Pharmacokinetics of the contraceptive steroids levonorgestrel and gestodene after single and multiple oral administration to women

Little is known about the pharmacokinetics of the two progestins levonorgestrel and gestodene during long-term administration compared with single-dose pharmacokinetics. The predictive value of single-dose administration for the pharmacokinetic behavior of a progestin during long-term treatment was investigated for two triphasic oral contraceptives. One contained levonorgestrel and the other gestodene, each in combination with ethinyl estradiol. In eight Japanese women who received the levonorgestrel-containing formulation over a treatment cycle, steady-state trough levels of levonorgestrel were higher than those obtained by computer simulation based on single-dose administration. An analogous observation was made in a group of 10 white women who received the gestodene-containing formulation. A close correlation between gestodene and sex hormone-binding globulin concentrations was demonstrated for eight subjects; the other two patients already had initially high sex hormone-binding globulin levels. Ethinyl estradiol-induced production of sex hormone-binding globulin seems to be a major factor that contributes to the accumulation of the two progestins in the plasma. Computer simulation, based on single-dose pharmacokinetics, allows an estimation of this contribution.     

Divergent effects of two low-dose oral contraceptives on sex hormone-binding globulin and free testosterone

The effect of a triphasic combination of ethinyl estradiol and levonorgestrel on the serum concentrations of total testosterone, free testosterone, and sex hormone-binding globulin as measured directly by radioimmunoassay and on the binding capacity of sex hormone-binding globulin was compared with that of a preparation containing ethinyl estradiol and desogestrel. Blood samples were taken on days 6, 11, 21, and 28 of a control cycle, the third cycle of treatment with either ethinyl estradiol-levonorgestrel or ethinyl estradiol-desogestrel (11 volunteers each), the third cycle of a 3-month washout period, and the third treatment cycle after crossover change of the preparations. There was a significant reduction in total testosterone by 16% during treatment with both preparations. Ethinyl estradiol-desogestrel increased the concentration (+175%) and binding capacity (+330%) of sex hormone-binding globulin to a much greater extent than with ethinyl estradiol-levonorgestrel (+92% and +160%). Contrary to this, a significant suppression of non-protein-bound testosterone by 35% was found during treatment with both oral contraceptives. The results demonstrate that an excessive elevation of the levels of sex hormone-binding globulin above the normal range does not cause a corresponding suppression of free testosterone. It is assumed that the decrease in the apparent binding affinity of high sex hormone-binding globulin concentrations to testosterone may be due to protein-protein interactions.     

Serum pharmacokinetics of orally administered desogestrel and binding of contraceptive progestogens to sex hormone-binding globulin

Serum levels of 3-ketodesogestrel and ethinyl estradiol were analyzed by radioimmunoassay in a balanced crossover study with two tablet formulations containing desogestrel (0.150 mg) and ethinyl estradiol (0.030 mg) in 25 women under steady-state conditions after 21 days of treatment. The pharmacokinetic properties of desogestrel were characterized by the following parameters: (1) maximum serum concentration, (2) time to maximum serum concentration, (3) total area under the serum concentration versus time curve, and (4) serum half-life of elimination. The interindividual variation in these parameters was comparable with that observed with other contraceptive combinations containing ethinyl estradiol and norethisterone, levonorgestrel, or gestodene. The serum distribution of contraceptive progestogens is known to be determined by their affinity to sex hormone-binding globulin and the concentration of sex hormone-binding globulin. We analyzed the structural features that determine binding to sex hormone-binding globulin. The 18-methyl group increased and the 11-methylene group weakened the binding to sex hormone-binding globulin. The double bond at C-15 reinforced the binding only when combined with an 18-methyl group. Therefore, the binding of levonorgestrel (the 18-methyl derivative of norethisterone) and gestodene (the Δ-15,18 methyl derivative of norethisterone) to sex hormone-binding globulin was much stronger than that of 3-keto-desogestrel and norethisterone.     

Carbohydrate metabolic studies in women using a levonorgestrel/ethinyl estradiol containing triphasic oral contraceptive for eighteen months.

Carbohydrate metabolism was evaluated in 17 women before and after 18 months of triphasic oral contraceptive use. The triphasic oral contraceptive contained levonorgestrel and ethinyl estradiol. An oral glucose tolerance test was utilized and both plasma glucose and insulin levels were measured. There were no significant changes in the glucose levels. The fasting insulin level was raised at the 18-month test, whereas the other insulin values were similar. These results demonstrate that the new triphasic oral contraceptive preparations produce minimal carbohydrate metabolic changes.     

Evaluation of interaction between fluconazole and an oral contraceptive in healthy women

OBJECTIVE: To evaluate the potential pharmacokinetic interaction between 2 x 150 mg fluconazole administered once weekly and an oral contraceptive (OC) containing ethinyl estradiol and norethindrone. METHODS: A placebo-controlled, double-masked, randomized, two-way crossover study was used to investigate the pharmacokinetic interaction between 300 mg fluconazole once weekly and the OC Ortho Novum 7/7/7 (Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ) in 26 healthy women, 18-36 years old. In the first cycle (28 days), subjects received OC only. In the second cycle, subjects were assigned randomly to receive OC-fluconazole or OC-placebo. In the third cycle, subjects were crossed over to the opposite treatment. RESULTS: Data for 21 subjects who completed the study were included in the pharmacokinetic analysis; data for all 26 subjects were included in the safety analysis (26 OC only; 24 OC-fluconazole; 23 OC-placebo). Treatment with OC-fluconazole resulted in small but statistically significant increases in 0-24 hour area under the plasma concentration-time curve (AUC(0-24)) for both ethinyl estradiol (mean 24%, 95% confidence interval [CI] 18%, 31%) and norethindrone (mean 13%, 95% CI 8%, 18%) as compared with treatment with OC-placebo. Ethinyl estradiol maximum plasma concentration (C(max)) was slightly (mean 8%, 95% CI 2%, 15%) though statistically significantly higher for OC-fluconazole treatment as compared with OC-placebo treatment. Norethindrone C(max) was not different (95% CI -6%, 11%) between the two treatment groups. No adverse events related to treatment were seen in the fluconazole treatment group. CONCLUSION: The concomitant administration of 300 mg fluconazole once weekly, twice the recommended dose for vaginal candidiasis, to women using OCs results in a slight increase in OC concentrations. Therefore, it appears that there is no threat of contraceptive failure because of concomitant fluconazole administration.     

Ethinyl estradiol administration and plasma steroid concentrations in ovariectomized women.

The effect of ethinyl estradiol treatment on the plasma levels of cortisol, corticosterone, deoxycorticosterone, progesterone, testosterone, dehydroepiandrosterone sulfate, delta4-androstenedione, and estrone was studied in eight women. All the subjects had undergone ovariectomy and hysterectomy at least one year prior to this study. The systemic concentration of cortisol and the binding of cortisol were significantly increased, paralleling the increased transcortin concentration due to ethinyl estradiol treatment. Corticosterone concentration was also significantly increased after three days of estrogen administration and this level continued to be higher than normal as long as patients were treated with estrogens, but there was no change in the plasma concentration of deoxycorticosterone. The plasma levels of progesterone testosterone, dehydroepiandrosterone sulfate, delat4-androstenedione and estrone or the ratio of estrone to delta4-androstenedione did not change with ethinyl estradiol treatment. These observations suggest that the administered estrogen increased the transcortin concentration and had only a limited effect on adrenocortical steroidogenesis.     

Glucose and insulin levels after six months of treatment with a triphasic oral contraceptive containing ethinyl estradiol and norethindrone

A prospective study of carbohydrate metabolism was done on 33 women who used a triphasic oral contraceptive (OC) containing ethinyl estradiol and norethindrone for six months. A three-hour oral glucose tolerance test was administered before and after the OC usage, and both the blood glucose and insulin levels were determined. A significant decrease in the fasting glucose level was found with treatment. All other glucose values and insulin levels were unchanged.     

Triphasic Randomized Clinical Trial: Comparison of effects on carbohydrate metabolism

One hundred thirty women were randomly assigned to treatment with one of three triphasic oral contraceptives and 43 women using nonhormonal methods served as controls for a 6-month study of the metabolic effects of these formulations. One of the oral contraceptives contained ethinyl estradiol and levonorgestrel, and the other two contained ethinyl estradiol and norethindrone. Compared with pretreatment assessment, all three triphasic oral contraceptives produced small increases in the mean plasma glucose levels that were statistically significant but clinically unimportant. No subjects had abnormal glucose response curves in glucose tolerance test results. Compared with pretreatment assessment, all of the oral contraceptive preparations produced small increases in the mean insulin levels at 3 months but not at 6 months. Overall there were no statistically significant differences among the three formulations in their effects on carbohydrate metabolism as measured by glucose or insulin levels after 6 months of treatment.     

Changes in coagulation and anticoagulation in women taking low-dose triphasic oral contraceptives: a controlled comparative 12-month clinical trial.

OBJECTIVE: The effects of two triphasic oral contraceptives on coagulation and anticoagulation factors were compared in a 12-month open-label study. STUDY DESIGN: Fifty-two women (mean age 26 years) were enrolled in and completed the study; 20 had been randomly assigned to receive levonorgestrel plus ethinyl estradiol, 24 had been randomly assigned to receive norethindrone plus ethinyl estradiol, and eight surgically sterile women acted as untreated controls. Coagulation and anticoagulation factors were measured at baseline and during the sixth and twelfth months. RESULTS: Both oral contraceptives produced significant decreases from baseline in prothrombin time and partial thromboplastin time; there were also significant changes in laboratory control times. Factor XII was significantly increased in both oral contraceptive groups after 6 and 12 months. Fibrinogen antigen was significantly increased for norethindrone plus ethinyl estradiol after 6 and 12 months and for levonorgestrel plus ethinyl estradiol after 12 months. Platelet counts were unchanged. There was a significant increase in antithrombin III activity with norethindrone plus ethinyl estradiol at 12 months. Antithrombin III antigen was unchanged with the oral contraceptives; however, significant increases existed for alpha 1-antitrypsin antigen and plasminogen antigen and activity after 6 and 12 months and for alpha 2-macroglobulin antigen after 12 months for both oral contraceptives. alpha 2-Antiplasmin antigen was significantly increased for norethindrone plus ethinyl estradiol at the 12-month evaluation. There were no significant differences between the oral contraceptives for any coagulation or anticoagulation factor, and mean values generally remained within reference ranges. CONCLUSIONS: Levonorgestrel plus ethinyl estradiol and norethindrone plus ethinyl estradiol had equivalent, minimal effects on hemostasis, and changes in coagulation factors appeared to be balanced by changes in anticoagulation factors.     

High serum prostate-specific antigen concentrations in hirsute women do not decrease with treatment by the combination of spironolactone and the contraceptive pill.

Using an ultrasensitive assay, prostate-specific antigen (PSA) has been detected in female serum and has been proposed as a potential marker of androgen excess in hirsute women. Measurement of PSA levels in serum may play a role in monitoring hirsutism during antiandrogen therapy. We investigated the role of PSA as a marker of androgen activity in hirsute patients taking spironolactone together with oral contraceptive pills containing ethinyl estradiol and gestodene. Twenty-eight hirsute patients were included in the study. Clinical and biochemical variables including serum levels of PSA (using an ultrasensitive chemiluminscent immunoassay), dehydroepiandrosterone sulfate, total testosterone, free testosterone and 17-hydroxyprogesterone concentrations were recorded at baseline and after six cycles of treatment. Fifteen healthy women were included in the study as controls. Serum PSA levels in hirsute women were clearly higher than in the control group (0.023 +/- 0.004 vs. 0.006 +/- 0.003 ng/ml, p < 0.001) and correlated with baseline serum free testosterone concentrations (r = 0.518, p = 0.005). After 6 months, serum PSA concentrations as compared with baseline values did not change significantly in patients who were given spironolactone plus contraceptive pills (p = 0.4) despite a marked decrease in total testosterone, free testosterone, 17-hydroxyprogesterone, dehydroepiandrosterone sulfate and hirsutism score (p < 0.05). Thus, serum PSA levels in hirsute women were higher than in non-hirsute healthy controls. A 6-month course of treatment with spironolactone combined with contraceptive pills containing ethinylestradiol and gestodene did not reduce high serum PSA levels in these subjects. In conclusion, the serum PSA level is not a convenient biochemical marker with the available assays for the management of hirsute women treated with the combination of spironolactone and oral contraceptives.     

Prospective study of carbohydrate metabolism in women using a triphasic oral contraceptive containing norethindrone and ethinyl estradiol for 3 months

Thirty-five women with normal carbohydrate metabolism were administered a 3-hour oral glucose tolerance test before and after 3 months' use of a triphasic oral contraceptive that contained ethinyl estradiol and norethindrone. The results show no significant change in either the plasma glucose or the insulin values. This is the first published study with regard to this type of triphasic oral contraceptive, and the study supports claims of the preparation's improved safety.     

炔雌醇对绝经后妇女糖代谢的影响

目的：探讨合成雌激素炔雌醇对绝经后妇女糖代谢的影响。方法：将绝经后妇女１９例随机分为两组，口服炔雌醇（ＥＥ）０．０２５ｍｇ９例为Ａ组，口服ＥＥ０．０５ｍｇ１０例为Ｂ组，共服药３个月。服药前后均进行口服葡萄糖耐量试验和多样本的静脉葡萄糖耐量试验，同时测定血糖、胰岛素和计算曲线下面积（ＡＵＣ）以及胰岛素敏感指数（ＳＩ）。结果：两组均可有效降低空腹血糖、胰岛素水平，明显减少胰岛素ＡＵＣ，提高胰岛素ＳＩ。Ａ组血糖ＡＵＣ无多大变化，Ｂ组血糖ＡＵＣ明显增加。结论：炔雌醇可有效降低绝经后妇女的空腹血糖、胰岛素水平，减弱胰岛素抵抗。０．０５ｍｇＥＥ可损害糖耐量。     

Effects of an oral contraceptive containing drospirenone on bone turnover and bone mineral density

OBJECTIVE: To compare the effects of a new 21-day combined oral contraceptive containing 30 microg ethinyl/estradiol plus 3 mg drospirenone with a 21-day preparation containing 30 microg ethinyl/estradiol plus 75 microg gestodene on bone turnover and bone mineral density in young fertile women. METHODS: A randomized, controlled trial was conducted with healthy fertile women treated with 30 microg ethinyl/estradiol plus 3 mg drospirenone (group A; n = 24), 30 microg ethinyl/estradiol plus 75 microg gestodene (group B; n = 24) and healthy controls (group C, n = 23). At 3, 6, 9, and 12 months of the study, serum and urinary calcium, osteocalcin, urinary pyridinoline, and deoxypyridinoline were measured. At baseline and after 12 months, lumbar bone mineral density was determined by dual-energy X-ray absorptiometry. RESULTS: In groups A and B, urinary pyridinoline and deoxypyridinoline at 6, 9, and 12 months were significantly reduced in comparison with basal values and group C (P < .05). Pyridinoline and deoxypyridinoline levels were lower in group A than in group B throughout the study, but not significantly. In group A serum calcium levels were significantly increased after 6 months. At 12 months, no significant difference was detected in lumbar bone mineral density values among the 3 groups and in comparison with basal values. CONCLUSION: Both combined oral contraceptives exert a similar positive influence on bone turnover and bone-sparing effect in young postadolescent women.     

Clitoral and vulvar vestibular sensation in women taking 20 mcg ethinyl estradiol combined oral contraceptives: a preliminary study

IntroductionMany women taking low‐dose (20 mcg) oral contraceptive pills (OCPs) complain of decreased libido and arousal and some develop vulvar vestibular pain and dyspareunia. Free testosterone concentrations are decreased by the OCP. Genital sensation has not been objectively measured in women taking OCPs.AimWe assessed whether the 20 mcg ethinyl estradiol combined OCP and associated decrease in free testosterone levels affected genital sensation in a pilot study of a group of asymptomatic OCP users and controls.MethodsClitoral thermal, vibratory, and vestibular pain thresholds, sexual functioning, and free testosterone levels were measured in 24 women taking 20 mcg ethinyl estradiol combined OCPs and 28 comparison women not using hormonal contraception.Main Outcome MeasuresFemale Sexual Functioning Index (FSFI), free testosterone, and clitoral heat, cold, and vibratory thresholds for sensation and vestibular pain thresholds.ResultsFree testosterone levels were lower in OCP users. There were no differences in FSFI scores, clitoral thermal or vibratory thresholds, or vestibular pain thresholds between groups.ConclusionsLow‐dose (20 mcg) oral contraceptives decrease free testosterone but are not associated with alterations in clitoral or vestibular sensation. Further studies of genital sensation in women with OCP‐related sexual dysfunction are warranted. Lee M, Morgan M, and Rapkin A. Clitoral and vulvar vestibular sensation in women taking 20 mcg ethinyl estradiol combined oral contraceptives: A preliminary study.     

The effect of oral estrogen therapy on serum FSH and LH levels in young women with hyper-gonadotrophic ovarian failure

Fourteen women, 18--46 years old (median age: 28 years) with hypergonadotrophic ovarian failure were each treated daily for 21 days with 10 micrograms, 20 micrograms, 40 micrograms, and 60 micrograms ethinyl estradiol, 2,000 micrograms estriol, and 1,250 micrograms conjugated estrogens in six or more consecutive treatment cycles in a randomly assigned sequences. Before treatment and at the beginning of the 3rd week of each of the mentioned estrogen regimens, basal serum FSH and LH levels were measured. During the last 5 days of each treatment cycle, 10 mg of oral norethisterone acetate were given in addition to the estrogen, and after a treatment-free interval of 7 days the next estrogen regimen was begun according to the random list. FSH values were inversely related to the various dosages of ethinyl estradiol; the upper normal range with the exception of the periovulatory phase was reached with 40--60 micrograms ethinyl estradiol. FSH levels during treatment with 1250 micrograms of conjugated estrogens were similar to those found during treatment with 20 micrograms ethinyl estradiol. When 2,000 micrograms of estriol were given daily, FSH levels rose of pretreatment values. LH behaved similarly except that during treatment with 2,000 micrograms of estriol and 10 micrograms of ethinyl estradiol values above pretreatment levels were found.     

Binding of levonorgestrel, norethisterone and desogestrel to human sex hormone binding globulin and influence on free testosterone levels

The progestogens desogestrel, levonorgestrel, lynestrenol and norethisterone are known to display certain androgenic effects. Apart from direct androgen receptor interaction, binding to sex hormone binding globulin (SHBG) and displacement of testosterone could lead to an increase in free, metabolically active testosterone. The affinities for SHBG binding of some progestogens including levonorgestrel, norethisterone and the active metabolite of desogestrel, 3-keto-desogestrel, were compared using an equilibrium partition method, and the distribution between free and protein-bound testosterone during progestogen therapy was calculated with the use of a computer program. During treatment with desogestrel, levonorgestrel and norethisterone alone, testosterone displacement could account for a slight increase in free testosterone, though the decrease in serum SHBG following treatment was found to be more important in this respect. Also during treatment with combinations of ethinyl estradiol and levonorgestrel for oral contraception, testosterone displacement could theoretically have a slight influence on free testosterone levels. Combinations with ethinyl estradiol and desogestrel or norethisterone, on the other hand, cause an increase in SHBG concentration and as a result a fall in free testosterone which could not be compensated via testosterone displacement.     

The effect of doxycycline on serum levels of ethinyl estradiol, norethindrone, and endogenous progesterone

Doxycycline and other antibiotics have been implicated in oral contraceptive (OC) failure, but information is sparse and studies of a doxycycline-OC interaction are nonexistent. Because an interaction between doxycycline and OCs, especially those containing low-dose estrogen, could result in an unplanned and unwanted pregnancy, a controlled clinical trial of the effects of doxycycline on OC hormone concentrations was performed. Twenty-four women aged 18-35 years were recruited as volunteers from among the patients seen in a University-based family planning clinic. While they were on a steady dose of the OC Ortho-Novum 1/35, serum concentrations of ethinyl estradiol, norethindrone, and endogenous progesterone were measured on days 18, 19, and 20 of the menstrual cycle (control phase). These measurements were repeated on days 18, 19, and 20 of the following menstrual cycle while the patient was taking doxycycline, 100 mg twice daily (treatment phase). No statistically significant differences in serum levels of ethinyl estradiol, norethindrone, or endogenous progesterone were seen between the control and treatment phases. However, there was large inter-patient and intra-patient variability in ethinyl estradiol and norethindrone levels. No elevations of endogenous progesterone occurred to suggest ovulation during antibiotic administration in either phase. It is not known what effects longer or earlier administration of doxycycline during the OC cycle would have on serum hormone concentrations or ovulation. Pregnancies attributed to failure of OCs because of tetracycline use could in fact be due to other causes or could represent a true interaction that only manifests itself in a small proportion of women at risk.     

Clinical evaluation of two biphasic and one triphasic norgestrel/ethinyl estradiol regimens.

Four hundred and fifty-eight women were followed for 3,586 cycles in a controlled, randomized, open trial designed to compare two biphasic and one triphasic norgestrel/ethinyl estradiol (ee) regimens. The three regimens are effective and no pregnancies were reported. Cycle control was good with all three regimens but the incidence of intermenstrual bleeding was higher with the triphasic. With this regimen, total hormonal ingestion is well below the lowest fixed dose norgestrel/ethinyl estradiol preparation (300 mcg norgestrel and 30 mcg ee) in the original 10:1 ratio. It is concluded that the staggering of hormonal doses opens the possibility of contraception with less hormone intake than is possible when a fixed dose regimen is used.     

Effect of long-term triphasic oral contraceptive use on glucose tolerance and insulin secretion

This study was designed to compare the effects of two low-dose triphasic oral contraceptives (OCs) on glucose tolerance and insulin secretion. Fifty-seven women were randomized to receive OCs containing ethinyl estradiol and either levonorgestrel or norethindrone. Ten subjects using nonhormonal contraception served as controls. Glucose tolerance and insulin secretion were measured at baseline and at 6 and 12 months after an oral glucose stimulus. Both preparations produced a relative hyperglycemia at 6 and 12 months compared with baseline, but within the norms for glucose tolerance. The insulin response, measured in 48 treated and eight control subjects, also increased over 12 months in both treated groups, but the total insulin area was within the range of the reference laboratory. Such minor changes have not been associated with cardiovascular diseases and support the safety of low-dose triphasic preparations.     

Oral contraceptive use and glucose metabolism in a national sample of women in the united states

OBJECTIVE: This study was undertaken to determine whether users of oral contraceptives in a nationally representative population of US women had elevated levels of measures of glucose metabolism. STUDY DESIGN: Cross-sectional data from the Third National Health and Nutrition Examination Survey (1988-1994) included hemoglobin A(1c) levels and fasting glucose, insulin, and C-peptide levels. Means were compared among those who had never used oral contraceptives, current users of oral contraceptives, and former users of oral contraceptives, with and without adjustment for potential confounders. RESULTS: The vast majority of current users of oral contraceptives were using low-dose estrogen formulations. The two most common preparations were a triphasic formulation containing 0. 035 mg ethinyl estradiol and 0.5, 0.75, and 1 mg norethindrone (23. 9%) and a monophasic formulation containing 0.035 ethinyl estradiol and 1 mg norethindrone (20.7%). Current users of oral contraceptives did not have elevated values for any of the four measures of glucose metabolism. Hemoglobin A(1c) level and fasting glucose, insulin, and C-peptide levels were not related to duration of current use, age at which use began, or major formulation type. Among women who were former users of oral contraceptives there was no evidence of higher values among those who had recently ceased use. CONCLUSION: Oral contraceptive formulations currently available in the United States are not associated with an adverse glucose metabolic profile.