See\tdiscussions,\tstats,\tand\tauthor\tprofiles\tfor\tthis\tpublication\tat:\thttps://www.researchgate.net/publication/8035797 A\tcomparative\tstudy\ton\tthe\teffects\tof\ta contraceptive\tvaginal\tring\tNuvaRing((R))\tand an\toral\tcontraceptive\ton\tcarbohydrate... Article in The\tEuropean\tJournal\tof\tContraception\tand\tReproductive\tHealth\tCare\t\tSeptember\t2004 DOI:\t10.1080/13625180400007199\t\tSource:\tPubMed CITATIONS READS 41 173 4\tauthors,\tincluding: Ingrid\tDuijkers Dinox\tBV\tand\tDinox\tConsultancy\tBV 49\tPUBLICATIONS 742\tCITATIONS SEE\tPROFILE Available\tfrom:\tIngrid\tDuijkers Retrieved\ton:\t18\tNovember\t2016 Eur J Contracept Reprod Health Care Downloaded from informahealthcare.com by University of Groningen on 01/05/11 For personal use only. The European Journal of Contraception and Reproductive Health Care 2004;9:131-140 A comparative study on the effects of a 1 contraceptive vaginal ring NuvaRing and an oral contraceptive on carbohydrate metabolism and adrenal and thyroid function I. Duijkers, S. Killick*, A. Bigrigg{ and T. O. M. Dieben{ Dinox BV Medical Investigations, Nijmegen, The Netherlands; *Academic Department of Obstetrics and Gynaecology, The Princess Royal Hospital, Hull, UK; {Centre for Family Planning and Sexual Health, Glasgow, UK; { Clinical Development Department, Contraception, NV Organon, Oss, The Netherlands ........................................................................................................................................................................................................... ABSTRACT Objectives To compare carbohydrate metabolism, adrenal and thyroid function during use of a combined contraceptive vaginal ring (NuvaRing1, NV Organon, Oss, The Netherlands) with those of a combined oral contraceptive. Methods Healthy women aged 18-40 years used either the vaginal ring, delivering 15 mg ethinylestradiol and 120 mg of etonogestrel per day, or a combined oral contraceptive containing 30 mg ethinylestradiol and 150 mg levonorgestrel, for six cycles. Each cycle comprised 3 weeks of use of the ring or the pill followed by 1 ring- or pill-free week. The following parameters were measured at baseline and at the end of cycles 3 and 6: carbohydrate metabolism (glucose, insulin, glycosylated hemoglobin); adrenal function (total cortisol, cortisol binding globulin, dehydroepiandrosterone sulfate); thyroid function (thyroid stimulating hormone, free thyroxine). Results Small and similar increases in insulin were seen in both groups. Concentrations of cortisol binding globulin and total cortisol rose significantly less during ring use than during combined oral contraceptive use (cycle 3, p = 0.0002; cycle 6, p 5 0.0001). Levels of dehydroepiandrosterone sulfate did not change in either group. Thyroid stimulating hormone levels increased significantly more in the ring group at cycle 3 (p = 0.0016) but free thyroxine levels were unchanged in both groups. Conclusions Both the vaginal ring and the oral contraceptive have no clinically relevant effects on carbohydrate metabolism, adrenal or thyroid function. KEY WORDS NuvaRing, Carbohydrate, Adrenal, Thyroid, Vaginal ring, Contraceptive, Safety ........................................................................................................................................................................................................... Correspondence: Dr T. O. M. Dieben, Clinical Development Department, NV Organon, PO Box 20, 5340 BH Oss, The Netherlands # 2004 European Society of Contraception DOI: 10.1080/13625180400007199 MS 4306 Received 30-09-03 Revised 5-02-04 Accepted 15-02-04 NuvaRing safety Duijkers et al. Eur J Contracept Reprod Health Care Downloaded from informahealthcare.com by University of Groningen on 01/05/11 For personal use only. INTRODUCTION The main advantages of vaginal administration of contraceptive steroids are the avoidance of gastrointestinal absorbance and hepatic first-pass metabolism, and the continuous release of steroids, resulting in stable concentrations. These factors offer the potential of achieving acceptable contraceptive efficacy and good cycle control with lower doses of steroids, thus minimizing steroid-associated adverse events. The first contraceptive ring on the market in the United States and Europe is NuvaRing1 (NV Organon, Oss, The Netherlands), a flexible, soft vaginal ring with an outer diameter of 54 mm and a cross-section of 4 mm. The ring releases 120 mg of the progestogen etonogestrel (ENG) and 15 mg of the estrogen ethinylestradiol (EE) per day; ENG is the active metabolite of desogestrel. Each ring is used continuously for 3 weeks, followed by a 1-week ring-free period. The ring has good contraceptive efficacy with a high safety margin and excellent cycle control1-5. In the early days of oral contraception, studies reported that combined oral contraceptives may be associated with alterations in carbohydrate metabolism, particularly the generation of insulin resistance6. Alterations in carbohydrate metabolism, mainly elevated plasma glucose levels and insulin levels, are recognized as risk factors for cardiovascular disease7. However, the commonly used, low-dose, oral contraceptives containing levonorgestrel (LNG) or desogestrel have been demonstrated to have only minor effects, if any, on carbohydrate metabolism8-12. With regards to adrenal function, previous findings have shown that an increase in cortisol levels during oral contraceptive use seems to be dependent on the dose of EE13. Most studies on the effects of oral contraceptives on thyroid function have revealed an increase in free thyroxine (T4), while levels of thyroid stimulating hormone (TSH) were increased or unchanged13. The minor changes in thyroid parameters also appear to be caused by EE, as treatment with desogestrel- or levonorgestrel-only preparations did not significantly affect TSH or T4 levels14. Assessment of the effects on carbohydrate metabolism during use of the vaginal ring compared with a commonly used oral contraceptive was required. Therefore, the objective of this study was to compare changes in carbohydrate metabolism, adrenal and 132 thyroid function during use of the vaginal ring with those of oral LNG 150 mg/EE 30 mg (LNG/EE) in healthy women. METHODS This open-label, randomized, comparative trial was performed in three centers in The Netherlands, England and Scotland between September 1998 and July 1999. The study was performed in accordance with the Declaration of Helsinki, International Conference for Harmonization Guidelines for Good Clinical Practice and with local ethical committee approval. All subjects provided informed, written consent prior to inclusion in the study. Study population The study planned to recruit 80 women between 18 and 40 years old, at risk of pregnancy and asking for contraception. The women were required to have a menstrual cycle with a usual length of between 24 and 35 days ( + 3 days) and a body mass index of 5 18 and 4 29 kg/m2. Subjects were excluded from the study if they had any abnormal findings of clinical relevance in carbohydrate metabolism, adrenal or thyroid function. Other exclusion criteria included contraindications to contraceptive steroid use; previous use of an injectable hormonal method of contraception (within 6 months) or any other hormonal contraceptive (within 2 months); genital prolapse; vaginitis or a bleeding cervical erosion; a Papanicolaou (PAP) class III-V cervical smear result; severe or chronic constipation; dysparunia or other coital problems; use of any drugs that interfere with the metabolism of sex steroids; a history of drug or alcohol abuse. Women already taking oral contraceptives were required to have two 'wash-out' cycles and use barrier methods before the start of treatment. Study design Enrolled subjects were randomized according to a randomization list in a 1 : 1 ratio using a block size of four to receive either the vaginal ring or a combined oral contraceptive containing LNG 150 mg/EE 30 mg (Microgynon1 30, Schering AG, Berlin, Germany). NuvaRing delivers 120 mg of ENG and 15 mg of EE The European Journal of Contraception and Reproductive Health Care Eur J Contracept Reprod Health Care Downloaded from informahealthcare.com by University of Groningen on 01/05/11 For personal use only. NuvaRing safety Duijkers et al. daily. The total treatment period of the trial was six consecutive cycles of 28 days. Rings were inserted on day 5 of the menstrual cycle and left in place for 3 weeks, then removed for 1 week; a new ring was used for each cycle. Women were instructed to use a barrier form of contraception (such as a condom without spermicide) for the first 7 days of ring use during the first cycle. All subjects received written and verbal instructions on ring use and removal. Prior to the first ring insertion or pill intake, a urine home pregnancy test was performed and the subject only proceeded with the study if the result was negative. Subjects in the combined oral contraceptive group took one tablet daily for 3 weeks, starting on the first day of the menstrual cycle. This was followed by a 1week pill-free period; the cycle was then repeated. In both groups, dosing compliance was assessed using diary cards. Subjects in the group using the vaginal ring were asked to record the number of hours of ring use per day, and the dates of new ring insertions and removals. In the combined oral contraceptive group, subjects used diary cards to record whether a pill was taken or not. London, UK. The methods used for the assessment of the various parameters are given in Table 1. Carbohydrate metabolism Carbohydrate metabolism parameters were assessed at screening (during the second half of the menstrual cycle preceding the first treatment period; baseline assessment), and during the last week of treatment in cycles 3 and 6 (i.e. days 15-21). When providing blood samples for carbohydrate metabolism assessments, subjects were requested to follow an unrestricted carbohydrate-rich diet for 3 days. Subjects were then asked to fast (except for one glass of water) for at least 10 h prior to sampling. Subjects were to refrain from vigorous exercise prior to the blood samples being taken and from smoking during the period of the test. The glucose tolerance test was used to assess carbohydrate metabolism. After oral glucose loading (75 g), glucose was assessed at 0, 30, 60, 90, 120 and 180 min. Oral glucose tolerance was analyzed using the (unadjusted) area under the curve (AUC) over the 3-h sampling period (AUC180) for glucose and insulin. The incremental AUC was also calculated; this is the area between the profile of the oral glucose tolerance and the fasting level; consequently it represents the AUC corrected for the fasting level15. It is defined as Incremental AUC = AUC180 7 180 x fasting concentration. Prior to glucose loading, the fasting glycosylated hemoglobin (HbA1c) concentration was assessed by taking one blood sample at 0 min. Glycosylated hemoglobin reflects the mean glucose levels over the Study assessments Blood samples were immediately processed to separate serum and plasma. For all tests, serum was used, except for the glucose samples. All samples were stored at room temperature except those used for insulin and cortisol determination, which were frozen at 7 208C and shipped on dry ice. Analyses were performed by UCT International, Central Laboratory Services, Table 1 Methods used for the assessment of carbohydrate metabolism and adrenal and thyroid function Parameter Glucose Insulin Glycosylated hemoglobin Total cortisol Cortisol binding globulin Dehydroepiandrosterone sulfate Thyroid stimulating hormone Free thyroxine Unit mmol/l mIU/l % nmol/l mg/l mmol/l mIU/l pmol/l Method hexokinase endpoint assay RIA HPLC fast protein immunoassay HPLC/RIA RIA microparticle enzyme immunoassay microparticle enzyme immunoassay RIA, radioimmunoassay; HPLC, high performance liquid chromatography The European Journal of Contraception and Reproductive Health Care 133 NuvaRing safety Duijkers et al. previous 2-6 weeks. Consequently, it provides a longer-term indication of carbohydrate metabolism. Eur J Contracept Reprod Health Care Downloaded from informahealthcare.com by University of Groningen on 01/05/11 For personal use only. Adrenal function Parameters of adrenal function were assessed at screening (blood sampling was performed on days 17-21 of the menstrual cycle preceding the first treatment period; baseline assessment) and during the last week of treatment in cycles 3 and 6 (days 15-21). All blood samples were taken between 7.00 and 10.00 and analyses were performed by UCT International. Total cortisol, cortisol binding globulin (CBG) and dehydroepiandrosterone sulfate (DHEAS) concentrations were determined. Thyroid function Parameters of thyroid function were assessed at the same time-points as adrenal function. All blood samples were taken between 7.00 and 10.00. Thyroid stimulating hormone and free thyroxine concentrations were measured. At screening, subjects provided a medical and gynecological history, and underwent a physical and gynecological examination (including cervical cytology) and assessment of routine laboratory parameters. Levels of b-human chorionic gonadotropin were assessed after treatment to confirm the absence of pregnancy. Vital signs were assessed at baseline, at the end of cycle 3 and post-treatment. Any adverse events that occurred during the study were recorded. If a subject withdrew from the study, her reason for withdrawal was recorded. variable. Analyses of covariance adjusted for baseline values were used to estimate treatment differences. A Bonferroni correction was applied as multiple tests were performed; differences were only considered significant at the level of p 4 0.0026. The analysis of routine safety parameters was restricted to descriptive statistics. RESULTS Subject disposition A total of 85 subjects were randomized, 44 to the NuvaRing group and 41 to the combined oral contraceptive group. Eight women withdrew from the trial before starting study medication; in six women, this was due to a clinically relevant abnormal laboratory variable. Seventy-seven subjects started treatment (37 in the ring group and 40 in the combined oral contraceptive group) and comprised the ITT population. During the trial, six women in the ring group discontinued, one due to adverse events and five due to non-medical reasons. Two women in the combined oral contraceptive group withdrew, one due to adverse events and one due to non-medical reasons (Figure 1). During the study, three subjects had major protocol violations, making the PP population 74 subjects: 35 in the ring group and 39 in the combined oral contraceptive group. There were no differences between the analyses of the ITT and the PP population, so the ITT results are presented. There were no pregnancies during the study. The baseline demographics (Table 2) and the baseline values for carbohydrate and adrenal and thyroid parameters (Table 3) were comparable in both groups. Statistical analysis Analyses of carbohydrate and adrenal and thyroid function parameters were performed on the intent-totreat (ITT) population (defined as all enrolled women who started treatment) and the per-protocol (PP) population (defined as all treated women without major protocol violations). For all variables, summary statistics, changes from baseline and relative changes from baseline were calculated for each treatment group. The ratio (NuvaRing to combined oral contraceptive) of the geometric mean concentrations (adjusted for baseline) was also calculated for each 134 Carbohydrate metabolism The median AUC of glucose did not alter substantially from baseline in either group during the study (Figure 2); there were no significant differences between the groups. Similarly, the incremental AUC of glucose did not change substantially relative to baseline in cycle 3 (NuvaRing, 1%; combined oral contraceptive, 1.5%), or cycle 6 (NuvaRing, 1.5%; combined oral contraceptive, 1.1%). In both groups, the median AUC of insulin increased slightly relative to baseline (Figure 2). The The European Journal of Contraception and Reproductive Health Care NuvaRing safety Duijkers et al. 85 subjects randomized COC group 41 subjects NuvaRing group 44 subjects Non-treated 1 subject Eur J Contracept Reprod Health Care Downloaded from informahealthcare.com by University of Groningen on 01/05/11 For personal use only. Non-treated 7 subjects Started treatment 40 subjects Started treatment 37 subjects Discontinued 6 subjects Discontinued 2 subjects Completed 31 subjects 1 due to adverse events 5 due to non-medical or ring related reasons Completed 38 subjects 1 due to adverse events 1 due to non-medical reasons Figure 1 Subject disposition. COC, combined oral contraceptive Table 2 Demographic characteristics (intent-to-treat [ITT] population). Continuous variables are presented as mean + standard deviation Glycosylated hemoglobin remained close to baseline level (Figure 2), with no significant differences between the treatment groups. NuvaRing (n = 37) COC (n = 40) Age (years) 26.5 + 5.9 27.2 + 6.2 Race (%) Asian Black Caucasian Other 35 (94.6) 2 (5.4) 1 (2.5) 1 (2.5) 37 (92.5) 1 (2.5) Body mass index (kg/m2) Nulligravid (%) Nulliparous (%) 23.0 + 2.6 23 (62.2) 25 (67.6) 23.7 + 2.3 25 (62.5) 27 (67.5) COC, combined oral contraceptive ratios of the geometric means between the two groups were 86.2% and 88.2% in cycles 3 and 6, respectively; there were no significant differences between the groups. Larger relative increases in the median incremental AUC of insulin, compared with baseline, were observed. At cycle 3, a median increase of 92% was noted in the NuvaRing group and 151% in the combined oral contraceptive group. At cycle 6, the median relative increases were lower, 31% in the NuvaRing group and 88% in the combined oral contraceptive group. The differences between the groups were not significant at either cycle. Adrenal function CBG concentrations increased in both groups relative to baseline; the increases were smaller in the NuvaRing than in the combined oral contraceptive group (Figure 3). The ratios of the geometric means between the groups (NuvaRing to combined oral contraceptive) were 83.5% at cycle 3 and 78.1% at cycle 6. The mean CBG level (adjusted for baseline) was significantly lower in the NuvaRing than in the combined oral contraceptive group at cycle 3 (p = 0.0002) and cycle 6 (p 5 0.0001). In both groups, the median concentration of total cortisol also increased from baseline (Figure 3); the increase was smaller in the NuvaRing group than in the combined oral contraceptive group. This was reflected in the ratio of the geometric means, 82.8% at cycle 3 and 81.0% at cycle 6. The difference between the groups was significant at cycle 6 (p = 0.001), but not at cycle 3. However, for the PP population, the difference was significant at both cycle 3 (p = 0.0022) and cycle 6 (p = 0.0009). The median level of DHEAS relative to baseline decreased in both groups (Figure 3). There were no significant differences between the groups. The European Journal of Contraception and Reproductive Health Care 135 NuvaRing safety Duijkers et al. Table 3 Median baseline values for parameters of carbohydrate metabolism and adrenal and thyroid function (intent-totreat [ITT] population) NuvaRing Median n Median Carbohydrate metabolism AUC of glucose (hr!mmol/l) AUC of insulin (hr!pmol/l) Incremental AUC of glucose Incremental AUC of insulin Glycosylated hemoglobin (HbA1c) (%) 35 36 35 36 37 16.65 766 0.48 573 5.3 39 39 39 39 40 16.30 854 0.13 673 5.3 Adrenal function Total cortisol (nmol/l) Corticosteroid binding globulin (nmol/l) Dehydroepiandrosterone sulfate (mmol/l) 37 37 37 528 790 5.34 39 40 40 523 782 6.00 Thyroid function Thyroid stimulating hormone (mU/l) Free thyroxine (pmol/l) 37 37 1.57 13.7 40 40 1.54 13.8 COC, combined oral contraceptive; AUC, area under the curve 100 NuvaRing Median percentage change Eur J Contracept Reprod Health Care Downloaded from informahealthcare.com by University of Groningen on 01/05/11 For personal use only. n COC COC 80 60 40 20 0 Cycle 3 Cycle 6 AUC glucose Cycle 3 Cycle 6 AUC insulin Cycle 3 Cycle 6 HbA1c Figure 2 Median percentage change from baseline in carbohydrate metabolism parameters, after three and six cycles of treatment with NuvaRing or a levonorgestrel 150 mg/ethinylestradiol 30 mg combined oral contraceptive (intent-to-treat [ITT] group). COC, combined oral contraceptive; AUC, area under the curve; HbA1c, glycosylated hemoglobin Thyroid function Relative to baseline, median TSH levels increased in both groups at cycles 3 and 6 (Figure 4); the increase was larger in the NuvaRing group than in the combined oral contraceptive group. Consequently, 136 this is reflected in the ratio of the geometric means: 128.3% at cycle 3 and 110.2% at cycle 6. The mean TSH level (adjusted for baseline) was significantly higher in the NuvaRing group than in the combined oral contraceptive group at cycle 3 (p = 0.0016), but not at cycle 6, or for the PP population at either time point. The European Journal of Contraception and Reproductive Health Care NuvaRing safety Duijkers et al. 120 NuvaRing Median percentage change COC 80 60 40 20 0 -20 -40 -60 Cycle 3 Cycle 6 CBG Cycle 3 Cycle 6 Total cortisol Cycle 3 Cycle 6 DHEAS Figure 3 Median percentage change in adrenal function parameters, compared with baseline, after three and six cycles of treatment with NuvaRing or a levonorgestrel 150 mg/ethinylestradiol 30 mg combined oral contraceptive (intent-totreat [ITT] group). COC, combined oral contraceptive; CBG, cortisol binding globulin; DHEAS, dehydroepiandrosterone sulfate 100 NuvaRing Median percentage change Eur J Contracept Reprod Health Care Downloaded from informahealthcare.com by University of Groningen on 01/05/11 For personal use only. 100 COC 80 60 40 20 0 Cycle 3 Cycle 6 TSH Cycle 3 Cycle 6 Free thyroxine Figure 4 Median percentage change in thyroid function parameters, compared with baseline, after three and six cycles of treatment with NuvaRing or a levonorgestrel 150 mg/ethinylestradiol 30 mg combined oral contraceptive (intent-totreat [ITT] group). COC, combined oral contraceptive; TSH, thyroid stimulating hormone Median free thyroxine levels did not differ significantly from baseline (Figure 4) and there were no significant differences between the groups. Tolerability Fifteen women (40.5%) in the NuvaRing group and 15 women in the LNG/EE group (37.5%) experi- enced adverse events that were considered at least possibly drug-related by the investigator (Table 4). No serious adverse events were reported during the study. One subject from each group discontinued the study due to an adverse event, vaginal discomfort in the NuvaRing group and increased appetite in the combined oral contraceptive group; both events were considered by the investigator to be treatment-related. The European Journal of Contraception and Reproductive Health Care 137 NuvaRing safety Duijkers et al. Table 4 Number of women with at least one adverse event during treatment (considered by the investigator to be at least possibly drug-related). Data presented are where events occurred in at least two women per group Eur J Contracept Reprod Health Care Downloaded from informahealthcare.com by University of Groningen on 01/05/11 For personal use only. Adverse event Nausea Breast tenderness Abdominal pain Headache Leukorrhea Nervousness Weight increase Dizziness Increased glucocorticoids Vaginitis Depression NuvaRing (n = 37) COC (n = 40) 6 2 2 2 2 2 2 1 1 1 0 2 5 1 1 0 0 0 2 2 2 2 COC, combined oral contraceptive. During the study, blood pressure showed no substantial changes from baseline in either group. The mean change in body weight in both groups from baseline at cycles 3 and 6 was small; there was a slight decrease in both the NuvaRing group (cycle 3, 7 0.75 + 1.87 kg; cycle 6, 7 0.49 + 2.42 kg) and the combined oral contraceptive group (cycle 3, 7 0.40 + 2.06 kg; cycle 6, 7 0.46 + 2.34 kg). Therefore, the ring had no relevant effect on blood pressure or body weight. The assessment of routine laboratory parameters, physical and pelvic examinations did not show any clinically relevant abnormalities, or changes, compared with baseline. DISCUSSION The findings from this study show that both NuvaRing and the LNG-containing combined oral contraceptive had little effect on carbohydrate metabolism over six cycles of use. The results from the oral glucose tolerance test indicate that both NuvaRing and the combined oral contraceptive had little or no effect on the plasma glucose AUC. There was a slight increase in insulin AUC after oral glucose loading compared with baseline in both groups. Similar changes have been reported previously for other LNG- and desogestrel-containing combined oral contraceptives9-11 and are thought to be due to the progestogen component of the contraceptive11,16. The 138 data suggest that a slight hyperinsulinemia may occur during the use of both contraceptives. The reasons for this are currently unclear, although it has been suggested that it is due to increased insulin resistance. This might possibly be attributable to a decreased affinity of insulin to the insulin receptor, or to a decreased amount of insulin receptors17,18. It seems unlikely that this slight increase would have any clinically relevant, long-term effects on carbohydrate metabolism. This is supported by the absence of any difference from baseline in HbA1c levels, an indicator of long-term glucose metabolism. The increases in the insulin AUC and incremental insulin AUC were slightly greater in the combined oral contraceptive group than in the NuvaRing group; however, the difference was not significant. Use of the vaginal ring or the combined oral contraceptive resulted in an increase in CBG levels compared with baseline. However, the mean increase was significantly lower in the ring group than in the combined oral contraceptive group. This increase in CBG levels has been commonly reported in women using various types of combined oral contraceptive19-21. It is due to an estrogen-dependent increase in hepatic CBG synthesis and is not counteracted by progestogen activity20,22. Consequently, the lower level during NuvaRing use is likely to be due to the lower dosage of EE (15 mg/day) released by NuvaRing compared with the combined oral contraceptive (30 mg/day). Total cortisol levels were increased in each group compared with baseline. This is because an increase in CBG levels is followed by a rise in total cortisol. The mean cortisol levels were significantly lower in the NuvaRing group than in the combined oral contraceptive group, consistent with the difference in the CBG concentrations between the groups. TSH levels were increased in both groups compared with baseline. During cycle 3, the mean TSH level was significantly higher in the NuvaRing group compared with the combined oral contraceptive group; at cycle 6, however, there was no significant difference between the groups. Consequently, it seems that the difference noted at cycle 3 is transient and not likely to be clinically relevant. This is supported by the reported absence of any significant effects on TSH levels by lowdose, desogestrel-containing combined oral contraceptives23,24. No alterations in free thyroxine levels were noted in either group, indicating that NuvaRing had no clinically relevant effect on thyroid function. The European Journal of Contraception and Reproductive Health Care Eur J Contracept Reprod Health Care Downloaded from informahealthcare.com by University of Groningen on 01/05/11 For personal use only. NuvaRing safety The relatively low incidence of treatment-related adverse events in both groups shows that both contraceptives were well tolerated. Furthermore, NuvaRing has a neutral effect on both body weight and blood pressure. These findings are in agreement with those from larger and longer-term NuvaRing studies4. In conclusion, this study shows that both contraceptives have no clinically relevant effects on carbohydrate metabolism; only insulin secretion was slightly increased during use. Both contraceptives produced little alteration in adrenal or thyroid function. Duijkers et al. ACKNOWLEDGEMENT We are grateful to E. van der Meulen for the statistical analysis. Conflict of interest T.O.M.D. is an employee of NV Organon. Source of funding This study was supported by NV Organon, Oss, The Netherlands. REFERENCES 1. Timmer CJ, Mulders TMT. Pharmacokinetics of etonogestrel and ethinylestradiol released from a combined contraceptive vaginal ring. Clin Pharmacokinet 2000;39:233-42 2. Mulders TMT, Dieben TOM. Use of the novel combined contraceptive vaginal ring NuvaRing for ovulation inhibition. Fertil Steril 2001;75:865-70 3. Mulders TMT, Dieben TOM, Bennink HJT. Ovarian function with a novel combined contraceptive vaginal ring. Hum Reprod 2002;17:2594-9 4. Dieben TOM, Roumen FJME, Apter D. 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The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism. N Engl J Med 1990;323:1375-81 16. Chez RA. Metabolic aspects of the new low-dose oral contraceptives. Int J Fertil 1989;34(Suppl):50-4 17. Spellacy WN. Carbohydrate metabolism during treatment with estrogen, progestogen, and low-dose oral contraceptives. Am J Obstet Gynecol 1982;142:732-4 18. De Pirro R, Forte F, Bertoli A, et al. Changes in insulin receptors during oral contraception. J Clin Endocrinol Metab 1981;52:29-33 19. van der Vange N, Blankenstein MA, Kloosterboer HJ, et al. Effects of seven low-dose combined oral contraceptives on sex hormone binding globulin, corticosteroid binding globulin, total and free testosterone. Contraception 1990;41:345-52 20. Hammond GL, Langley MS, Robinson PA, et al. Serum steroid binding protein concentrations, distribution of progestogens, and bioavailability of testosterone during treatment with contraceptives containing desogestrel or levonorgestrel. Fertil Steril 1984;42:44-51 The European Journal of Contraception and Reproductive Health Care 139 NuvaRing safety Duijkers et al. 23. Kuhl H, Gahn G, Romberg G, et al. A randomized crossover comparison of two low-dose oral contraceptives upon hormonal and metabolic serum parameters. II. Effects upon thyroid function, gastrin, STH, and glucose tolerance. Contraception 1985;32:97-107 24. Penttila IM, Makkonen M, Castren O. Thyroid function during treatment with a new oral contraceptive combination containing desogestrel. Eur J Obstet Gynecol Reprod Biol 1983;16:269-74 Eur J Contracept Reprod Health Care Downloaded from informahealthcare.com by University of Groningen on 01/05/11 For personal use only. 21. Jung-Hoffmann C, Kuhl H. Interaction with the pharmacokinetics of ethinylestradiol and progestogens contained in oral contraceptives. Contraception 1989; 40:299-312 22. Humpel M, Tuber U, Kuhnz W, et al. Comparison of serum ethinyl estradiol, sex-hormone-binding globulin, corticoid-binding globulin and cortisol levels in women using two low-dose combined oral contraceptives. Horm Res 1990;33:35-9 140 The European Journal of Contraception and Reproductive Health Care