Baseline Predictors of High Adherence to a Coitally Dependent Microbicide Gel Based on an Objective Marker of Use: Findings from the Carraguard Phase 3 Trial.

A randomized, placebo-controlled, efficacy trial of Carraguard was unable to demonstrate a reduction in women's risk of HIV infection, which may have been due, in part, to low adherence (gel used in 42 % of vaginal sex acts, on average). A secondary analysis was undertaken to understand baseline factors associated with high adherence (gel used in ≥85 % of sex acts). Women who reported ≥1 vaginal sex act, returned ≥1 opened applicator, and had ≥1 conclusive post-enrollment HIV test (N = 5990) were included. Adherence was estimated as the ratio of average weekly applicator insertions (based on a dye stain assay indicating vaginal insertion)/average weekly sex acts (by self-report). Multivariate logistic regression modeling indicated that coital frequency, site, contraception, and partner age difference had a significant impact on adherence. Women reporting >1 and ≤2 vaginal sex acts per week, on average, were half as likely to be adherent as those reporting 1 vaginal sex act per week or less [adjusted odds ratio (AOR): 0.48; 95 % CI 0.38-0.61]; women from the Western Cape had one-third the odds of being adherent compared to women from KZN (AOR: 0.31; 95 % CI 0.23-0.41); compared to women using injectable contraception, women using any other or no method were more likely to be adherent (AOR: 1.30; 95 % CI 1.04-1.63); and women who had a larger age gap from their partners were more likely to be adherent (AOR: 1.03; 95 % CI 1.01-1.05; p = 0.001). Despite low adherence, overall, 13 % of participants achieved nearly perfect adherence, indicating a potential niche for a coitally dependent microbicide. More research is needed on the impact of sexual patterns and HIV risk perception on product acceptability and adherence to improve counseling in ongoing trials and when products are eventually introduced.

Menstrual characteristics and ultrasonographic uterine cavity measurements predict bleeding and pain in nulligravid women using intrauterine contraception.

STUDY QUESTION: Is small uterine cavity size as assessed by ultrasonography associated with bleeding problems or pain in nulligravid women using intrauterine contraception, or do other factors affect these parameters? SUMMARY ANSWER: Among levonorgestrel intrauterine system (LNG-IUS) users, small uterine cavity size is not associated with worsened clinical outcome, but is beneficial as women with the smallest cavity measurements were frequently amenorrhoeic and painless at the end of the first year but among copper intrauterine device (IUD) users, no associations between uterine cavity dimensions and clinical outcome were found. WHAT IS KNOWN ALREADY: Nulligravid and nulliparous women have smaller uterine dimensions than parous women. Previously, many studies have revealed increased discontinuation rates of IUD use as a result of bleeding, pain or expulsion in these women, while recent studies with current models of IUS/IUDs indicate similar continuation and satisfaction rates irrespective of parity. STUDY DESIGN, SIZE, DURATION: In a pilot study, 165 adult nulligravid women requesting their first IUD between 1 January 2011 and 31 July 2012 were given a free choice between two IUDs with equal frames measuring 32 × 32 mm-the LNG-IUS 52 mg or a copper-releasing IUD. The women were followed for 1 year. PARTICIPANTS/MATERIAL, SETTING, METHODS: The LNG-IUS was chosen by 113 women (68.5%) and the copper IUD by 52 (31.5%). Prior to insertion the women were interviewed concerning their menstrual characteristics and uterine cavity size was measured by 2-D ultrasonography. After insertion the women kept daily records of bleeding and pain for two reference periods of 90 days during the first year (Months 1-3 and 10-12). The correlation between uterine cavity measurements and numbers of days of bleeding/spotting and pain during the reference periods was analysed. Continuation rates were assessed and reasons for discontinuation as well as the effects of baseline participant characteristics on outcomes were analysed in regression models. MAIN RESULTS AND THE ROLE OF CHANCE: Both uterine cavity size and baseline menstrual characteristics prior to IUD insertion predicted the numbers of days of bleeding/spotting and pain in LNG-IUS users. Women with small uterine cavity dimensions reported less bleeding/spotting in both reference periods and less pain in the second reference period compared with women with larger dimensions. Baseline scanty spontaneous menstrual bleeding prior to LNG-IUS use (OR 9.4, 95% CI 1.7-51.8, P = 0.01) and smoking (OR 7.8, 95% CI 1.8-33.8, P = 0.006) predicted amenorrhoea in the second reference period. Women with baseline dysmenorrhoea reported more pain with both IUDs. Continuation rates and reasons for discontinuation were similar with both IUDs. LIMITATIONS, REASONS FOR CAUTION: No sample size could be calculated to estimate the power as this was a pilot study. As the majority of women chose the LNG-IUS we did not achieve our initial aim of equally sized IUD groups and thus the size of the copper IUD group may have been insufficient to detect differences. WIDER IMPLICATIONS OF THE FINDINGS: These data further encourage promotion of intrauterine contraception among nulligravid women. Routine use of ultrasonography to assess uterine cavity dimensions prior to IUD insertion is not indicated. STUDY FUNDING/COMPETING INTERESTS: Supported by Helsinki University Central Hospital research funds, the Swedish Cultural Foundation in Finland and Finska Läkaresällskapet, who provided funds for J.K. O.H. serves on advisory boards for Bayer Healthcare, Gedeon Richter and MSD Finland (part of Merck & Co. Inc.) and has designed educational events with these companies. S.S. has lectured in educational events at Bayer and MSD Finland (part of Merck & Co. Inc.) and is a member of the Advisory Board for Contraception at MSD Finland. The other authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: www.clinicaltrials.gov, NCT01685164.

Predicting painful or difficult intrauterine device insertion in nulligravid women.

OBJECTIVE: To assess the relationship of preinsertion vaginal ultrasound assessment and menstrual and gynecologic history as predictors of difficult or painful intrauterine device insertion in nulligravid women. METHODS: Nulligravid women seeking contraception were invited to participate in this nonrandomized study and given the choice between the levonorgestrel-releasing intrauterine system or a copper-releasing intrauterine device. All 165 enrolled women were interviewed and a pelvic examination, including vaginal ultrasonography, was performed before insertion. Insertion difficulties and pain intensity were recorded and assessed against uterine measurements and background characteristics. RESULTS: Most insertions were assessed as easy (n=144 [89.4%]) and only two (1.2%) failed. Most women had uterine measurements smaller than the studied devices. Odds for difficulties at insertion decreased with every increasing millimeter in total uterine length (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.78-0.96, P=.006) and cervical length (OR 0.85, 95% CI 0.74-0.97, P=.02) and similarly with every decreasing degree of (straighter) flexion angle (OR 0.96, 95% CI 0.94-0.99, P=.005). No absolute threshold measurements could be determined. Still, the majority of insertions in small and flexed uteri were uneventful. Severe insertion pain was common (n=94 [58.4%]). Severe dysmenorrhea was the only predictor of insertion pain (OR 8.16 95% CI 2.56-26.02, P<.001). CONCLUSION: Ultrasonographic evaluation does not give additional information compared with clinical pelvic examination and sound measure. Although smaller uterine length measurements and steeper flexion angle more often predicted difficulties, the majority of insertions were uneventful in women with small measures. Dysmenorrhea was the only predictor of pain. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01685164. LEVEL OF EVIDENCE: II.

Uterine perforation caused by intrauterine devices: clinical course and treatment.

STUDY QUESTIONS: What are the symptoms of uterine perforation caused by modern copper intrauterine devices (Cu-IUDs) and the levonorgestrel-releasing intrauterine system (LNG-IUS); how is perforation detected and what are the findings in abdominal surgery? SUMMARY ANSWER: Symptoms are mostly mild and ∼30% of women are asymptomatic. Surgical findings are mainly minimal; no visceral complications were found in this study. However, adhesions as well as pregnancies seem to be more common among women using Cu-IUDs. WHAT IS KNOWN ALREADY: Prior studies and case reports have suggested that uterine perforation by modern IUDs/IUSs is rarely serious. STUDY DESIGN, SIZE, DURATION: A retrospective study of 75 patients (54 LNG-IUS and 21 Cu-IUD) treated surgically for uterine perforation between 1996 and 2009. PARTICIPANTS/MATERIALS, SETTING, METHODS: The patients treated for uterine perforation by an IUD/IUS at clinics of the Helsinki and Uusimaa Hospital District were identified using the National Care Register for Health Institutions in Finland. The clinical data were collected from individual patient records. MAIN RESULTS AND THE ROLE OF CHANCE: The majority of patients (n = 53; 71%) had mild symptoms of abnormal bleeding or abdominal pain or both, in combination with missing IUD/IUS threads. Asymptomatic patients (n = 22; 29%) were examined because of missing threads or pregnancy. Failure to remove the IUD/IUS by pulling visible threads was the reason for referral in seven women (9%) requesting removal of the device. Eleven women (15%) were pregnant. Misplaced IUDs/IUSs were localized by a combination of vaginal ultrasonography (US) and X-ray, hysteroscopy or curettage. Only after this were patients treated by means of laparoscopy. The majority (n = 44; 65%) of the 68 intra-abdominal devices were located in the omentum, the remaining 24 (35%) around the uterus. Partial perforation or myometrial embedding was diagnosed in all seven cases (9%) with visible threads, but unsuccessful removal by pulling. During laparoscopy, filmy adhesions were found in 21 patients (30%). Pregnancy (33 versus 7%, P = 0.009) and intra-abdominal adhesions (58 versus 20%, P = 0.002) were significantly more common in the Cu-IUD group. Infections were rare; one non-specific acute abdominal infection, later found to be unrelated to the IUD, led to laparoscopy and in four cases the IUD was surrounded by pus, but there were no symptoms of infection. LIMITATIONS, REASONS FOR CAUTION: The study setting revealed only surgically treated symptomatic patients and asymptomatic women attending regular follow-up. Women not treated, but only followed or not attending follow-up, were not identified, excluding the possibility to analyse missed undiagnosed perforations, or conservative follow-up as a treatment option. WIDER IMPLICATIONS OF THE FINDINGS: As surgical findings are minimal, asymptomatic women may need no treatment at all. An alternative form of contraception is, however, important as pregnancies do occur. If a woman plans a pregnancy, a misplaced LNG-IUS should be removed, as it may act as a contraceptive.

Intrauterine contraception: incidence and factors associated with uterine perforation--a population-based study.

STUDY QUESTION: What are the incidence and factors associated with uterine perforation by modern copper intrauterine device (Cu-IUD) and the levonorgestrel-releasing intrauterine system (LNG-IUS)? SUMMARY ANSWER: Perforation incidence was similar to that reported in prior studies and did not vary between Cu-IUD and LNG-IUS groups. Lactation, amenorrhoea and a post-partum period of <6 months were common. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: The study supports findings in prior studies. The incidence rate was low and factors associated with uterine perforation were similar to those in earlier reports. DESIGN AND DATA COLLECTION METHOD: This retrospective population-based registry study included 68 patients surgically treated for uterine perforation by an intrauterine device (IUD)/intrauterine system (IUS) at clinics in the Helsinki and Uusimaa hospital district. PARTICIPANTS AND SETTING: Records of 108 patients with probable uterine perforation by an IUD/IUS were analysed, leaving 68 patients treated for uterine perforation. RECRUITMENT/SAMPLING STRATEGY: Patients with diagnostic and surgical treatment codes indicating uterine perforation by an IUD/IUS between 1996 and 2009 were retrospectively selected from the Finnish National Hospital Register. DATA ANALYSIS METHOD: Patients with Cu-IUDs (n = 17) and the LNG-IUS (n = 51) were analysed as one group and also compared using Mann-Whitney and chi-square tests. IUD/IUS sales numbers were used to calculate incidences. MAIN FINDINGS: The overall incidence of perforation was 0.4/1000 sold devices, varying annually from 0 to 1.2/1000. The proportion of both sold and perforating LNG-IUSs increased during the study period, but perforation incidence was not affected. Demographic characteristics in the Cu-IUD and LNG-IUS groups were similar. More than half of the devices (55%) were inserted at <6 months post-partum. Breastfeeding at the time of insertion was common, comprising 32% of all patients. Moreover, of the breastfeeding women, 90% had delivered within 6 month prior to insertion. IMPLICATIONS: The population-based study setting represents a good overview of patients experiencing uterine perforation with an IUD/IUS. As previously reported, the post-partum period, lactation and amenorrhoea may increase the risk of perforation. BIAS, LIMITATIONS AND GENERALIZABILITY: As the study setting revealed only symptomatic patients or those attending regular follow-up, the true incidence might be somewhat higher. As there is no specific diagnostic code for uterine perforation or treatment, it is unlikely that all cases of uterine perforation can be identified in a retrospective study.

Hormonal contraception and the risk of HIV acquisition among women in South Africa.

OBJECTIVES: To evaluate the effect of hormonal contraception including combined oral contraceptives (COCs), and the injectable progestins depo-medroxyprogesterone acetate (DMPA) and norethisterone enanthate (Net-En) on the risk of HIV acquisition among women in South Africa. DESIGN/METHODS: We analyzed data from 5567 women aged 16-49 years participating in the Carraguard Phase 3 Efficacy Trial. Participants were interviewed about contraceptive use and sexual behaviors and underwent pelvic examinations and HIV testing quarterly. We used marginal structural Cox regression models to estimate the effect of hormonal contraception exposure on HIV acquisition risk among women overall and among young women (16-24 years) in particular. RESULTS: Two hundred and seventy participants became HIV-infected (3.7 per 100 woman-years); HIV incidence was 2.8, 4.6, 3.5 and 3.4 per 100 woman-years in the COC, DMPA, Net-En and nonhormonal contraceptive groups, respectively (P = 0.09). The adjusted hazard ratios (AHRs) were 0.84 [95% confidence interval (CI) 0.51-1.39], 1.28 (95% CI 0.92-1.78) and 0.92 (95% CI 0.64-1.32) among COC, DMPA and Net-En users, respectively, compared with the nonhormonal group controlling for covariates. Age modified the effect of hormonal contraception on HIV acquisition risk; among young women, the AHRs were 1.02 (95% CI 0.46-2.28) for COCs, 1.68 (95% CI 0.96-2.94) for DMPA and 1.36 (95% CI0.78-2.35) for Net-En users. CONCLUSIONS: In this study conducted among South African women, hormonal contraception did not significantly increase the risk of HIV acquisition. However, the effect estimate does not rule out a moderate increase in HIV risk associated with DMPA use found in some other recent studies.

Contraception and HIV infection in women.

BACKGROUND: More than 15 million women, many of reproductive age, were infected with human immunodeficiency virus (HIV) at the end of 2007. As the HIV epidemic evolves, heterosexual intercourse is increasingly risky: the risk of infection in exposed young women is 4- to 7-fold higher than in young men and nearly half a million newborns annually have HIV. This review aims to show the effect of contraceptive choices on risk of HIV and on the course of disease in women with HIV. METHODS: Relevant citations were selected by agreement between the authors after a search of MEDLINE using the terms HIV/AIDS and contraception. RESULTS: Risk of transmission of HIV varies from 1 in 200 to 1 in 10 000 coital incidents, depending in part on the integrity of the vaginal epithelium. Consistent use of male condoms has been proven to reduce horizontal transmission of HIV by 80% among HIV-serodiscordant couples. Hormonal contraception may increase the risk of HIV acquisition in high-risk women such as commercial sex workers, but not in women at low risk of HIV. While hormonal contraception did not affect progression of disease in two cohort studies involving 370 women, in a randomized trial among women not receiving antiretroviral medication, clinical disease accelerated in the oral contraception group (13.2/100 woman-years) compared with the copper intrauterine devices group (8.6/100 woman-years; hazard ratio, 1.5; 95% confidence interval, 1.04-2.1). Hormonal contraception does not interfere with antiviral drug effectiveness. CONCLUSIONS: All the available reversible contraceptive methods can generally be used by women at risk of HIV infection and by HIV-infected women. Further studies are needed to investigate the safety and efficiency of hormonal contraception in women living with HIV/AIDS.

Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Female-initiated HIV-prevention options, such as microbicides, are urgently needed. We assessed Carraguard, a carrageenan-based compound developed by the Population Council, for its efficacy and long-term safety in prevention of HIV infection in women. METHODS: We undertook a randomised, placebo-controlled, double-blind trial in three South African sites in sexually-active, HIV-negative women, aged 16 years and older. 6202 participants, who were randomly assigned by a block randomisation scheme to Carraguard (n=3103) or placebo (methylcellulose [n=3099]), were instructed to use one applicator of gel plus a condom during each vaginal sex act. Participants were followed up for up to 2 years. Visits every 3 months included testing for HIV presence and pregnancy, pelvic examinations, risk reduction counselling, and treatment for curable sexually transmitted infections and symptomatic vaginal infections. The primary outcome was time to HIV seroconversion. Analysis was in the efficacy population (a subset of the intention-to-treat population, excluding participants for whom efficacy could not be assessed). This study is registered with ClinicalTrials.gov, number NCT00213083. FINDINGS: For the primary outcome (time to HIV seroconversion) we analysed 3011 women in the Carraguard group and 2994 in the placebo group. HIV incidence was 3.3 per 100 woman-years (95% CI 2.8-3.9) in the Carraguard group (134 events) and 3.8 per 100 woman-years (95% CI 3.2-4.4) in the placebo group (151 events), with no significant difference in the distribution of time to seroconversion (p=0.30). The covariate-adjusted hazard ratio was 0.87 (95% CI 0.69-1.09). Rates of self-reported gel use (96.2% Carraguard, 95.9% placebo) and condom use (64.1% in both groups) at last sex acts were similar in both groups. On the basis of applicator testing, however, gel was estimated to have been used in only 42.1% of sex acts, on average (41.1% Carraguard, 43.1% placebo). 1420 (23%) women in the intention-to-treat population had adverse events (713 Carraguard, 707 placebo), and 95 (2%) women had adverse events that were related to gel use (48 Carraguard, 47 placebo). Serious adverse events occurred in 72 (2%) women in the Carraguard group and 78 (3%) in the placebo group, only one of which was considered possibly related to gel use (placebo group). INTERPRETATION: This study did not show Carraguard's efficacy in prevention of vaginal transmission of HIV. No safety concerns were recorded.

Effect of a single vaginal administration of levonorgestrel in Carraguard gel on the ovulatory process: a potential candidate for "dual protection" emergency contraception.

OBJECTIVE: The study was conducted to evaluate the effect of Carraguard vaginal gel containing 0.75 mg of levonorgestrel (CARRA/LNG gel) administered in a single dose at different stages of follicle development over subsequent follicle rupture and hormonal levels. METHOD: Randomized, blinded, cross-over study comparing the effects of a single administration of CARRA/LNG gel or Carraguard (CARRA) gel. Twenty-four healthy women were enrolled in two centers. The gels were administered when the follicle had reached diameters of 12-14, 15-17 and > or =18 mm in eight women each. Volunteers were followed for one treatment, one washout cycle and a second treatment cycle. Follicle rupture or nonrupture was assessed by transvaginal ultrasound. Luteinizing hormone, estradiol and progesterone levels were measured daily for 5 days following treatment, and three times per week until menses. RESULTS: No follicular rupture within the 5-day period following administration was observed in 74% and 30% of the CARRA/LNG and CARRA gel treatment cycles, respectively, while ovulation was documented in 4% and 61%, respectively. The overall proportion of cycles with lack of follicular rupture or ovulatory dysfunction (follicle rupture preceded by an inadequate LH surge) was 96% for CARRA/LNG and 39% in the CARRA gel cycles. CONCLUSION: Single vaginal administration of 0.75 mg LNG in CARRA gel in the late follicular phase is effective for interfering with the ovulatory process.

Determining the feasibility of utilizing the microbicide applicator compliance assay for use in clinical trials.

INTRODUCTION: Participant's adherence to use of study product is a major concern in microbicide clinical trials, which can impact on proving product efficacy. In a previously described assay, single-use microbicide applicators exposed to the vagina were tested by spraying the applicator with trypan blue dye, resulting in vaginal mucus staining on inserted applicators. As subjects in our Phase 3 trials return applicators only at quarterly visits, often mixing inserted and not-inserted applicators together in the same bag, cross-contamination could confound results. In addition, trypan blue is carcinogenic and thus potentially hazardous to technicians spraying daily. METHODS: Applicators that were exposed to the vagina were placed in the same bag as unexposed applicators and shaken daily for up to 4 months. Validation was carried out in three clinical sites in South Africa. RESULTS: Trypan blue was replaced with FD&C Blue #1 granular food dye. Cross-contamination did not occur, nor did the length of time affect reaction to dye. In South Africa, the assay was validated with an accuracy of over 95%. CONCLUSION: Applicator assay modifications render the test safe and suitable for use in clinical trials.

Contraceptive vaginal rings releasing Nestorone and ethinylestradiol: a 1-year dose-finding trial.

In a multicenter 1-year trial of contraceptive vaginal rings (rings) involving 150 women, three dose combinations of the progestin Nestorone (NES) and ethinylestradiol (EE) were compared with respect to effectiveness, safety and acceptability. Mean in vitro drug release rates for the three doses were 150 and 15, 150 and 20 and 200 and 15 microg/day of NES and EE, respectively. Each ring remained in situ for 21 days, removed for 7 days and then reinserted for a total of 13 cycles of use. We studied ring performance with respect to pregnancy and other termination events, adverse events, the extent of ovulation inhibition, serum drug levels and bleeding control. We also assessed the rings' effects on the vagina using a standardized colposcopy procedure. Seventy-two percent of the women completed the 1-year (> or = 350 days) study. In studied cycles, luteal activity (progesterone > or = 10 nmol/L) was noted in 17%, 7% and 12% of subjects with monitored cycles at the 150/15, 150/20 and 200/15 doses, respectively (p = .34). Two pregnancies occurred, both in subjects using the 200/15 microg/day ring. Breakthrough bleeding during ring use averaged about 2 days/year and breakthrough bleeding and spotting averaged about 7 days/year. In the entire trial, only two women discontinued because of bleeding problems. Medical conditions, chiefly vaginal problems, personal reasons and device loss or repeated expulsion were the principal reasons given for study discontinuation. Vaginal and cervical colposcopy, conducted with standardized techniques and standardized interpretations, revealed no elevated event incidence attributable to ring use. Clinical performance and adverse event profiles indicate that each of these 1-year NES/EE rings, used on a 21-day-in and 7-day-out regimen, provided women effective, acceptable and safe long-acting contraception under their own control.

The pharmacokinetics of mifepristone in humans reveal insights into differential mechanisms of antiprogestin action.

The pharmacokinetics of mifepristone is characterized by rapid absorption, a long half-life of 25-30 h, and high micromolar serum concentrations following ingestion of doses of >/=100 mg of the drug. The serum transport protein-alpha 1-acid glycoprotein (AAG)-regulates the serum kinetics of mifepristone in man. Binding to AAG limits the tissue availability of mifepristone, explaining its low volume of distribution and low metabolic clearance rate of 0.55 L/kg per day. In addition, the similar serum levels of mifepristone following ingestion of single doses exceeding 100 mg can be explained by saturation of the binding capacity of serum AAG. Mifepristone is extensively metabolized by demethylation and hydroxylation, the initial metabolic steps being catalyzed by the cytochrome P-450 enzyme CYP3A4. The three most proximal metabolites, namely, monodemethylated, didemethylated and hydroxylated metabolites of mifepristone, all retain considerable affinity toward human progesterone and glucocorticoid receptors. Also, the serum levels of these three metabolites are in ranges similar to those of the parent mifepristone. Thus, the combined pool of mifepristone-plus its metabolites-seems to be responsible for the biological actions of mifepristone. Recent clinical studies on pregnancy termination and emergency contraception have focused on optimization of the dose of mifepristone. In these studies it has become apparent that the doses efficient for pregnancy termination differ from those needed in emergency contraception-mifepristone is effective in emergency contraception at a dose of 10 mg, which results in linear pharmacokinetics. However, the >/=200 mg doses of mifepristone needed for optimal abortifacient effects of mifepristone result in saturation of serum AAG and thus nonlinear pharmacokinetics. In view of the pharmacokinetic data, it may be speculated that dosing of mifepristone for pregnancy termination and for emergency contraception could be reduced to approximately 100 mg and 2-5 mg, respectively. It remains to be seen whether the newly synthesized, more selective antiprogestins will prove more efficacious in the clinical arena.

Subdermal progestin implant (Nestorone) in the treatment of endometriosis: clinical response to various doses.

OBJECTIVE: To evaluate the efficacy of three different doses of Nestorone progestin administered by implants for relief of pain, as well as bleeding patterns and symptoms in women with endometriosis. DESIGN: An open clinical study without a control group. PATIENTS: Twenty-one women in whom endometriosis was diagnosed and treated at laparoscopy or at laparotomy. INTERVENTIONS: The patients were randomly allocated to one of three groups receiving a daily dose of either 150 micro g, 200 micro g or 400 micro g Nestorone for two to four implants inserted subcutaneously for 7 months. After removal of the implants the follow-up period was 6 months. Six patients in the 150 micro g group, seven in the 200 micro g group and five in the 400 micro g group completed the study. MEASUREMENTS: Records of bleeding and registered side-effects and endometriosis-related symptoms were kept by the patients. Ovarian status was evaluated by vaginal ultrasonography. Serum concentrations of Nestorone and of lipids were measured. RESULTS: Pelvic pain decreased significantly in response to the treatment in all groups but returned to pretreatment levels during the post-treatment period. Bleeding and spotting was the most common side-effect followed by hypoestrogenic and psychic symptoms, with no significant difference among the groups. No significant changes in the serum levels of total, HDL or LDL cholesterol were found. One patient during the treatment period and four patients during the follow ups underwent surgical procedures. CONCLUSION: All three doses of Nestorone effectively alleviated endometriosis-related pain. While the Nestorone implant provides an interesting option for the treatment of endometriosis-related pain, its role needs to be assessed in comparative trials.