Effects of a low-dose and ultra-low-dose combined oral contraceptive use on bone turnover and bone mineral density in young fertile women: a prospective controlled randomized study

In this prospective, controlled, randomized study, we compared the effect of a low-dose 21-day combined oral contraceptive (COC) containing 20 microg ethinyl estradiol (EE) and 75 microg gestodene (GTD) (Group A; n = 19) with an ultra-low-dose 24-day COC containing 15 microg EE and 60 microg GTD (Group B; n = 18) on bone turnover and bone mineral density (BMD) in young, fertile women. Nineteen healthy fertile women were used as untreated controls (Group C). At 3, 6, 9 and 12 months of the study serum osteocalcin (BGP), urinary pyridinoline (PYD) and deoxypyridinoline (D-PYD) were measured in all subjects. At baseline and after 12 months BMD was determined at lumbar spine by dual-energy X-ray absorptiometry in all patients. In both Groups A and B, urinary levels of PYD and D-PYD at 6, 9 and 12 months, were significantly reduced in comparison with basal values and with control subjects (p < 0.05). No significant differences in urinary PYD and D-PYD levels were observed between Groups A and B during the entire period of treatment. At 12 months, no statistically significant difference in spinal BMD values was detected between the three groups and in comparison with basal values. The present study suggests that the two COCs could exert a similar positive effect on bone turnover in young postadolescent women, without any significant and appreciable modification of BMD.     

Bone mineral density at various anatomic bone sites in women receiving combined oral contraceptives and depot-medroxyprogesterone acetate for contraception

The association between users of combined oral contraceptives and depot-medroxyprogesterone acetate (DMPA) for contraception and bone mineral density (BMD) has been controversial because of variations among studies. Like other studies, this cross-sectional study compares BMD in users of combined oral contraceptives and DMPA with that in nonusers. Unlike previous studies, we defined long-term use as >2 years, and we measured more bone sites than previous studies including lumbar spines, femurs, and forearms. The study group consisted of 59 women aged 30 years to 34 years who had been using combined oral contraceptives for 57.36 ± 27.02 months with a minimum period of 24 months, 34 women of the same age who had been using DMPA as contraceptive for 55.76 ± 35.31 months, and 62 women of the same age who had not used any steroid hormonal contraceptives for more than 6 months. BMD was measured by dual energy photon absorptiometer at lumbar spine 2–4, neck of femur, Ward’s triangle of femur, greater trochanter of femur, ultradistal radius, and distal ulnar, respectively. Age, body mass index, and lifestyles of both groups were matched with nonusers. Mean BMD at lumbar spine (L2–4) in the DMPA users was significantly lower than in the controls (1.031 ± 0.090 vs. 1.096 ± 0.116, P = 0.007). There were no significant differences in BMD values at bone sites other than lumbar spine between DMPA users and the controls. There were no significant differences in BMD values at all bone sites between combined oral contraceptives users and the controls. We conclude that combined oral contraceptives are not associated with changes in values of BMD, while DMPA is associated with decreased BMD only at lumbar spine. We comment that steroid hormonal contraceptives are safe to use for long-term contraception regarding bone mass effects.     

复方口服避孕药对青春期女性骨矿物质密度的影响

目的:观察16～18岁女性应用妈富隆和炔雌醇醋酸环丙孕酮对骨矿物质密度(BMD)的影响。方法:选择376例16～18岁青春期女性,其中127例女性应用妈富隆,134例应用炔雌醇醋酸环丙孕酮,115例应用非激素避孕(对照组),应用双能X线吸收法测量腰椎和股骨颈BMD,比较口服复方避孕药者与对照组女性BMD的改变。结果:用药24个月,应用妈富隆的女性腰椎、股骨颈BMD与基础值相比轻度降低,但差异无统计学意义(P>0.05);而应用炔雌醇醋酸环丙孕酮的女性腰椎和股骨颈BMD与基础值相比轻度增高,差异无统计学意义(P>0.05);与对照组相比,腰椎和股骨颈BMD增加幅度减小。应用妈富隆和炔雌醇醋酸环丙孕酮者与对照组女性相比,腰椎和股骨颈BMD没有明显差异(P>0.05)。结论:16～18岁青春期女性应用妈富隆或炔雌醇醋酸环丙孕酮2年对BMD没有不利影响,但是继续应用是否影响BMD峰值的获得有待进一步研究。     

Bone mineral density in women aged 40-49 years using depot-medroxyprogesterone acetate, norethisterone enanthate or combined oral contraceptives for contraception

Most studies show that depot-medroxyprogesterone acetate (DMPA) has a negative effect on bone mass. There are conflicting reports with respect to recovery of bone mass with long-term use of DMPA. No information is available on the effect of norethisterone enanthate (NET-EN) on bone mass, and combined oral contraceptives (COCs) have not been found to be associated with loss of bone mass. The aim of this study was to investigate bone mineral density (BMD) in older women (40-49 years) in relation to use of DMPA, NET-EN and COCs for at least 12 months preceding recruitment into the study. One-hundred twenty-seven users of DMPA, 102 NET-EN users and 106 COC users were compared to 161 nonuser controls. Bone mineral density was measured at the distal radius and midshaft of the ulna using dual X-ray absorptiometry. There was no significant difference in BMD between the four contraceptive user groups (p=.26) with and without adjustment for age. Although a small decrease in BMD was noted in the age range of 40-49 years, this was not statistically significant (p=.7). The BMD was found to be significantly associated with body mass index (BMI) (por=25.8 mIU/mL was associated with a decrease of 0.017 g/cm2 in radius BMD relative to women with FSH <25.8 mIU/mL. Significant interaction between FSH and BMI in their effect on BMD was observed (p=.006). This study found no evidence that long-term use of DMPA, NET-EN and COCs affects BMD in this population.     

A 3-year double-blind, randomized, controlled study on the influence of two oral contraceptives containing either 20 microg or 30 microg ethinylestradiol in combination with levonorgestrel on bone mineral density

In this first prospective, double-blind, randomized, parallel-group study we evaluated the influence of two combined oral contraceptives on bone mineral density (BMD) and metabolic bone parameters. One dose-reduced preparation contained 20 microg ethinylestradiol (EE) in combination with 100 microg levonorgestrel (LNG) (20/100) was compared with the reference preparation which contained 30 microg EE in combination with 150 microg LNG (30/150). Data from 48 volunteers aged 20-35 years were obtained over an observation period of 36 treatment cycles. The direction of the change (increase or decrease) in all investigated bone-related variables was similar in both treatment groups. As compared to baseline, bone mineral density decreased by 0.4% in the 20/100 group and by 0.8% in the 30/150 group after 36 treatment cycles. These changes were not significantly different between the two treatment groups (p = 0.902). For bone-specific alkaline phosphatase, we measured a mean increase of 55.4% (20/100 group) and of 113.2% (30/150 group) after 36 treatment cycles. The two treatments did not differ statistically significantly (p = 0.522). With respect to cross-linked N-telopeptides (NTx), we detected a decrease of the mean NTx urine concentrations of 21.1% (20/100) and of 13.4% (30/150). These changes also did not significantly differ between the two treatments (p = 0.613). Both study treatments were safe and well-tolerated by all volunteers participating in the study. In conclusion, BMD did not change during the 3-year observation period. Thus, both trial preparations containing either 20 or 30 microg EE in combination with LNG were capable of maintaining BMD in young fertile women. There is no reason to assume that the EE dose reduction had any negative impact on BMD. Because there were no differences in BMD between the treatment groups, it can be assumed that even lower dosages than 20 microg EE might be sufficient for bone protection. Biochemical markers provided evidence for a reduced bone resorption.     

Bone mineral density in adolescents using norethisterone enanthate, depot-medroxyprogesterone acetate or combined oral contraceptives for contraception

PURPOSE: Most studies have shown a negative effect of depot-medroxyprogesterone acetate (DMPA) on the bone mineral density (BMD) of adolescents. There is no information available on the effect of norethisterone enanthate (NET-EN) on BMD in adolescents and the effect of combined oral contraceptives (COCs) on adolescent BMD is inconclusive. The aim of this longitudinal study was to investigate BMD in adolescent (aged 15-19 years) new users of hormonal contraception (DMPA, NET-EN and COCs). METHOD: New users of DMPA (n=115), NET-EN (n=115), COCs (n=116) and 144 nonuser controls were recruited. BMD was measured at the distal radius and midshaft of the ulna using dual X-ray absorptiometry. RESULTS: In total, 275 women were included in this interim analysis and total follow-up time was 553 person-years. There was no significant difference in radius BMD between users of different contraceptive methods at baseline (p=.40). Overall, an increase in radius BMD of 0.00522 per person-year was observed. This result was similar when adjusting for BMI in the random effects regression model (p=.88). The regression model showed that BMI was significantly associated with radius BMD, with each unit increase in BMI corresponding to an increase of 0.0029 g/cm2 in BMD (95% CI 0.0023 to 0.0036, p<.001). Interaction between contraceptive method and follow-up time adjusted for BMI was not significant (p=.07). The increase in BMD for NET-EN users of 0.0013 g/cm2 per person-year (95% CI -0.0017 to 0.0043) was significantly lower than that of nonusers (p=.017). For DMPA and COC users, the increase in BMD was not significantly different compared to the nonusers. This study suggests that NET-EN users had lower increase in BMD over time compared to the other user groups.     

口服复方避孕药对青春期女性骨密度的影响

目的:观察复方口服避孕药(COCs)妈富隆(去氧孕烯/炔雌醇)对青春期女性骨矿物质密度(BMD)的影响。方法:接纳150例年龄16～18岁女性应用COCs避孕为观察组,用药24个月;接纳150例年龄16～18岁从未应用激素避孕药女性做对照组;应用双能X-线吸收法测量腰椎和股骨颈BMD。结果:观察组用药2年后腰椎和股骨颈BMD从基础值1.010±0.107g/cm3和0.818±0.089g/cm3降低到1.007±0.108g/cm3和0.813±0.090g/cm3,分别降低了0.29%和0.61%;而对照组则从基础值1.008±0.109g/cm3和0.816±0.087g/cm3增高至1.027±0.106g/cm3和0.824±0.089g/cm3,分别增高了1.88%和0.98%;用药2年后,观察组与对照组相比BMD无明显差异(P>0.05)。结论:青春期女性应用COCs避孕2年对BMD无明显影响。     

Influence of smoking and oral contraceptives on bone mineral density and bone remodeling in young women: a 2-year study

The objective of the study was to explore the influence of menstrual irregularities, oral contraceptives and smoking on bone mineral density (BMD) development and bone turnover with time. Healthy young women (n = 118) were divided into four categories: (a) women neither smoking nor using oral contraceptives; (b) women who were smokers; (c) women using oral contraceptives; (d) women who were smoking and using oral contraceptives. They responded to a validated questionnaire with 34 questions concerning lifestyle and the Sense of Coherence scale (SOC). BMD was measured by dual energy x-ray absorptiometry (DEXA). Deoxypyridinoline (DPD) was measured in urine. Data were analyzed by multiple linear regression analysis. Among smokers, BMD level decreased during a 2-year period and smoking was associated with a larger negative change in BMD. Use of oral contraceptives moderated the negative impact of smoking. Women using oral contraceptives at baseline and with regular bleeding induced by contraceptive pills had a significantly higher BMD at baseline and at follow-up. They also had lower SOC than women who had natural regular bleedings. Use of oral contraceptives in combination with smoking was linked to high alcohol consumption and higher frequency of self-reported body weight reduction, which reduced the negative BMD change in this category. DPD level and difference were strongly associated with estrogen influence. It is concluded that smokers without OCs had a negative BMD development and BMD in young women with irregular menstruations seems to be improved by OC.     

Short-term variations in bone remodeling markers of an oral contraception formulation containing 3 mg of drospirenone plus 30 microg of ethinyl estradiol: observational study in young postadolescent women

The clinical study of treated subjects and nontreated controls was made in healthy eumenorrheic young postadolescent women volunteers in the Department of Obstetrics and Gynaecology at Cagliari University, to investigate whether an oral contraceptive (OC) containing drospirenone (3 mg) plus ethinyl estradiol (30 microg) (DRSP+EE) can affect bone metabolism. Control group (n = 26) and OC group (n = 28) women did not differ in age, body mass index, waist-to-hip ratio and main outcome measures [urinary levels of deoxypyridinoline and pyridinoline, serum levels of osteocalcin, bone specific alkaline phosphatase (bSAP), total testosterone (total-T), sex hormone-binding globulin (SHBG), progesterone and bone mineral density (BMD) at the heel]. The control group was studied at the luteal phase (LP) during both the first and the sixth menstrual cycle; the OC group was studied during the first cycle at the LP, and on days 16-18 of the sixth cycle of DRSP+EE treatment. At the sixth cycle, in the control group, the main outcome measures did not change compared to baseline. In the OC group, deoxypyridinoline, pyridinoline, osteocalcin, bSAP, total-T and progesterone levels were reduced, whereas SHBG levels were increased. The BMD was unchanged compared to baseline. The results suggest that 6-month DRSP+EE treatment decreases bone turnover.     

Efficacy and safety of a low-dose 24-day combined oral contraceptive containing 20 micrograms ethinylestradiol and 3 mg drospirenone

The aim of this open-label, multicenter, noncomparative study was to determine the efficacy, safety and bleeding profile of a new low-dose, monophasic combined oral contraceptive containing 20 micrograms ethinylestradiol and 3 mg drospirenone administered daily for 24 days followed by a 4-day hormone-free interval. Contraceptive efficacy was analyzed for 1018 women completing 11,140 treatment cycles. Eleven pregnancies occurred, giving a Pearl Index (PI) of 1.29 (upper limit of the 95% confidence interval [CI], 2.30); of these pregnancies, five were considered due to method failure, giving an adjusted PI of 0.72 (upper limit of the 95% CI, 1.69). A total of 7 (0.7%) women discontinued study medication because of irregular bleeding, suggesting a favorable bleeding profile. Overall, the treatment was well tolerated with an excellent safety profile. The majority of women (86%) stated that they were satisfied or very satisfied with the treatment and over 70% of women would have continued with the study medication.     

Efficacy and safety of a low-dose combined oral contraceptive containing drospirenone 3 mg and ethinylestradiol 20 mcg in a 24/4-day regimen

Objective

The study was conducted to assess the efficacy of a low-dose combined oral contraceptive (COC) containing drospirenone (drsp) 3 mg/ethinylestradiol (EE) 20 mcg administered for 24 days of active treatment followed by a 4-day hormone-free interval (24/4 regimen).

Study Design

In this open-label uncontrolled study conducted in 50 European centers, healthy females aged 18-35 years with a body mass index of less than 30 kg/m² received drsp 3 mg/EE 20 mcg 24/4 over 13 cycles. The primary efficacy variable was the number of unintended pregnancies.

Results

Five pregnancies occurred among 1101 women over 13,248 treatment cycles, resulting in a Pearl Index (PI) of 0.49 with an upper two-sided 95% CI limit of 1.14. Of these pregnancies, three were attributed to noncompliance with tablet use resulting in an adjusted PI for ‘perfect use’ of 0.22 (upper limit of two-sided 95% CI: 0.80) based on 11,755 cycles.

Conclusion

Drospirenone 3 mg/EE 20 mcg 24/4 is a highly effective COC in nonobese women.     

Bone mineral density in adolescent and young Thai girls receiving oral contraceptives compared with depot medroxyprogesterone acetate: a cross-sectional study in young Thai women

This cross-sectional study of bone mineral density in adolescent and young Thai girls receiving oral contraceptives compared with depot medroxyprogesterone acetate was performed to evaluate the differences among these groups. Thirty current OC users and 30 current depot medroxyprogesterone acetate (DMPA) users were included in the study. The mean duration of OC use was 28.8 +/- 3.4 months and of DMPA 24.6 +/- 3.3 months. Dual energy X-ray absorptiometry (DEXA) was used to measure bone mineral density (BMD) at distal and ultradistal forearm of the nondominant side. The BMD of ultradistal forearm of OC users and that of DMPA users were 0.423 +/- 0.048 and 0.403 +/- 0.039 g/cm(2) and at distal forearm of OC and DMPA users were 0.566 +/- 0.043 and 0.571 +/- 0.064 g/cm(2), respectively. However, there were no statistical differences in BMD in these two groups.     

Short-term response of bone turnover to low-dose oral contraceptives in exercising women with hypothalamic amenorrhea

BACKGROUND: We examined the response of bone turnover markers and indices of energy status after 2 weeks of oral contraceptive (OC) therapy in premenopausal women with exercise-associated menstrual disturbances (EAMD). STUDY DESIGN: Six women with EAMD received one 28-day cycle of a triphasic OC containing 180-250 mcg norgestimate/25 mcg ethinyl estradiol (EAMD+OC) and six were controls (EAMD controls). Bone turnover markers amino-terminal propeptide of Type I procollagen and serum carboxy-terminal telopeptides of Type I collagen (PINP and SCTX-I) were assessed at baseline and after 2 weeks of OC therapy (EAMD+OC) or after a 30-day monitoring period (EAMD controls). Total triiodothyronine, resting energy expenditure (REE) and dietary intake were assessed as secondary end points. The absolute and percent changes from baseline in the primary and secondary outcomes were evaluated using an analysis of covariance, adjusting for baseline values of the corresponding outcome. RESULTS: Compared to EAMD controls, a significant change from baseline was observed in the EAMD+OC group for PINP (mean+/-SEM, 9.9+/-6.1 vs. -33.9+/-9.0 mcg/L; p=.005) and SCTX-I (-0.02+/-0.11 vs. -0.25+/-0.07 ng/mL; p=.017), but not osteoprotegerin (-0.53+/-0.22 vs. 0.20+/-0.44 pmol/L; p=.429) after 2 weeks (14.7+/-0.3 days) of OC therapy. Total triiodothyronine levels were elevated in the EAMD+OC group after therapy compared with EAMD controls (19.7+/-4.1 vs. -8.4+/-4.9 ng/dL; p=.002); however, no differences between groups were observed for the changes in REE or dietary intake. CONCLUSION: Our data demonstrate that 2 weeks of low-dose OC therapy rapidly reduced markers of bone resorption and formation, without any significant impact on energy status in women with EAMD.     

育龄妇女应用炔雌醇环丙孕酮对骨矿物质密度的影响

目的:观察复方口服避孕药(COCs)炔雌醇环丙孕酮片对骨矿物质密度(BMD)的影响。方法:对55例年龄25～40岁,口服炔雌醇环丙孕酮片避孕24个月的妇女(观察组)应用双能X光线吸收测量腰椎和股骨颈BMD,并以53例年龄25～40岁从未应用激素避孕药妇女(对照组)做对照。结果:观察组腰椎和股骨颈BMD与基础值和对照组相比差异无统计学意义(P>0.05)。结论:年龄25～40岁妇女应用炔雌醇环丙孕酮避孕药避孕与非激素避孕者相比,BMD没有改变。     

Oral contraceptive use and bone density in adolescent and young adult women

Background

Most of the millions of oral contraceptive (OC) users are under 30 years of age and in the critical period for bone mass accrual.

Study Design

This cross-sectional study of 606 women aged 14-30 years examined both OC duration and estrogen dose and their association with bone mineral density (BMD) at the hip, spine, and whole body (dual-energy X-ray absorptiometry).

Results

Of 389 OC users and 217 nonusers enrolled, 50% were adolescents (14-18 years). Of OC users, 38% used “low-dose” OCs [<30 mcg ethinyl estradiol (EE)]. In adolescents, mean BMD differed by neither OC duration nor EE dose. However, 19- to 30-year-old women's mean BMD was lower with longer OC use for spine and whole body (p=.004 and p=.02, respectively) and lowest for >12 months of low-dose OCs for the hip, spine and whole body (p=.02, .003 and .002, respectively).

Conclusions

Prolonged use of today's OCs, particularly <30 mcg EE, may adversely impact young adult women's bone density while using these agents.     

Use of combined oral contraceptives among women with migraine and nonmigrainous headaches: a systematic review

This systematic review examines evidence evaluating whether women with headaches who use combined oral contraceptives (COCs) have a greater risk of stroke than women with headaches who do not use COCs. We searched MEDLINE for articles published from 1966 through March 2005 relevant to headaches and COC use as risk factors for stroke. Of the 79 articles identified, nine met our selection criteria (eight reports of six observational studies plus one meta-analysis). All studies reported specifically on migraine headaches. Evidence from six case-control studies suggested that COC users with a history of migraine were two to four times as likely to have an ischemic stroke as nonusers with a history of migraine. The odds ratios for ischemic stroke ranged from 6 to almost 14 for COC users with migraine compared with nonusers without migraine. The three studies that provided evidence on hemorrhagic stroke reported low or no risk associated with migraine or with COC use.     

A prospective randomized trial comparing low-dose ethinyl estradiol and drospirenone 24/4 combined oral contraceptive vs. ethinyl estradiol and drospirenone 21/7 combined oral contraceptive in the treatment of hirsutism

Background

A prospective randomized trial was conducted to compare the clinical efficacy of two oral contraceptives containing drospirenone in the treatment of hirsutism in women.

Study Design

Fifty women with moderate to severe hirsutism were recruited. Three women were lost to follow-up. Twenty-four patients received oral 0.03 mg ethinyl estradiol and 3 mg drospirenone 21/7 regimen (Group 1) for 6 months. Another group of 23 patients received oral 0.02 mg ethinyl estradiol and 3 mg drospirenone 24/4 regimen (Group 2) for 6 months. Hirsutism was assessed after 6 months using the Ferriman–Gallwey (F-G) scoring system. Hormonal levels after 6 months of both therapies were compared with baseline values and each other.

Results

An improvement in the F-G scores for hirsutism (mean±SD) was observed in Group 1 (17.3±5.2 to 8.7±2.5, p<.001) and in Group 2 (17.5±4.8 to 7.9±2.8, p<.001). Pre- and post-treatment hirsutism scores were comparable between the groups (p>.05). Total and free testosterone levels decreased significantly after the therapy in both groups. The sex hormone-binding globulin levels increased significantly in both groups during the 6-month period.

Conclusion

The treatment of hirsutism with both combined oral contraceptives (COCs) containing drospirenone offered comparable effects and was well tolerated.     

中老年女性骨密度和骨代谢生化指标关系的研究

目的了解中老年女性骨密度和骨代谢生化指标随年龄变化的特点,分析骨代谢生化指标在骨质疏松症早期诊断中的价值。方法测定162例中老年女性腰椎正位骨密度,同时检测所有受检者空腹血清骨钙素、血清碱性磷酸酶及晨尿吡啶啉,尿吡啶啉用肌酐校正。按年龄段和不同骨密度组对骨代谢生化指标值分别进行统计分析。结果骨质疏松在中老年女性中普遍存在,发病率很高,达51.2%。骨代谢指标按年龄分析,中老年女性骨钙素和尿吡啶啉/肌酐在50~69岁时明显升高。70岁以后又趋于下降。而血清碱性磷酸酶各年龄段无显著性差异。按骨密度分析,中老年女性骨质疏松组和骨量减低组的骨钙素和尿吡啶啉/肌酐均明显高于正常组。而骨质疏松组和骨量减低组的骨钙素和尿吡啶啉/肌酐值无显著性差异。各骨密度组的血清碱性磷酸酶无显著性差异。结论骨质疏松症是1种危害极大的疾病,在中老年女性中患病率很高,因此早期诊断尤为重要。血清骨钙素、尿吡啶啉/肌酐分别是反映骨形成和骨吸收特异性和敏感性较高的指标,有助于原发性骨质疏松症的早期诊断。