Contraception 86 (2012) 332 – 336
Original research article
Effect of two kinds of different combined oral contraceptives use on bone mineral density in adolescent women☆ Ling Gai a,⁎, Yifang Jia b , Meihua Zhang a , Ping Gai b , Sumei Wang a , Hong Shi a , Xiaojie Yu a , Yonghong Liu c a
Key Laboratory for Improving Birth Outcome Technique, Shandong Provincial Institute of Science and Technology for Family Planning, Jinan, Shandong 250002, China b Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China c Shandong Medical Imaging Research Institute, Jinan, Shandong 250021, China Received 26 December 2011; revised 16 January 2012; accepted 18 January 2012
Abstract Background: Steroid hormonal contraceptives are highly effective and widely used. Most studies have shown a negative effect of combined oral contraceptives (COCs) on the bone mineral density (BMD) of adolescents. The study was conducted to compare BMD among users of ethinylestradiol/desogestrel, users of ethinylestradiol/cyproterone acetate and nonhormonal control subjects in women aged 16–18 years. Study Design: The study included 450 women 16–18 years of age. One hundred fifty women were using ethinylestradiol/desogestrel, 150 women were using ethinylestradiol/cyproterone acetate, and 150 women were using nonhormonal contraception as control subjects. BMD of the lumbar spine and femoral neck was obtained using dual-energy X-ray absorptiometry, and mean BMD changes in COCs users and nonusers were compared. Results: At 24 months of treatment, lumbar spine and femoral neck mean BMD values in women (n=127) who used ethinylestradiol/ desogestrel were slightly lower compared with baseline, but these effects did not reach statistical significance (p=.837 and p=.630, respectively). The mean lumbar spine and femoral neck BMD values in women (n=134) who used ethinylestradiol/cyproterone acetate were slightly higher compared with baseline, but there was no statistical significance (p=.789 and p=.756, respectively). The increases in mean percent change in lumbar spine and femoral neck BMD in the ethinylestradiol/cyproterone acetate group were less than those in the control group (1.88% vs. 0.30% and 0.98% vs. 0.49%, respectively). There were no significant differences in mean BMD of the lumbar spine and femoral neck between the users of ethinylestradiol/desogestrel or ethinylestradiol/cyproterone acetate and nonusers (pN.05). Conclusion: Our study indicates that 2 years of COCs therapy had no significant effect on bone density in adolescents, but it remains unknown whether therapy longer than 2 years has a significant adverse effect on the attainment of peak bone mass. © 2012 Elsevier Inc. All rights reserved. Keywords:
Combined oral contraceptive (COCs); Ethinylestradiol/desogestrel; Ethinylestradiol/cyproterone acetate; Bone mineral density (BMD); Contraception
1. Introduction
☆ This study was supported by a grant from the Research Foundation of the Shandong Provincial Committee of Family Planning Research, Jinan, Shandong, China. ⁎ Corresponding author. Key Laboratory for Improving Birth Outcome Technique, Shandong Provincial Institute of Science and Technology for Family Planning, Jinan, Shandong 250002, China. Tel.: +86 531 82597813; fax: +86 531 82597807. E-mail address: linggai5239@yahoo.com.cn (L. Gai).
0010-7824/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2012.01.009
Steroid hormonal contraceptives, including oral and injectable contraceptives, are highly effective and widely used. These contraceptives have important health benefits, including contraceptive and noncontraceptive benefits, but also have some health risks, such as bone health. Some studies have demonstrated that use of progestin-only contraceptive depot medroxyprogesterone acetate (DMPA) may cause bone loss [1,2]. Combined oral contraceptives (COCs) may also adversely affect bone health, especially when used in adolescents [3] and young women [4]. Use of COCs may
L. Gai et al. / Contraception 86 (2012) 332–336
impede attainment of peak bone mass [4]. Most COCs users are under 30 years of age [5]. Previous investigations have examined the effect of COCs on bone mineral density (BMD) in adolescents [3–9], but the results are inconsistent. The objective of the present study was to evaluate whether use of ethinylestradiol (EE)/desogestrel and EE/ cyproterone acetate affects bone health in adolescent women by comparing their BMDs with those of controls.
2. Materials and methods 2.1. Subjects We originally enrolled 450 women from 16 to 18 years old attending family planning clinics and requesting birth control. All of these women had never used hormonal contraception prior to recruitment to this study. Three hundred women requesting COCs contraception were randomized into two treatment groups by drawing lots, receiving either an EE/desogestrel oral contraceptive with EE 30 mcg and desogestrel 0.15 mg (N.V. Organon, the Netherlands) (group A, n=150) or EE/cyproterone acetate oral contraceptives with EE 35 mcg and cyproterone acetate 2 mg (Schering GmbH and Co., Germany) (group B, n=150). Women of groups A and B were instructed to start pill intake from the fifth day after the beginning of the next spontaneous menses for 21 days with a 7-day pill-free interval. Women who did not wish to use hormonal birth control were recruited as nonhormonal controls (group C, n=150). They used intrauterine device or condom for contraception. Inclusion and exclusion criteria include the following: All subjects had regular menses, should not have used any kind of hormonal contraception, and had no breastfeeding or delivery for at least 6 months. They were also required not to become pregnant. They did not take any calcium, vitamin D and bone-affecting medication. Women who had chronic disease, such as diabetes mellitus, renal dysfunction, thyroid and parathyroid diseases, hepatitis or pituitary diseases, were excluded from this study. Written informed consent was obtained from subjects and their parents or legal guardians when the subjects were under the age of 18 years. Study protocols were approved by the Institutional Review Board of Shandong Provincial Institute of Family Planning Research.
333
baseline. All subjects had BMD determined approximately every 12 months for 24 months. The data were statistically analyzed. 2.3. Statistical analysis All analyses were performed using SPSS version 13.0. The one-way analysis of variance was used to test for differences of BMD values and selected characteristics among the three groups, and two-group comparisons for these variables were conducted using t tests. A statistical test with a p valueb.05 was considered statistically significant. Data are presented as mean±SD. 3. Results 3.1. Demographic and anthropometric characteristics In total, 450 women aged 16–18 years were recruited. A total of 138 (92.0%) EE/desogestrel users, 139 (92.7%) EE/ cyproterone acetate users and 136 (90.7%) nonhormonal users completed the first 12 months of observation, and a total of 127 (84.7%) women in the EE/desogestrel group, 134 (89.3%) women in EE/cyproterone acetate group and 115 (76.7%) women in the nonhormonal group completed the entire 24 months of observation. The reasons for treatment-phase withdrawal (n=23) in group A were as follows: nine (39.1%) women terminated for side effects of the method, such as irregular bleeding, nausea, etc.; three (13.0%) became pregnant; five (21.7%) moved; four (17.4%) were noncompliant; and two (8.7%) were lost to follow-up. The reasons for treatment-phase withdrawal (n=16) in group B were as follows: two (12.5%) had irregular bleeding, two (12.5%) became pregnant, three (18.8%) moved, six (37.5%) were noncompliant, and three (18.8%) were lost to followup. The reasons for treatment-phase withdrawal (n=35) in group C were as follows: 22 (62.9%) became pregnant, 6 (17.1%) moved, 3 (8.6%) were noncompliant, and 4 (11.4%) were lost to follow-up. Table 1 shows baseline information about these women. There were no significant differences between the three contraceptive user groups regarding mean age, BMI, age at menarche, menstrual cycle or number of pregnancies. 3.2. BMD measurements
2.2. Variables The subjects were asked about their age, number of pregnancies and deliveries, menstrual status, etc. Physical measurements were carried out for their height and weight. Height was measured using a stadiometer. Body weight was measured with calibrated electronic scales. Body mass index (BMI) was calculated as body mass/(height) 2. BMD at the lumbar spine (L2-4) and femoral neck was measured by dual-energy X-ray absorptiometry (QDR4500W, Hologic, Bedford, MA, USA). Results were recorded as g/cm 2. Before using COCs, BMD was determined at
There were no significant differences in lumbar spine and femoral neck mean BMD among groups A, B and C at baseline. At 24 months of treatment, in group A, as compared to baseline, the mean BMD in lumbar spine and femoral neck revealed a slight decrease. The mean percentage change from baseline in lumbar spine and femoral neck had decreased by 0.30% and 0.61%, respectively. The mean lumbar spine and femoral neck BMD values at 24 months were not significantly different compared to baseline and subjects in the nonuser group (pN.05). While in groups B and C, there was a trend toward increasing BMD. In group B, the mean
334
L. Gai et al. / Contraception 86 (2012) 332–336
Table 1 Demographic and anthropometric characteristics of the participants Group A
Group B
Group C
p value
N 150 150 150 Chronological age 17.09±0.79 17.05±0.78 17.13±0.78 .718 (years) Gynecologic age (years) 3.72±1.22 3.65±1.20 3.72±1.32 .867 Weight (kg) 49.51±3.49 49.53±4.01 49.46±3.66 .987 Height (cm) 158.11±4.29 158.92±4.27 158.17±4.36 .194 BMI (kg/m 2) 19.79±0.95 19.58±0.92 19.75±0.84 .107 Age at menarche (years) 13.38±1.02 13.35±0.98 13.41±1.08 .879 Menstrual cycle (days) 9.63±2.56 9.71±2.64 9.71±2.57 .945 No. of pregnancies .21±0.47 .22±0.53 .17±0.47 .618 No. of deliveries .027±0.16 .020±0.14 0.013±0.12 .713 Data are expressed as mean±SD. There were no significant differences among the three groups.
percentage change at 24 months from baseline in the lumbar spine and femoral neck increased by 0.30% and 0.49%, respectively. There were no significant differences compared to baseline and nonusers. In group C, the mean percentage change from baseline in lumbar spine and femoral neck increased by 1.88% and 0.98%, respectively. There were also no significant differences compared to baseline. There were no significant differences in lumbar spine and femoral neck BMD among the three groups after 24 months of treatment (pN.05) (Table 2).
4. Discussion Osteoporosis is characterized by low BMD, compromised architectural stability and increased risk of fracture. Attainment of peak bone mass is essential for the prevention of osteoporosis. Adolescence is the critical period for bone mass accrual. Maximizing peak bone mass in the adolescent period may reduce the risk of osteoporotic fractures in later life. There is no agreement on whether the use of COCs during the adolescent ages has any effect on BMD. Our study indicated that, at 24 months of treatment, there were no significant differences in mean BMD of the lumbar spine and femoral neck between the users of EE/desogestrel or EE/cyproterone acetate and nonusers (pN.05). Age, BMI, age at menarche, menstrual and pregnancy status of the three groups were statistically matched to eliminate possible confounding factors. Some cross-sectional studies were conducted to assess the effects of COCs on BMD in adolescent women. Hartard et al. [4] reported that women aged between 18 and 24 years who had ever used COCs had significantly lower mean bone mass at the femoral neck and at the tibial shaft relative to control subjects who had never used COCs, and long duration and early start of COCs use were associated with lower area mean BMD of the femoral neck and lower total bone mineral content (BMC) at the distal tibia and the tibial shaft. Scholes et al. [5] enrolled 606 women aged 14 to 30 years to evaluate the effect of COCs duration of use and estrogen dose on BMD. They found that, in
adolescents (14–18 years), mean BMD did not differ by COCs duration of use or EE dose. However, in women aged between 19 and 30 years, the mean BMD was lower with longer COCs use for the spine and whole body (p=.004 and .02, respectively) and lowest for N12 months of low-dose COCs for the hip, spine and whole body (p=.02, .003 and .002, respectively). Puberty is very important for the achievement of peak bone mass in adolescent girls. Estrogen is required for normal pubertal skeletal growth and maturity in adolescent women. COCs inhibit the hypothalamic–pituitary axis and maintain a constant serum estradiol concentration comparable to the level present in the early follicular phase of the menstrual cycle [10]. Hypoestrogenemia is one of the most important causes of bone loss in women. Therefore, the suppression of endogenous sex steroid production by COCs may interfere with the increase in bone mass during the adolescence. The high levels of ethinyl estradiol may overcome this interference. Many longitudinal studies have examined the effect of COCs on BMD changes in the adolescent population. Although COCs may have beneficial effect on BMD in perimenopausal or postmenopausal women, studies of adolescent and young women generally found lower mean BMD among COCs users than nonusers [11]. Pikkarainen et al. [3] followed BMC in 122 adolescent women aged 12–19 years. After 4 years of follow-up, there was a significant trend showing less increase in the mean BMC of lumbar spine in the group of adolescent women who had used COCs for more than 2 years compared with the groups with 1–2 years of use and the nonusers. In the mean BMC of the femoral neck, there was a significant trend of a smaller increase in COCs users of more than 2 years compared with those with 1–2 years of use. Beksinska et al. [9] investigated BMD in 15- to 19-year-old new users of DMPA, norethisterone enanthate and COCs. They found that, in nonusers, mean BMD increased by 1.49% per annum, while in the COCs Table 2 Changes in lumbar spine and femoral neck BMD after 24 months of contraceptive use Group A Value of BMD at baseline N 150 Lumber spine 1.010±0.107 Femoral neck 0.818±0.089 Value of BMD during treatment N 138 Lumber spine 1.008±0.106 (12 months) Femoral neck 0.815±0.089 (12 months) N 127 Lumber spine 1.007±0.108 (24 months) Femoral neck 0.813±0.090 (24 months)
Group B
Group C
p value
150 1.009±0.107 0.818±0.087
150 1.008±0.109 0.816±0.087
.998 .970
139 1.011±0.105
136 1.018±0.106
.751
0.819±0.087
0.819±0.088
.931
134 1.012±0.107
115 1.027±0.106
.340
0.822±0.088
0.824±0.089
.562
Data are expressed as mean±SD. There were no significant differences among the three groups.
L. Gai et al. / Contraception 86 (2012) 332–336
users, the increases were less, only 0.84%. There was evidence for lower BMD increases per annum in COCs users compared to nonusers (p=.010). Cromer et al. [7] compared the BMD of 12- to 18-year-old women who were current users of COCs and DMPA for 2 years with that of same-age nonusers. They found that, over the first 12 months, the mean percent changes in BMD at the spine were as follows: COCs +2.3% [95% confidence interval (CI) +1.49, +3.18]; untreated +3.8% (95% CI +3.11, +4.57). At the femoral neck, the mean percent changes were as follows: COCs +0.3% (95% CI −0.87, +1.41); untreated +2.3%. Mean percent change in BMD at the lumbar spine over 24 months was+4.2% in the COCs group and +6.3% in the untreated group. At the femoral neck, mean percent change in BMD over 24 months was +3.0% in the COCs group and +3.8% in the untreated group. One comparison between the COCs group and untreated group reached marginal statistical significance: BMD at the lumbar spine was lower in mean absolute value among the COCs users than among the untreated group (p=.03). Berenson et al. [8] found that COCs users 16–33 years old had a slight mean BMD increase at the spine during the first 12 months, followed by a slow and gradual decrease in the second and third years. However, COCs users 16–24 years old lost significantly less mean bone density at the spine (0.4% vs. 0.8%, p=.013) than women 25–33 years of age. In contrast, nonhormonal users 16–24 years old gained significantly more BMD at the spine (3.3% vs. 1.3%, p=.001) than those 25–33 years of age. Reed et al. [12] reported that COCs users showed a nonsignificant trend for smaller changes in mean BMD at all sites after 24 and 36 months when compared with similarly aged nonusers. Their results were similar with ours. Our results showed that, at 24 months of treatment, in the EE/desogestrel group, the mean percentage change from baseline in lumbar spine and femoral neck had decreased by 0.30% and 0.61%, respectively, while in the EE/cyproterone acetate group, the mean percentage change from baseline in lumbar spine and femoral neck had increased by 0.30% and 0.49%, respectively. But there were no significant differences in mean BMD of the lumbar spine and femoral neck between the COCs users and nonusers. Our study compares the effects of two different types of COCs on BMD. We found that, at 24 months of treatment, in the users of EE/desogestrel, the mean BMD in lumbar spine and femoral neck had slightly decreased as compared to baseline, but did not reach significance, whereas in the users of EE/cyproterone acetate, the mean BMD in lumbar spine and femoral neck slightly increased as compared to baseline. In the study of adult women (25–40 years), we observed a similar scenario [13]. A study of women with a mean age of 25 years by Berenson et al. [14] found that women who used desogestrel- and norethindrone-containing COCs experienced a mean BMD gain of approximately 0.33% and 2.33%, respectively, compared with a mean 0.37% loss in nonhormonal users, which was significantly
335
different from controls among users of norethindronecontaining COCs (p=.01), but not among users of desogestrel-containing COCs (p=.99). It is not clear whether use of a desogestrel-containing COCs affects BMD. Our results showed a trend toward a decrease in BMD with EE/ desogestrel use, which did not reach significance. Further studies are needed to determine whether there is any effect of desogestrel on bone heath. Our study suggests that, at 24 months of treatment, mean lumbar spine and femoral neck BMD values in women who used EE/desogestrel were slightly lower compared with baseline values, while the mean lumbar spine and femoral neck BMD values in women who used EE/cyproterone acetate were slightly higher compared with baseline values. There were no significant differences in BMD of the lumbar spine and femoral neck between the users of EE/desogestrel or EE/cyproterone acetate and nonusers. But it remains unknown whether therapy longer than 2 years has a significant adverse effect on the attainment of peak bone mass. Further studies are needed to determine whether there is any effect of desogestrel on bone heath, Acknowledgment We thank Xiaoruo Gai, University of Michigan, USA, for data analysis and assistance in manuscript revision.
References [1] Harel Z, Johnson CC, Gold MA, et al. Recovery of bone mineral density in adolescents following the use of depot medroxyprogesterone acetate contraceptive injections. Contraception 2010;81:281–91. [2] Gai L, Zhang JL, Zhang HZ, Gai P, Zhou L, Liu YH. The effect of depot medroxyprogesterone acetate (DMPA) on bone mineral density (BMD) and evaluating changes in BMD after discontinuation of DMPA in Chinese women of reproductive age. Contraception 2011; 83:218–22. [3] Pikkarainen E, Lehtonen-Veromaa M, Mottonen T, Kautiainen H, Viikari J. Estrogen-progestin contraceptive use during adolescence prevents bone mass acquisition: a 4-year follow-up study. Contraception 2008;78:226–31. [4] Hartard M, Kleimond C, Wiseman M, Weissenbacher ER, Felsenberg D, Erben RG. Detrimental effect of oral contraceptives on parameters of bone mass and geometry in a cohort of 248 young women. Bone 2007;40:444–50. [5] Scholes D, Ichikawa L, LaCroix AZ, et al. Oral contraceptive use and bone density in adolescent and young adult women. Contraception 2010;81:35–40. [6] Nappi C, Di Spiezio Sardo A, Greco E, Tommaselli GA, Giordano E, Guida M. Effects of an oral contraceptive containing drospirenone on bone turnover and bone mineral density. Obstet Gynecol 2005;105: 53–60. [7] Cromer BA, Bonny AE, Stager M, et al. Bone mineral density in adolescent females using injectable or oral contraceptives: a 24-month prospective study. Fertil Steril 2008;90:2060–7. [8] Berenson AB, Rahman M, Breitkopf CR, Bi LX. Effects of depot medroxyprogesterone acetate and 20-microgram oral contraceptives on bone mineral density. Obstet Gynecol 2008;112:788–99. [9] Beksinska ME, Kleinschmidt I, Smit JA, Farley TM. Bone mineral density in a cohort of adolescents during use of norethisterone
336
L. Gai et al. / Contraception 86 (2012) 332–336
enanthate, depot-medroxyprogesterone acetate or combined oral contraceptives and after discontinuation of norethisterone enanthate. Contraception 2009;79:345–9. [10] Agostino H, Di Meglio G. Low-dose oral contraceptives in adolescents: how low can you go? J Pediatr Adolesc Gynecol 2010;23: 195–201. [11] Martins SL, Curtis KM, Glasier AF. Combined hormonal contraception and bone health: a systematic review. Contraception 2006;73: 445–69.
[12] Reed SD, Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM. Longitudinal changes in bone density in relation to oral contraceptive use. Contraception 2003;68:177–82. [13] Liu RJ, Gai L, Jia YF, Gai P, Yu XJ. Effect of two kinds of different combined oral contraceptives use on bone mineral density in women of reproductive age. J Reprod Contracept 2011;22:145–51. [14] Berenson AB, Radecki CM, Grady JJ, Rickert VI, Thomas A. A prospective, controlled study of the effects of hormonal contraception on bone mineral density. Obstet Gynecol 2001;98:576–82.