval, but remained higher by 90-100% than the pretreatment cycle. Only the estrogenic component affected the increase in CBG. Both OCs increased cortisol serum levels by 110-140% (p 0.01). These findings show that both OCs significantly suppressed some androgen parameters and peripheral androgen metabolism.

Oral contraceptive containing natural estradiol for premenopausal women.

An open multicenter trial was performed in six centers in Finland to study the efficacy, safety and acceptability of a new biphasic oral contraceptive pill containing natural estradiol and cyproterone acetate. The participants were 288 women with a mean age of 39.3 +/- 3.4 years (range 30-49) who were willing to use the new pill as their only contraceptive method. In total, 23% of the women were smokers. The cumulative experience was 2800 treatment cycles during the first year. The net 12-month continuation rate was 63%. One pregnancy occurred in a woman who lost 5 tablets in the second treatment cycle, which gives a 12-month cumulative pregnancy rate of 0.4%. Serum progesterone values, determined twice during the third treatment cycle, showed ovulation inhibition in 95% of women. There were no serious side effects. Intermenstrual bleeding was recorded by 35.5% and 24.5% of women at 3 and 12 months, respectively. The bleedings became scantier in most women and dysmenorrhoea disappeared. No changes were observed in total and high density lipoprotein cholesterol concentrations after 1 year. With the exception of intermenstrual spotting, the efficacy, safety and acceptability of the new pill was almost as good as that of the modern low dose oral contraceptives. This is the first pill containing natural estradiol that has gained clinical acceptance and which can also be prescribed for smokers over 35 years old until the climacteric.

PIP: Gynecologists accepted 288 women aged 30-49 from six different clinics in Finland into a clinical trial of a new biphasic oral contraceptive (OC) containing natural estradiol and cyproterone acetate (manufactured by Leiras Oy, Turku, Finland). They aimed to determine the contraceptive efficacy, safety, cycle control, and acceptability of this OC. 24% of the women smoked cigarettes. Gastrointestinal upset in one woman led to failure to take the fourth and fifth tablets at the beginning of the second treatment cycle. She became pregnant (pregnancy rate = 0.35%). 9.3% and 13.3% of women missed pills at the 3-month and 12-month follow-up visits, respectively. 95% of the women had serum progesterone values lower than 9 nmol/l, indicating ovulation suppression. OC use reduced excessive menstrual bleeding (30% before study vs. 3% after 13 cycles; p 0.0005). It also reduced dysmenorrhea (14% vs. 2%; p 0.0005). No one had any serious side effects. The minor side effects (breast tension, edema, headache, and depression) subsided with time. The 12-month continuation rate was 63%. The main reason for discontinuation was side effects (25.9%). Total serum cholesterol and HDL-cholesterol levels did not change significantly, while serum triglyceride levels increased from 0.92 to 1.14 mmol/l (p = 0.02). Even though serum potassium and creatinine levels changed significantly, the 13-month levels fell within the normal range. These findings show that this new OC is an effective contraceptive for premenopausal women. The absence of adverse effects on the blood coagulation system and lipoprotein metabolism make this new OC safe for smokers.

Pharmacokinetics of levonorgestrel and ethinylestradiol in 14 women during three months of treatment with a tri-step combination oral contraceptive: serum protein binding of levonorgestrel and influence of treatment on free and total testosterone levels in the serum.

The pharmacokinetics of levonorgestrel (LNG) and ethinylestradiol (EE2) were determined in 14 healthy women (age 18 to 27 years) during a treatment period of three months with a tri-step combination oral contraceptive (Triquilar). Prior to this treatment period, the same women received a single administration of a coated tablet containing 0.125 mg LNG together with 0.03 mg EE2. There was a washout phase of one week between both treatments. Following single dose administration, a mean terminal half-life of 22 h was observed for LNG. The total clearance was 1.0 ml x min-1 x kg-1 and the volume of distribution was 128 l. During a treatment cycle, LNG levels in the serum accumulated by a factor of about four as compared to single dose administration. Steady-state drug levels were reached during the second half of each cycle. As compared to single dose administration, the following changes were observed for LNG at the end of treatment cycles one and three: reduced total (0.5 ml x min-1 x kg-1) and free clearance (50 ml x min-1 x kg-1) and a reduced volume of distribution (52 l). A concomitant increase in the SHBG concentrations by a factor of two as compared to pretreatment values was observed during treatment and appeared to be mainly responsible for the changes in the pharmacokinetics of LNG. Marked changes were also seen for the serum protein binding of LNG. After single dose administration, the free fraction of LNG was 1.4% and the fractions bound to SHBG and albumin were 55.0% and 43.6%, respectively. At the end of cycle one, the free fraction was only 1.0% and the fractions bound to SHBG and albumin were 69.4% and 30.0%, respectively. There was no difference in corresponding pharmacokinetic parameters and in the serum protein binding of LNG at the end of cycles one and three. On the last day of treatment cycles one and three, the AUC(0-4h) values of EE2 were 331.2 and 369.6 pg x ml-1 x h, respectively, which corresponds to an about 11-24% increase as compared to single dose administration, where an AUC(0-4h) value of 298.3 pg x ml-1 x h was found. Total and free testosterone concentrations decreased during treatment cycles one and three by about 41% and 55%, respectively, compared with the corresponding values measured prior to treatment.

PIP: In Germany, an open, intraindividual comparative study was conducted among 14 women, 18-27 years old, to examine the pharmacokinetics of levonorgestrel (LNG) and ethinyl estradiol (EE2) during a 3-month period of treatment with a tristep oral contraceptive (OC) called Triquilar. The women first received a single oral dose of 0.125 mg LNG and 0.03 mg EE2 followed by a washout period of 1 week. They received Triquilar during 3 cycles (days 1-6, 0.05 mg LNG + 0.03 EE2; days 7-11, 0.075 mg LNG + 0.04 mg EE2; and days 12-21, 0.125 LNG + 0.03 mg EE2). The mean terminal half-life for LNG was 22 hours. Total clearance of LNG was 1 ml x min-1 x kg -1. LNG volume distribution was 128.1. At the end of the treatment cycles 1 and 3, when compared to single dose administration, the total and free LNG clearance was reduced (0.5 ml x min-1 x kg-1 and 50 ml x min-1 x kg-1, respectively). LNG volume distribution was also lower after treatment cycles than after single dose administration (52 l). LNG serum levels during Triquilar treatment accumulated by a factor of 4 when compared to the level of single dose administration. Steady-state LNG levels of around 2-3 ng/ml were achieved on day 16-18 of each treatment cycle. Sex hormone binding globulin (SHBG) levels increased by a factor of 2 when compared to pretreatment levels. This simultaneous increase in SHBG likely accounted for the changes in the pharmacokinetics of LNG. After a single dose, the free fraction of LNG was 1.4% and fractions bound to SHBG and albumin were 55% and 43.6%, respectively. At the end of cycles 1 and 3, no difference in these pharmacokinetic parameters and in the serum protein binding of LNG existed. At the end of cycles 1 and 3, the 0-4 hour area under the curve (AUC) values of EE2 increased from 298.3 to 331.2 and 369.6 pg x ml-1 x h, respectively, a 11% and 24% increase, respectively. When compared to pretreatment levels, total and free testosterone levels fell during treatment cycles 1 and 3 by around 41% and 55%, respectively.

The effects of CTR-24, a biphasic oral contraceptive combination, compared to Diane-35 in women with acne.

One-hundred-and-eighty-three women were enrolled in an open, randomized, multicentre study in which the effects on acne of a low-dose biphasic oral contraceptive containing a daily dosage of 25 micrograms desogestrel and 40 micrograms ethinylestradiol (7 days) and a daily dosage of 125 micrograms desogestrel and 30 micrograms ethinylestradiol (15 days) were compared to Diane-35 containing a daily dosage of 2.0 mg cyproterone acetate and 30 micrograms ethinylestradiol (21 days) during four cycles of treatment. Clinical and photographic evaluation of acne plus laboratory assessments were done before treatment and at the end of cycle 4. A reduction with regard to the number of lesions and the degree of severity was observed in both groups. No differences were found between the two treatments in the clinical and photographic evaluation. In both treatment groups, a decrease in total testosterone and 3 alpha-17 beta-androstanediol glucuronide was observed and an increase in SHBG. The decrease in 3 alpha-17 beta-androstanediol was statistically significantly more pronounced in the Diane-35 group.

A two-year clinical study of the effects of two triphasic oral contraceptives on plasma lipids.

OBJECTIVE: Oral contraceptive formulations can alter plasma lipid and lipoprotein levels; however, lower-dose triphasic tablets show only minimal metabolic effects during 6 or 12 cycles of use. Involvement of lipids in chronic cardiovascular conditions, plus long-term use of oral contraceptive tablets, prompted this first 24-cycle study of the effect of triphasic formulations on young women. METHODS: 69 women assigned randomly to an ethinyl estradiol/levonorgestrel formulation (Triphasil) or an ethinyl estradiol/norethindrone formulation (Ortho 7/7/7) and 25 control women (no hormonal contraception) had blood sampled for lipids and lipoproteins pre-trial, and at 3- or 6-cycle intervals for 24 cycles. RESULTS: At cycle 24, control women experienced no significant change from baseline in any variable except apolipoprotein B (apo B). Plasma apo B increased 42% (P < .01), reflecting the LDL apo B increase (42%, P < .01). Both combination formulations significantly increased apo B (plasma, VLDL, IDL and LDL); the increases ranged between 47% and 84%. Plasma apo A1 rose (15%, P < .001) in the Ortho 7/7/7 group only. Plasma and LDL triglycerides were increased significantly (P < .001) by the norethindrone product, 43% and 81%, respectively, and plasma and LDL cholesterol, 14% and 28%, respectively. Cholesterol decreased in all other subfractions, including HDL (11%, P < .01). HDL cholesterol decreased significantly in the Triphasil group (8%, P < .05); no other cholesterol subfractions changed significantly. All cycle-24 lipid and lipoprotein values remained well within respective normal ranges. CONCLUSION: Although 2-year exposure to the triphasic oral contraceptive formulations changed the lipid risk factors for cardiovascular disease only within normal ranges, there remains potential for long-term health effects when compounded with other risk factors.

PIP: The first 24-cycle study of the metabolic effects of triphasic oral contraceptives (OCs) recorded significant changes in lipid values, yet none of these values moved outside the normal range. Included in the study were 69 non-smoking Canadian women 19-29 years of age with no history of obesity, diabetes, or alcohol misuse. Subjects were randomly assigned to receive either an ethinyl estradiol-norethindrone formulation (Ortho 7/7/7) or an ethinyl estradiol-levonorgestrel preparation (Triphasic). 25 controls underwent periodic blood samplings for lipid and lipoprotein levels. The only significant change recorded among controls was a 42% increase in the plasma apo B level resulting from changes in the low density lipoprotein (LDL) apo B subfraction. In the Ortho 7/7/7 and Triphasic groups, both plasma and LDL triglycerides were increased above baseline and above values for controls at the 24-month point. In Ortho 7/7/7 acceptors, LDL cholesterol increased by 28%, high density lipoprotein (HDL) decreased by 11%, and plasma cholesterol increased by 14%; other cholesterol levels decreased significantly. In the Triphasic group, HDL decreased by 8%, but no other significant changes occurred. Apo A1 increased by 15% in the Ortho 7/7/7 group, but not among Triphasic users; all apo B values increased significantly in both treatment groups. Although these changes in lipid profiles among triphasic OC users do not seem to increase the risk of cardiovascular disease, there is potential for adverse health effects when other cardiovascular risk factors, especially smoking, are present.

Cycle control and side effects of a new combiphasic oral contraceptive regimen.

In a multicentre study 882 women were treated during a total of 12,850 cycles with a new combiphasic contraceptive: CTR 24. The study period was 18 cycles. The combiphasic preparation CTR 24 contains 25 micrograms desogestrel (CAS 54024-22-5) plus 40 micrograms ethinylestradiol (CAS 57-63-6) daily for the first 7 days followed by the combination of 125 micrograms desogestrel and 30 micrograms ethinyl-estradiol daily for the subsequent 15 days. The bleeding patterns were analysed over pill cycles and a comparison was made between starters and switchers. The cycle control of the combination was very good. The side effect profile was favourable.

PIP: Physicians recruited 882 women into a multicenter trial of a new biphasic oral contraceptive (OC) (25 mcg + 125 mcg desogestrel and 40 mcg + 30 mcg ethinyl estradiol). Trial sites were in Belgium, Denmark, Finland, France, Germany, Norway, Sweden, and the former Yugoslavia. After 3 cycles, women who had switched from using another OC in the 2 months before the study (switchers) were less likely to continue the new OC than were women who had not used any OC in the last 2 months (starters) (6 cycles = 87.2% vs. 90.6%, 12 cycles = 74.7% vs. 79.5%; and 18 cycles = 59.8% vs. 64.9%). Withdrawal bleeding did not occur in 3.2% of all cycles. Absence of withdrawal bleeding became less common over time (cycle 1 = 7.6%, cycle 3 = 5%, cycle 6 = 3.2%, and cycle 18 = 1.8%). Duration of withdrawal bleeding was no more than 5 days in 80% of all women. More and more women had no more than 5 days of withdrawal bleeding as time passed (cycle 1 = 81.7%, cycle 6 = 85.6%, and cycle 18 = 90.6%). Irregular bleeding was more common in the first cycles of the study than in subsequent cycles (e.g., spotting during cycles 1-3 = 8.5-4.8% vs. 3.7-3.1% during cycles 6-18). By cycle 18, 96% of all women had no irregular bleeding. The drop-out rate for irregular bleeding was 2.2% at the end of the study. In 5% of cycles, at least 1 tablet was forgotten. In the first cycles, starters were somewhat more likely to complain of nausea, headache, and breast tenderness than switchers (e.g., nausea, cycle 1 = 5.8% vs. 3.4%). The gap between the 2 groups disappeared after 3 cycles. Starters were more likely to have minor complaints before OC use than after OC use (e.g., 6.5% fewer frequencies of headaches at 18 months). These findings show that the new OC has very good cycle control and a agreeable side effect profile.