Determining the Exposure Threshold for Levonorgestrel Efficacy Using an Integrated Model Based Meta-Analysis Approach.

Combined oral contraceptive pills are the most commonly used hormonal contraceptives for the prevention of unintended pregnancies in United States. They consist of a progestin (e.g., levonorgestrel (LNG)) and an estrogen component, typically ethinyl estradiol (EE). In addition to adherence issues, drug-drug interactions (DDIs) and obesity (women with body mass index (BMI) ≥ 30 kg/m2 ) are prime suspects for decreased LNG efficacy. Therefore, we developed an integrated physiologically-based pharmacokinetic modeling and model-based meta-analysis approach to determine LNG's efficacy threshold concentrations and to evaluate the impact of DDIs and obesity on the efficacy of LNG-containing hormonal contraceptives (HCs). Based on this approach, co-administration of strong CYP3A4 inducers and LNG-containing HCs (LNG150: LNG 150 µg + EE 30 µg and LNG100: LNG 100 µg + EE 20 µg) resulted in a predicted clinically relevant decrease of LNG plasma exposure (women with BMI < 25 kg/m2 : 50-65%; obese women: 70-75%). Following administration of LNG150 or LNG100 in the presence of a CYP3A4 inducer, there was an increase in mean Pearl Index of 1.2-1.30 and 1.80-2.10, respectively, in women with BMI < 25 kg/m2 (incidence rate ratios (IRRs): 1.7-2.2), whereas it ranged from 1.6-1.80 and 2.40-2.85 in obese women (IRR: 2.2-3.0), respectively. Our results suggest that the use of backup or alternate methods of contraception is not necessarily required for oral LNG + EE formulations except within circumstances of both obesity and strong CYP3A4 inducer concomitance following administration of LNG100.

Low dose combined oral contraceptives induced thrombotic anterior wall myocardial infarction: a case report.

BACKGROUND: Combined oral contraceptive pills are associated with an established risk for venous thrombosis; however, their risk for arterial thrombosis remains uncertain, especially with the development of low dose new generations of combined oral contraceptive. Arterial thrombosis is less likely to occur with the use of oral contraceptive pills in the absence of cardiovascular risk factors. CASE PRESENTATION: We report a 35-year old female with no cardiovascular risk factors who presented with thrombotic anterior wall myocardial infarction 6 months after using a third generation low dose combined oral contraceptive pills (Marvelon; ethinylestradiol 30 mcg and desogestrel 150 mcg). CONCLUSION: Third generation low dose combined oral contraceptives may lead to myocardial infarction in young women, even in the absence of other cardiovascular risk factors.

Acute pancreatitis secondary to oral contraceptive-induced hypertriglyceridemia: a case report.

Hypertriglyceridemia is the third most common cause of acute pancreatitis. Among the causes that lead to secondary hypertriglyceridemia, the use of contraceptive agents is the main reason to be assessed in young women. We report a case of a 31-year-old woman who had suffered two acute pancreatitis episodes secondary to hypertriglyceridemia. In the investigation, the previous medical team indicated a genetic screening before ruling out all secondary causes. LPL, apo CII and apo AV genes were negative for mutations. In the first appointment with us, the patient reported the use of a contraceptive agent for about 2 years. She was instructed to discontinue the drug. After one year of follow-up, her serum triglycerides are within the normal range and a copper intrauterine device was the method chosen by the patient for contraception.

Norethindrone acetate versus extended-cycle oral contraceptive (Seasonique®) in the treatment of endometriosis symptoms: A prospective open-label comparative study.

INTRODUCTION: This patient preference prospective study was designed to compare patients' satisfaction in women with endometriosis treated either by an extended-cycle oral contraception (OC) or by norethindrone acetate (NETA). METHODS: This patient preference prospective study included women of reproductive age with endometriosis. Patients were submitted to one of the following 12 months' treatments: Group A, continuous oral treatment with NETA (2.5 mg/day) and Group B, a 91-day extended-cycle OC (LNG/EE 150/30 mcg for 84 days and EE 10 mcg for 7 days). Patient satisfaction was the primary endpoint. RESULTS: There was no statistically significant difference in the rate of satisfied patients at 12-month follow up between the two study groups, 82.2% and 68.4% in Group A and Group B respectively (p = 0.143). At 6 and 12-months, there was a significant amelioration in the intensity of all pain in both groups. The median number of days of unscheduled bleeding during the first cycle was significantly higher in Group B compared to Group A. CONCLUSION: Both NETA and extended-cycle OC are effective in treating pain symptoms related to endometriosis. Extended-cycle OC may cause more unscheduled bleeding, but the rate of satisfaction for those who completed the treatment was similar in the two groups.

Hormonal contraception: venous and arterial disease.

OBJECTIVES: The aim of this review was to evaluate whether the biological and epidemiological evidence is concordant in suggesting that levonorgestrel (LNG)-based hormonal contraceptives (HCs) are safer than newer formulations with regard to their effect on the cardiovascular system. METHODS: A narrative review was carried out of the modification of risk factors for venous thromboembolism (VTE) and arterial diseases induced by different HCs. Limits and concordance with epidemiological data were addressed. RESULTS: The data indicate general concordance between modifications of risk factors and epidemiology of VTE, with LNG-based HCs showing lower risk compared with most new formulations. Evidence for drospirenone (DRSP)-containing HCs is conflicting. LNG-based HCs are less favourable than HCs containing non-androgenic progestins, particularly DRSP, on risk factors for arterial events. Epidemiological studies do not consistently show a difference in arterial disease outcomes between different HCs; however, by evaluating women up to the age of 50, they do not take into consideration the time lag necessary for atherosclerosis to develop. CONCLUSIONS: As a consequence of the different risk factors involved, and the different time lags between HC use and the manifestation of VTE or arterial diseases, the available epidemiological data do not give a reliable estimate of the cardiovascular risk associated with the use of different HCs. LNG-based HCs are safer than newer HCs as regards VTE risk, but biological data indicate that they are less favourable, particularly than HCs containing DRSP, on risk factors for atherosclerosis. Because of the limits of actual epidemiological evidence regarding arterial disease, modifications of arterial risk factors should be taken into consideration when considering individual long-term safety of HC use.

Effect of BMI and body weight on pregnancy rates with LNG as emergency contraception: analysis of four WHO HRP studies.

OBJECTIVE: To estimate the effect of increased body weight and body mass index (BMI) on pregnancy rates with levonorgestrel (LNG) 1.5mg used as emergency contraception (EC). METHODS: The study reviewed data from 6873 women in four WHO-HRP randomized trials on EC conducted between 1993 and 2010. Participants took either 1.5mg of LNG as a single dose or in two doses 12h apart, up to 120h of unprotected intercourse. Contraceptive efficacy (pregnancy rates) at different weight and BMI categories was evaluated. RESULTS: Overall pregnancy rate was low at 1.2%. Pregnancy rates were also low in women weighing over 80kg (0.7%) and who were obese (BMI over 30kg/m2) (2.0%). The pooled analyses for pregnancy demonstrated that BMI over 30kg/m2 decreased efficacy significantly (odds ratio 8.27, 95% confidence interval = 2.70-25.37) when compared to women in lower BMI categories, mainly influenced by pregnancies in obese women from one study site. Sensitivity analyses excluding that site showed that obesity was no longer a risk factor; however, the other studies included too few obese women in the sample to exclude a substantial decrease in efficacy. CONCLUSIONS: Pregnancy rates with use of LNG 1.5mg for EC were low at less than 3% across different weight and BMI categories. Pooled analyses showed an increase in pregnancy rates among obese women (BMI more than 30kg/m2) compared to women with normal BMI levels, influenced by pregnancies all coming from one study site. IMPLICATIONS: Access to LNG as EC should still be promoted to women who need them, and not be restricted in any weight or BMI category, with additional attention for counselling and advice for obese women.

Oral contraceptives caused venous sinus thrombosis complicated with cerebral artery infarction and secondary epileptic seizures: A case report and literature review.

RATIONALE: Venous sinus thrombosis is a special type of cerebrovascular disease. Its incidence is low and its symptoms are lack of specificity. And its early diagnosis and treatment are very difficult. PATIENT CONCERNS: This paper reported a rare case of a 43-year-old female who presented with cerebral venous thrombosis (CVT) complicated with cerebral artery infarction and secondary epileptic seizures due to oral contraceptives. DIAGNOSES: The final diagnosis was intracranial venous sinus thrombosis, acute cerebral infarction in the left parietal lobe, intracranial hypertension syndrome, and continuous epilepsy. INTERVENTIONS: The patient recovered well after active treatment. OUTCOMES: Three months after discharge, the muscle strength of the right limb of the patient was significantly increased, and no recurrence of neurological symptoms occurred. LESSONS: In conclusion, early diagnosis, correct evaluation, and standard treatment are still important challenges for CVT. Active treatment is recommended.

Impact of Contraceptive Type on Sexual Desire of Women and of Men Partnered to Contraceptive Users.

INTRODUCTION: Research investigating the impact of contraceptive use on sexual desire has produced mixed results. This scholarship also has had inconsistent methodology, with some studies not separating contraceptive types and others lacking non-hormonal comparison groups. Relationship context of contraceptive use and sexual behavior also have not been well represented. AIMS: To investigate the impact of contraceptive type on sexual desire in women and in men who are partnered to contraceptive-using women. METHODS: In two separate studies we examined the impact of contraceptives on the sexual desire of women currently using contraceptives and men partnered to women using contraceptives. The first study examined the impact of contraceptive type on sexual desire in women and in men partnered to contraceptive users in relationships of different lengths. The second study examined this impact in heterosexual couples in long-term relationships. MAIN OUTCOME MEASURES: Solitary and dyadic sexual desire as measured by the Sexual Desire Inventory and contraceptive type as categorized into three types: oral hormonal contraceptive, other hormonal contraceptive, and non-hormonal contraceptive. RESULTS: Contraceptive type significantly affected solitary and dyadic desire. Women on non-hormonal contraceptives reported higher solitary sexual desire than women on other hormonal contraceptives. Women on oral hormonal contraceptives reported significantly higher dyadic sexual desire than women on non-hormonal contraceptives. In male partners of female contraceptive users, solitary and dyadic sexual desires were not affected by partner contraceptive type. In the multivariate model, relationship length and age were stronger predictors of contraceptive type than was solitary or dyadic sexual desire. At the couple level, contraceptive type also was not related to solitary or dyadic sexual desire in men and women. CONCLUSION: Contraceptive type can affect solitary and dyadic sexual desire in women; however, contextual factors seem to be stronger predictors of sexual desire for long-term coupled women and men than contraception type.

Efficacy of combined hormonal vaginal ring in comparison to combined hormonal pills in heavy menstrual bleeding.

OBJECTIVE: To compare the efficacy, acceptability and compliance of combined hormonal vaginal ring (CVR), with combined hormonal pills (CHP) in patients with heavy menstrual bleeding (HMB). STUDY DESIGN: This prospective study was conducted in 50 women with HMB in age group of 25-40 years. Patients were divided in two groups of 25 each and followed for six treatment cycles. In each group, cycle comprised of three weeks of CVR (releases 15µg of EE and 120µg of the etonogestrel per day) or CHP (containing 30µgm of EE and 150µgm of LNG) use, followed by one ring or pill free week. After each cycle, patients were evaluated about the amount of blood loss and duration of bleeding by the pictoral blood assessment chart (PBAC), early bleeding (EWB), continued bleeding (CWB), intermenstrual bleeding, intended bleeding, compliance, and user acceptability. The collected data were analyzed using the Chi square test, t-test and ANOVA test. RESULT: Reduction in PBAC score for CVR (70.73%) and CHP group (70.02%), duration of bleeding and incidence of EWB was comparable among the two groups. The incidence of intermenstrual bleeding was lower in CVR than in CHP group in cycle 3 and 4 with significant p value. The incidence of CWB was significantly lower and the incidence of intended bleeding pattern in CVR group was significantly higher in cycle 3, 4, 5 and 6, signifying better cycle control. Compliance was also higher in CVR (88%) than CHC (75.33% of all cycles). CONCLUSION: This trial suggests that both the CVR and CHP are very effective short-term treatments for HMB in reproductive age group. However, women had better cycle control and compliance with CVR. This may be an attractive option among the wide variety of medications used to treat HMB.

A 12-month multicenter, randomized study comparing the levonorgestrel intrauterine system with the etonogestrel subdermal implant.

OBJECTIVE: To compare the levonorgestrel intrauterine system (LNG-IUS 8), which has an average levonorgestrel release rate of ∼8 µg/24 hours during the first year (total levonorgestrel content 13.5 mg; Jaydess/Skyla), with the etonogestrel (ENG) subdermal implant (total content, 68 mg) with regard to the 12-month discontinuation rate (primary outcome). DESIGN: Randomized, open-label, phase III study. SETTING: Thirty-eight centers in six European countries. PATIENT(S): Study population of 766 healthy nulliparous and parous women aged 18-35 years. INTERVENTION(S): The LNG-IUS 8 or the ENG implant. MAIN OUTCOME MEASURE(S): Discontinuation rate, by treatment group, at Month 12. RESULT(S): The 12-month discontinuation rates were 19.6% and 26.8% in the LNG-IUS 8 and ENG implant groups, respectively. The -7.2% difference was statistically significant (95% confidence interval -13.2%, -1.2%). Fewer women in the LNG-IUS 8 group than in the ENG implant group discontinued because of increased bleeding (3.2% vs. 11.3%) or adverse events (14.3% vs. 21.8%). At 12 months, more women in the LNG-IUS 8 group than in the ENG implant group were "very/somewhat satisfied" with their bleeding pattern (60.9% vs. 33.6%) and reported a preference to use their study treatment after study completion (70.1% vs. 58.5%). CONCLUSION(S): The LNG-IUS 8 was associated with a significantly lower 12-month discontinuation rate compared with the ENG implant; mainly because ENG implant users frequently discontinued due to increased bleeding. More LNG-IUS 8 users than ENG implant users reported being "very/somewhat satisfied" with their bleeding pattern, and reported a preference to continue using their study treatment after the study. CLINICAL TRIAL REGISTRATION NUMBER: NCT01397097.

A prospective, open-label, single arm, multicentre study to evaluate efficacy, safety and acceptability of pericoital oral contraception using levonorgestrel 1.5 mg.

STUDY QUESTION: Will the use of levonorgestrel (LNG) 1.5 mg taken at each day of coitus by women who have relatively infrequent sex be an efficacious, safe and acceptable contraceptive method? SUMMARY ANSWER: Typical use of LNG 1.5 mg taken pericoitally, before or within 24 h of sexual intercourse, provides contraceptive efficacy of up to 11.0 pregnancies per 100 women-years (W-Y) in the primary evaluable population and 7.1 pregnancies per 100 W-Y in the evaluable population. WHAT IS KNOWN ALREADY: LNG 1.5 mg is an effective emergency contraception following unprotected intercourse. Some users take it repeatedly, as their means of regular contraception. STUDY DESIGN, SIZE, DURATION: This was a prospective, open-label, single-arm, multicentre Phase III trial study with women who have infrequent coitus (on up to 6 days a month). Each woman had a follow-up visit at 2.5, 4.5 and 6.5 months after admission or until pregnancy occurs if sooner, or she decided to interrupt participation. The study was conducted between 10 January 2012 and 15 November 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 330 healthy fertile women aged 18-45 years at risk of pregnancy who reported sexual intercourse on up to 6 days a month, were recruited from four university centres located in Bangkok, Thailand; Campinas, Brazil; Singapore and Szeged, Hungary to use LNG 1.5 mg pericoitally (24 h before or after coitus) as their primary method of contraception. The participants were instructed to take one tablet every day she had sex, without taking more than one tablet in any 24-h period, and to maintain a paper diary for recording date and time for every coital act and ingestion of the study tablet, use of other contraceptive methods and vaginal bleeding patterns. Anaemia was assessed by haemoglobin evaluation. Pregnancy tests were performed monthly and pregnancies occurring during product use were assessed by ultrasound. At the 2.5-month and final visit at 6.5 months, acceptability questions were administered. MAIN RESULTS AND THE ROLE OF CHANCE: There were 321 women included in the evaluable population (which includes all eligible women enrolled), with 141.9 woman-years (W-Y) of observation and with a rate (95% confidence interval [CI]) of 7.1 (3.8; 13.1) pregnancies per 100 W-Y of typical use (which reflects use of the study drug as main contraceptive method, but also includes possible use of other contraceptives from admission to end of study) and 7.5 (4.0; 13.9) pregnancies per 100 W-Y of sole use. In the primary evaluable population (which includes only eligible enrolled women <35 years old), the rate was 10.3 (5.4; 19.9) pregnancies per 100 W-Y of typical use, and 11.0 (5.7; 13.1) pregnancies per 100 W-Y of sole use. There were three reported severe adverse events and 102 other mild adverse events (most common were headache, nausea, abdominal and pelvic pain), with high recovery rate. The vaginal bleeding patterns showed a slight decrease in volume of bleeding and the number of bleeding-free days increased over time. There was only one case of severe anaemia, found at the final visit (0.4%). The method was considered acceptable, as over 90% of participants would choose to use it in the future or would recommend it to others. LIMITATIONS, REASONS FOR CAUTION: This was a single-arm study with small sample size, without a control group, designed as a proof of concept study to explore the feasibility of this type of contraception. WIDER IMPLICATIONS OF THE FINDINGS: A larger clinical study evaluating pericoital contraception with LNG is feasible and our data show that this method would be acceptable to many women. STUDY FUNDING/COMPETING INTERESTS: This study received partial financial support from the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research (RHR) and the World Health Organization. Gynuity and the Bill and Melinda Gates Foundation (BMGF) provided financial support for project monitoring. HRA Pharma donated the LNG product. N.K. was the initial project manager when she was with WHO/HRP and was employed by HRA Pharma, which distributes LNG for emergency contraception. The other authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: This study was registered on ANZCTR, Trial ID ACTRN12611001037998. TRIAL REGISTRATION DATE: 4 October 2011. DATE OF FIRST PATIENT'S ENROLMENT: 10 January 2012.

Body mass index does not affect the efficacy or bleeding profile during use of an ultra-low-dose combined oral contraceptive.

OBJECTIVES: Safe and effective contraceptive options for obese women are becoming more important due to the obesity epidemic within the United States. This study evaluated the impact of body mass index (BMI) on efficacy, safety and bleeding patterns during use of an ultra-low-dose combined oral contraceptive (COC). STUDY DESIGN: Data are from a Phase 3 clinical efficacy and safety study of an ultra-low-dose COC containing 1.0-mg norethindrone acetate and 10-mcg ethinyl estradiol. Pearl Indices, adverse events and bleeding profile were calculated for BMI ranges of <25, 25-30 and >30 kg/m(2). RESULTS: Of the 1581 participants included in the analysis, 28.3% were overweight, and 18.0% were obese. For women aged 18-45 years, the Pearl Indices were 2.49, 2.32 and 1.89 for women with a BMI <25, 25-30 and >30 kg/m(2), respectively. The ultra-low dose of ethinyl estradiol did not impact scheduled bleeding or intensity of bleeding, but we observed a slight decline in amenorrhea and slight increase in unscheduled bleeding in obese women compared with other BMI categories. CONCLUSIONS: Our analysis of an ultra-low-dose COC did not find clinically important differences in contraceptive failure rates, adverse events or bleeding profile with increasing BMI. IMPLICATIONS: Our analysis of an ultra-low ethinyl estradiol dose COC did not find clinically important differences in contraceptive failure rates, adverse events or bleeding profile with increasing BMI. An ultra-low-dose COC provides another safe and effective contraceptive option for obese women.

Risk of HIV Infection in Depot-Medroxyprogesterone Acetate (DMPA) Users: A Systematic Review and Meta-analysis.

OBJECTIVE: As the HIV/AIDS epidemic continues to spread in Africa and Asia, use of the injectable contraceptive steroid DMPA is widespread and has been increasing. Since studies dating back to 1992 have suggested that DMPA may increase the transmission of HIV to women, we endeavored to determine if the extant epidemiological and biological evidence is sufficient to conclude that DMPA use constitutes a definite hazard to women's health. METHODS: We searched Medline using the search terms: contraceptives or contraception AND HIV and searched bibliographies of articles thus identified. We included in the meta-analysis all studies examining the association between use of DMPA (or injectable contraceptives comprising mostly DMPA) and the presence (cross-sectional studies, n = 8) or acquisition (longitudinal studies, n = 16) of HIV+ status in women, using a random effects models to estimate odds ratios (ORs; cross-sectional studies) and hazard ratios (HRs; longitudinal studies). Studies were excluded if the comparison group included women using any form of steroidal contraception. RESULTS: Statistically significant positive associations between DMPA use and HIV positivity were observed both in cross-sectional (OR = 1.41, 95% CI 1.15 - 1.73) and longitudinal studies (HR = 1.49, 95% CI 1.28 - 1.73). The biological plausibility of increased vulnerability to HIV infection due to progestational action (via thinning of the vaginal epithelial barrier and immunosuppression) as well as glucocorticoid agonistic immunosuppression, are discussed. CONCLUSION: The epidemiological and biological evidence now make a compelling case that DMPA adds significantly to the risk of male-to-female HIV transmission.

Bleeding and thrombosis in a patient with primary antiphospholipid syndrome using norethisterone: a case report.

INTRODUCTION: Antiphospholipid syndrome is known to be associated with the occurrence of venous and/or arterial thrombosis. There are several factors that might trigger the risk of thrombosis in antiphospholipid syndrome, including drugs, however bleeding is rare. Only a few cases of antiphospholipid syndrome have reported simultaneous bleeding and thrombosis, and only a few of these cases have reported thrombosis induced by norethisterone when used by patients with an underlying risk factor for thromboembolism. CASE PRESENTATION: We report the case of a 35-year-old Saudi woman diagnosed with antiphospholipid syndrome with a history of several spontaneous miscarriages and two previous lower limb deep vein thromboses. She had used norethisterone to postpone her menstruation and presented to our institution with severe menorrhagia. During admission, she developed thrombocytopenia, and at the same time she was found to have extensive inferior vena cava and bilateral common iliac thrombosis. CONCLUSIONS: This case report is of interest to rheumatologists, hematologists and radiologists because we have found that the presence of bleeding and thrombocytopenia do not preclude the concomitant occurrence of thrombotic complications of antiphospholipid syndrome. Norethisterone is normally safe to take, but it is not suitable for patients with an increased risk of deep vein thrombosis. Also, the simultaneous management of thrombosis and heavy vaginal bleeding is a challenge for clinicians since there are no evidence-based guidelines regarding the management of these patients.

Depot medroxyprogesterone acetate in combination with a twice-daily lopinavir-ritonavir-based regimen in HIV-infected women showed effective contraception and a lack of clinically significant interactions, with good safety and tolerability: results of the ACTG 5283 study.

We conducted an open-label, steady-state pharmacokinetic (PK) study of drug-drug interactions between depot medroxyprogesterone acetate (DMPA) and twice-daily lopinavir (LPV) plus low-dose ritonavir (RTV) (LPV/r) among 24 HIV-infected women and compared the results to those for HIV-infected women receiving DMPA while on no antiretroviral therapy or on nucleosides only (n = 14 subjects from the control arm of AIDS Clinical Trials Group [ACTG] study 5093). The objectives of the study were to address the effect of LPV/r on DMPA and to address the effect of DMPA on LPV/r therapy. PK parameters were estimated using noncompartmental analysis with between-group comparisons of medroxyprogesterone acetate (MPA) PKs and within-subject comparisons of LPV and RTV PKs before and 4 weeks after DMPA dosing. Plasma progesterone concentrations were measured every 2 weeks after DMPA dosing through week 12. Although the MPA area under the concentration-time curve and maximum concentration of drug in plasma were statistically significantly increased in the study women on LPV/r compared to those in the historical controls, these increases were not considered clinically significant. There were no changes in LPV or RTV exposure after DMPA. DMPA was well tolerated, and suppression of ovulation was maintained. (This study has been registered at ClinicalTrials.gov under registration no. NCT01296152.).

The impact of copper-containing and levonorgestrel-releasing intrauterine contraceptives on cervicovaginal cytology and microbiological flora: a prospective study.

OBJECTIVE: To compare vaginal microflora and cervical cytology before and after insertion of a copper-containing intrauterine device (Cu-IUD) or a levonorgestrel releasing-intrauterine system (LNG-IUS). METHODS: Between April 2009 and February 2011, all women requesting insertion of an intrauterine contraceptive for family planning or noncontraceptive indications were enrolled. One hundred and eight Cu-IUDs and 42 LNG-IUSs were placed. Cervical cytological and vaginal microbiological findings before insertion and after 12 months were recorded. RESULTS: With regard to cervical cytology, nonspecific inflammatory changes became more frequent (but not significantly so; p = 0.062) after one year of use of a Cu-IUD, whereas their prevalence remained unchanged among women fitted with a LNG-IUS. Colonisation by Candida spp. and mycoplasma infections were diagnosed significantly more often after one year of use of the Cu-IUD than at baseline. During the study period, women wearing a Cu-IUD complained significantly more frequently of vaginal discharge, pelvic pain, and increased menstrual flow. CONCLUSION: Use of a Cu-IUD - but not that of a LNG-IUS - was associated with an alteration of the vaginal flora and showed a trend towards a higher frequency of nonspecific inflammatory changes affecting cervical cytology.