Triphasic oral contraceptives: review and comparison of various regimens

OBJECTIVE: To review and compare the risk-benefit profile of triphasic oral contraceptives with that of low-dose monophasic oral contraceptives.DESIGN: Literature on currently marketed triphasics and monophasics.Patient(s): Healthy women of reproductive age.MAIN OUTCOME MEASURE(S): Comparison of the rationale for development, composition, mechanism, efficacy, menstrual cycle control, side effects, health benefits, and risk-benefit profile.RESULT(S): All triphasics contain ethinyl estradiol (0.025-0.040 mg/d) and one of several progestins in doses (0.05-1.0 mg/d) related to their relative potencies, which are substantially lower overall (total dose) than those in monophasics. The triphasics are highly efficacious. In general, menstrual cycle control and side effects are similar in both types, but triphasics containing the newer progestins (desogestrel, gestodene, and norgestimate) have better cycle control and a reduced incidence of androgenic side effects compared with those with norethindrone or levonorgestrel. Both triphasics and monophasics have minimal effects on carbohydrate and lipid metabolism and hemostasis parameters, and therefore comparable low risks of coronary heart disease. The health benefits of triphasics and monophasics are similar and include decreased incidence of unwanted and ectopic pregnancies, ovarian cysts, endometrial and ovarian cancers, benign breast disease, and acute pelvic inflammatory disease; less menstrual blood loss and iron deficiency anemia; and lower frequency of irregular bleeding and menorrhagia.CONCLUSION(S): The risk-benefit profiles of both triphasics and monophasics are favorable and similar.     

The effect of multivitamin supplements on continuation rate and side effects of combined oral contraceptives: A randomised controlled trial

Abstract

Objectives This study aimed to assess the effect of multivitamin use during the pill-free interval on the continuation rate and side effects of combined oral contraceptives (COCs) within the first few cycles of use.

Methods In this trial, 332 women presenting to public health centres in an Iranian city each received a COC pack containing 21 pills and were randomised to one of three groups: two of the groups also received 42 multivitamin pills or 42 placebo pills to be taken once a day for 7 days before starting COCs and again during the 7-day pill-free interval for five cycles, while the third group received no multivitamin or placebo pills with their COCs. The groups were compared using Cox regression and χ² tests.

Results There were no losses to follow-up. Continuation rates at the sixth cycle were 88% for the multivitamin group, 75% for the placebo group and 67% for the no intervention group. Compared with the multivitamin group, the six-cycle discontinuation rate was significantly higher in the placebo group (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.15–4.45; p = 0.019) and no intervention group (HR 3.15, 95% CI 1.66–5.99; p < 0.001). Nausea, mood changes, weight gain and breast tenderness were significantly less common in the multivitamin group than in the other groups in all cycles, and spotting/irregular bleeding and dizziness were significantly less common in most of the second, third and sixth cycle follow-up.

Conclusions Multivitamin supplements could significantly reduce the side effects of COCs in the initial cycles and improve continuation rates. However, the study limitations do not allow for any definite conclusion for their use in clinical practice, especially in communities rich in nutrients.

Chinese Abstract

摘要

目的：本研究旨在评估在不服避孕药的间歇期口服多种维生素对续用率的影响,及服用复方避孕药（COCS）最初几个周期的副作用。

方法：在这项试验中,在伊朗城市代表公众健康中心的332名女性均收到含有21粒药物的复方口服避孕药包,并被随机分到3组。其中2组的妇女还分别收到了42粒维生素或42粒安慰剂,这些药物需要在服用口服避孕药之前及不同周期的间歇期内每天服用1次,连续服用7天;第三组只有复方口服避孕药。不同组之间用COX回归及卡方检验进行比较。

结果：目前还没有丢失的随访。三个组在第六个周期的续用率分别为：口服维生素组88%,口服安慰剂组75%,无干预组67%。与口服多种维生素组比较,口服安慰剂组在第六周期的停药率明显高（HR2.26,95%CI1.15-4.45;p=0.019）,无干预组的停药率也明显高于口服维生素组（HR 3.15, 95% CI 1.66 ? 5.99; p = 0.001）。在所有周期中,恶心、情绪变化、体重增加及乳房触痛在维生素组明显少于其他2组,瘀点、不规则出血、眩晕在第二、三、六周期很少见。

结论：多种维生素的应用可以显著降低开始口服复方避孕药的最初几个周期内的副作用,同时可以提高续用率。然而,由于这篇文章的限制,并无明确结论支持他们广泛应用于临床,尤其是在有丰富营养物质的社区。

关键词：副作用,复方口服避孕药,续用率,维生素     

The effects of a low-dose gestodene-containing oral contraceptive on endometrial histology in healthy women

Objective In women who use oral contraceptives with low estrogen doses, a quiescent endometrium is frequently produced. Further reduction of the estrogen dose would not be expected to alter this effect. In this open-label study, the effects on the endometrium of a monophasic oral contraceptive containing 75 Jig gestodene and 20 fig ethinylestradiol were assessed.

Method Biopsies were performed on 25 women on therapy. The biopsies were performed during the late luteal phase (last 7 days) in the pretreatment cycle and during days 15–21 in cycle 6 for 13 subjects (Group A) and during days 15–21 in cycle 3 and during the late luteal phase (last 7 days) in the post-treatment cycle for 12 subjects (Group B).

Results All subjects completed six cycles of treatment. Nine of 13 subjects pretreatment and nine of 12 subjects at cycle 3 were characterized by the pathologist as having a secretory endometrium. Four of 13 subjects at cycle 6 and ten of 11 subjects post-treatment also demonstrated a secretory endometrium. Predecidual changes were seen in one, two, two and zero subjects at pretreatment, after three cycles, six cycles, and post-treatment, respectively. Six subjects had an atrophic endometrium at cycle 6.

Conclusions With monophasic gestodene/ethinylestradiol 75 μ/20 μg, a secretory or inactive endometrium was present in most subjects. Thus, the effects on the endometrium of this oral contraceptive containing a reduced estrogen dose are consistent with those produced by other low-estrogen-dose combination oral contraceptives.     

Oral contraceptives and coronary heart disease: Modulation of glucose tolerance and plasma lipid risk factors by progestins

Widespread use of oral contraceptive formulations by women throughout their reproductive life has given rise to concerns about the effects of oral contraceptives on risk factors for coronary heart disease. Oral contraceptive-induced changes in both carbohydrate and lipoprotein risk factors may contribute to an increased risk of coronary heart disease. Carbohydrate and lipoprotein risk factors for coronary heart disease are reviewed, and oral contraceptive-induced changes in carbohydrate and lipoprotein metabolism, which may lead to altered risk status for coronary heart disease, are discussed. The importance of methodology in evaluating the results of studies assessing such oral contraceptive-induced changes is stressed. The role of progestins in influencing coronary heart disease risk factors is surveyed, and differences among progestins commonly used in oral contraceptive formulations are discussed. In addition, the effect of various combination oral contraceptives on risk factor status is outlined. Finally, the implications of available evidence for the selection of progestins for oral contraceptive formulations of the future are discussed. Current data indicate that medium- and low-fixed-dose oral contraceptive formulations containing estrogen/norethindrone acetate have less metabolic impact than do comparable levonorgestrel-containing formulations, including multiphasic formulations. Triphasic formulations may have less effect on coronary heart disease risk factors, although data are not yet conclusive. Novel progestins such as desogestrel may also have lesser effects on metabolic functions, but the reduced androgenicity of such compounds may expose women to an increased risk of estrogen-induced hypertriglyceridemia.     

Lipid composition of serum lipoproteins in relation to gonadal hormones during the normal menstrual cycle

Twenty-two normally menstruating women were studied during one menstrual cycle. Blood was collected on 4 occasions and was analysed for free and total cholesterol and triglycerides and phospholipids in the lipoprotein fractions, very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL) and high-density lipoproteins (HDL). Fluctuations in lipid parameters were correlated to serum levels of estradiol-17β, progesterone, androstenedione, testosterone and sex-hormone-binding globulin (SHBG).Elevated concentrations of SHBG and HDL-cholesterol and a suppression of LDL-cholesterol were found during the luteal compared to the follicular phase and these findings were interpreted as an estrogenic influence. Consequently the ratio LDL-cholesterol/HDL-cholesterol was depressed during the luteal phase. Triglycerides in serum and VLDL reached a peak at midcycle. When effects on lipid metabolism induced by endogenous steroids were compared to lipoprotein fluctuations exerted by exogenous hormones a parallelism was found in certain variables. However, obvious discrepancies were also found in effects on lipid metabolism, especially for hormones with androgenic properties.The present data underline the necessity of defining in which menstrual phase blood has been collected when lipid metabolism is studied in women of fertile age. Knowledge about metabolic events induced by exogenous sex steroids does not allow conclusions concerning the effects exerted by corresponding endogenous hormones.     

Effects of oral contraceptives on natriuretic peptide levels in women with hypothalamic amenorrhea: a pilot study

Natriuretic peptides, which are important regulators of salt handling and blood pressure, are 60%-75% higher in healthy young women than in men, consistent with a gender dimorphism. In this randomized, placebo-controlled study in women with functional hypothalamic amenorrhea, we show that administration of oral contraceptives (OC) increases natriuretic peptide levels and that end-of-study free T levels are inversely associated with amino-terminal pro-B-type natriuretic peptide levels, consistent with the hypothesis that natriuretic peptide levels may be mediated by differences in gonadal steroid concentrations-estrogens (E) or androgens.     

大豆苷元对去卵巢大鼠血脂及肝脏ERα和LDLR表达的影响

目的:探讨不同剂量大豆苷元对绝经后血脂的保护作用。方法:选用4月龄SD雌性大鼠66只,随机分为:假手术组(Sham)、去势组(OVX)、戊酸雌二醇组(E2)、大豆苷元高剂量(H-Dai,200mg/kg)组、中剂量(M-Dai,50mg/kg)组和低剂量(L-Dai,10mg/kg)组,每组11只。于去势术后4周开始分别给予相应的药物灌胃,3个月后处死大鼠,取血和肝脏,检测血清甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-c)、高密度脂蛋白胆固醇(HDL-c),以及肝脏ERα和LDLRmRNA的表达量。结果:与OVX组相比,大豆苷元可以降低血清LDL-c,且随着剂量的增加其作用更明显(P<0.01);大剂量可以降低血清TG(P<0.05)。大豆苷元还增加肝脏ERα和LDLRmRNA的表达量,且也有剂量依赖效应,低、中剂量组与高剂量组差异显著(P<0.01)。结论:大豆苷元对去势大鼠血脂有一定保护作用,其降低血清LDL-c的作用可能是通过ERα途径增加LDLR的表达而实现的。     

Effect of oral contraceptives and intrauterine devices on midcycle myometrial contractions

OBJECTIVE: To determine the effects of oral contraceptives and intrauterine devices (IUDs) on midcycle myometrial contractions. DESIGN: Prospective cohort study. SETTING: Academic tertiary care center. PATIENT(S): Thirty four patients who received oral contraceptives, 20 patients with an IUD, 28 controls, and 6 patients who were evaluated before and after oral contraceptive use. INTERVENTION(S): All groups underwent endovaginal ultrasonography to visualize myometrial contractions at midcycle. MAIN OUTCOME MEASURE(S): Contractions were analyzed for direction, frequency, amplitude, and distance traveled. RESULT(S): Fifty percent of women taking oral contraceptives had no contractions, whereas all controls had contractions. Women taking oral contraceptives also had decreased frequency, amplitude, and distance traveled of contractions compared with controls. Women evaluated before and after taking oral contraceptives had decreased frequency, amplitude, and distance traveled of contractions. Women with an IUD had significantly more asymmetrical uncoordinated contractions, with decreased frequency and distance traveled, compared with controls. CONCLUSION(S): Oral contraceptives dramatically suppressed midcycle contractility. Since the normal midcycle peak of estrogen is suppressed by oral contraceptives, these contractions may be regulated by cyclic estrogen and progesterone. Uncoordinated contractions in IUD bearing women indicate that the foreign body reaction of the IUD affects the normal physiology of these contractions.     

Oral contraceptives and their minor side effects: comparison of three low-dose estroprogestinic combinations

3 groups of women aged 19-25 with normal weight and in good physical health were studied. In the first group, 40 subjects received a monophasic oral contraceptive (OC) containing .15 mg of levonorgestrel (LNG) and .03 mg of ethinyl estradiol (EE). In the second group, 32 women received a triphasic OC containing LNG and EE (.05 mg of LNG + .03 mg of EE; .075 mg of LNG + .04 mg of EE; .125 mg of LNG + .03 mg of EE). In the third group, 34 women received a monophasic OC containing .15 mg of desogestrel (DSG) and .03 mg of ethinyl estradiol (EE). The observation lasted 6 month, involving 646 menstrual cycles. 3 months and 6 months later, checkups were conducted to find out about characteristics of the cycles, spotting or BTB (hemorrhagic rupture), weight change, and other minor disorders. After 3 months, spotting occurred in 4.1% of the monophasic LNG group, in 5.8% of the monophasic DSG group, and in 1% of the triphasic group (significantly higher in the DSG group). Heavy bleeding decreased from 25% in the LNG group, 25% in the triphasic group, and 17.6% in the DSG group to 0 after 6 months. Likewise, dysmenorrhea disappeared in all 3 groups. Weight change occurred in 50% of the LNG group, in 57% of the triphasic group, and in 76% of the DSG group. Premenstrual disorders, such as mastodynia, dropped from 40 to 25% in the LNG group, from 75 to 50% in the triphasic group, and from 54.5 to 36.3% in the DSG group after 6 months. Depression decreased from 20 to 8.3% in the LNG group and from 18.1 to 4.5% in the DSG group. Acne fell from 25% to 0 in the triphasic group and from 31.8 to 9 in the DSG group. These OCs were well tolerated without major differences between their minor side effects.     

The effect of triphasic oral contraceptives on plasma lipids and lipoproteins

To determine the effect of triphasic oral contraceptives on plasma lipid transport, 150 nonsmoking women with normolipidemia, ages 18 to 35 years, were randomly assigned to receive one of three contraceptive formulations: (1) ethinyl estradiol, 30, 40, and 30 micrograms/day, each for 6, 5, and 10 days per menstrual cycle, and levonorgestrel, 50, 75, and 125 micrograms/day, each for 6, 5, and 10 days; (2) ethinyl estradiol, 35 micrograms/day for 21 days, and phased norethindrone, 500, 750, and 1000 micrograms/day each for 7 consecutive days; and (3) ethinyl estradiol, 35 micrograms/day for 21 consecutive days, and norethindrone, 500, 1000, and 500 micrograms/day for 7, 9, and 5 days, respectively. A control group consisting of 49 women taking a nonhormonal form of contraception was also included. After 6 months of oral contraceptive treatment, significant increases in plasma triglyceride (28% to 52%) and plasma apolipoprotein B levels (20% to 23%) were observed in each treatment group. The changes in total plasma cholesterol (3% to 10%) and low-density lipoprotein cholesterol values (0% to 11%) were less striking. Changes in total high-density lipoprotein cholesterol levels were statistically insignificant (-2% to -4%); however, high-density lipoprotein2 cholesterol levels decreased by 29% to 33% and high-density lipoprotein3 cholesterol levels increased by 20% to 23%. Concomitantly, plasma apoliporprotein A-1 values increased by 5% to 12%. No consistent significant differences among analyses were observed between and of the groups receiving different oral contraceptives for 6 months.     

Sex hormone--binding globulin--a surrogate marker for the prothrombotic effects of combined oral contraceptives

OBJECTIVE: The purpose of this study was to investigate the plausibility of serum sex hormone-binding globulin (SHBG) concentration as a risk marker for venous thromboembolism (VTE) during use of combined oral contraceptives (COC).Study design This was a prospective, randomized cross-over study. Thirty-five women were treated with COCs containing the same amount of ethinyl estradiol and either levonorgestrel (LNG/EE) or desogestrel (DG/EE). Serum SHBG and markers of hemostasis were determined before and after 2 months on each treatment. RESULTS: SHBG increased significantly with both preparations. Treatment with DG/EE caused more pronounced prothrombotic changes in hemostatic parameters than LNG/EE. With both treatment regimens, there was a significant correlation between changes in resistance to activated protein C (APCr) and changes in plasma SHBG. CONCLUSION: The correlation between SHBG and the well-established risk factor APCr might indicate the usefulness of SHBG as a risk marker for VTE during COC treatment.     

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.     

Effect of oral contraceptives on balance in women: A randomized controlled trial

Objective

To detect the effect of combined oral contraceptive pills (COC) on dynamic postural balance in healthy middle aged women.

A randomized, double-blind, placebo-controlled comparison of the impact of low-dose and triphasic oral contraceptives on follicular development.

OBJECTIVE: This investigation tests the hypothesis that triphasic oral contraceptives are associated with the development of large, persistent ovarian cysts. STUDY DESIGN: Weekly vaginal ultrasonography was used in a randomized, double-blind, placebo-controlled, parallel-group, single-center study that compared the incidence, risk, size, and time to resolution of ovarian follicles in healthy women who took Estrostep or Loestrin oral contraceptives (manufactured by Parke-Davis) or a placebo during three consecutive menstrual cycles. RESULTS: Sixty-three percent of placebo-treated subjects developed follicles greater than 18 mm, compared with 39% and 23% in the Estrostep and Loestrin groups. The risks for each group of developing a large follicle during a single cycle were not different. No dominant follicle persisted for greater than 2 weeks for any subject. CONCLUSION: These results demonstrate that follicular development continues during treatment with oral contraceptives. In addition, the findings fail to support the hypothesis that triphasic oral contraceptives result in persistent ovarian cysts.     

Comparison of transdermal and oral estrogen-progestin replacement therapy: effects on serum lipids and lipoproteins.

OBJECTIVE: We attempted to ascertain whether transdermal postmenopausal estrogen-progestin therapy has the typical effects of oral therapy on serum lipoprotein risk markers for cardiovascular disease. STUDY DESIGN: Sixty-one postmenopausal women were randomized to receive either transdermal continuous 17 beta-estradiol, 0.05 mg/day, with transdermal cyclic norethindrone acetate, 0.25 mg/day, or oral continuous conjugated equine estrogens, 0.625 mg/day, with oral cyclic dl-norgestrel, 0.15 mg/day. Twenty-nine untreated subjects served as controls. Lipoprotein profiles at 3 and 6 months were compared with baseline values by means of analysis of variance. RESULTS: In the estrogen-alone phase both therapies reduced serum levels of total and low-density lipoprotein cholesterol; high-density lipoproteins were largely unchanged. Oral therapy increased triglycerides whereas this lipid fell with transdermal therapy. In the combined phase of the cycle both therapies reduced triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. CONCLUSION: Transdermal and oral therapies had similar effects on lipoprotein cholesterol but different effects on triglycerides.