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This study aimed to determine the effect of oophorectomy on baseline serum levels of androgens and estrogens in premenopausal and postmenopausal women.Fourteen premenopausal and 10 postmenopausal women underwent total hysterectomy and bilateral oophorectomy for benign disease of the uterus. Serum levels of dehydroepiandrosterone sulfate (DHEAS), androstenedione (A), testosterone (T), dihydrotestosterone (DHT), 5α-androstane-3α,17β-diol-17β-glucuronide (3α-diol G), estrone (EIn premenopausal women, postop levels of total and free T, DHT, and total and free EThe significant decrease in serum T in postmenopausal women following oophorectomy adds to the evidence that the postmenopausal ovary continues to produce T.

Although vaccination against the Human Papilloma Virus (HPV) reduces the risk of related morbidities, the vaccine uptake remains low in adolescents. This has been attributed to limited parental knowledge and misconceptions. In this cross sectional study, we assessed the (1) clarity of educational material informing Hispanic mothers about HPV, cervical cancer and the HPV vaccine, (2) determined vaccination acceptability and (3) identified predictors of vaccine acceptance in an underserved health setting. 418 Hispanic mothers received the educational material and completed an anonymous survey. 91 % of participants understood most or all of the information provided. 77 % of participants reported vaccine acceptance for their children; this increased to 84 % when only those with children eligible to receive vaccination were included. Significant positive predictors of maternal acceptance of the HPV vaccine for their children were understanding most or all of the provided information, older age and acceptance of the HPV vaccine for themselves. Concerns about safety and general dislike of vaccines were negatively associated with HPV vaccine acceptance. Prior knowledge, level of education, previous relevant gynecologic history, general willingness to vaccinate and other general beliefs about vaccines were not significantly associated with HPV vaccine acceptance. The majority of participants reported understanding of the provided educational material. Vaccine acceptability was fairly high, but was even higher among those who understood the information. This study documents a cost-effective way to provide Hispanic mothers with easy-to-understand HPV-related information that could increase parental vaccine acceptability and future vaccine uptake among their children.

Objective To evaluate skin irritation and patch adhesiveness of a new weekly low-dose levonorgestrel (LNG) and ethinyl estradiol (EE) contraceptive patch (LNG/EE patch). Study design This analysis was part of an open-label, parallel-group, multicenter, phase 3 study that randomized healthy women to the LNG/EE patch (one patch weekly for three consecutive weeks, followed by a patch-free week for 13 cycles) or to an oral contraceptive for six cycles followed by seven LNG/EE patch cycles. Participants selected patch application sites of abdomen, buttock or upper torso. Investigators rated patch adhesiveness and skin irritation using standardized scales. Participants rated skin irritation and itching daily using standardized scales and recorded patch fall-off on daily diary cards. Results A total of 32,508 patches were applied (n= 1273). At the five clinic visits in which investigators rated the patches, they rated adhesiveness=0 (no lift) for ≥ 84% of participants and skin irritation=absent/mild for 97% of patches. Participants reported that 2–3.7% of patches fell off and rated skin irritation as absent or mild for 92– 95% of patches, according to site. Conclusion Investigator- and participant-rated assessments of LNG/EE patch adhesiveness and irritation demonstrated a low incidence of patch detachment, skin irritation and pruritus. Implications statement This secondary analysis of a phase 3 clinical trial of a new weekly low-dose LNG and EE contraceptive patch, which used assessment by both investigators and participants, observed a low incidence of skin irritation, pruritus and patch detachment.

Pregnancy rates in US contraceptive clinical trials are increasing due to decreased treatment compliance. This study compared compliance with a new low-dose levonorgestrel (LNG) and ethinyl estradiol (EE) contraceptive patch (CP, Twirla™) with that of a low-dose combination oral contraceptive (COC) in a demographically diverse population.This analysis was part of an open-label, parallel-group, multicenter phase 3 study that randomized healthy sexually active women (17-40years) to 13cycles of LNG/EE CP or 6cycles of COC, then 7cycles of LNG/EE CP. We defined self-reported compliance as cycles that, according to diaries, show 21days of patch wear without missed days or any patch worn7days or 21days of pill-taking without missed pill days. We verified compliance by detectable plasma presence of LNG and EE at cycles 2, 6, and 13.Of the intention-to-treat population with diary information (N=1328, mean age 26.4years, 46% minorities, 33% obese), 10.0% of the CP (n=998) versus 21.2% of the COC group (n=330) self-reported noncompliance after 6cycles (p.001). Laboratory assessments verified 10-14% of participants in both groups as noncompliant. Self-reported perfect use did not vary between obese [body mass index (BMI) ≥30kg/m(2)] versus nonobese (BMI30kg/m(2)) participants in both groups or when stratified by age, education, or race/ethnicity in the CP group.Self-reported compliance was significantly greater in the CP than COC group and did not vary by obesity status. Discrepancies between self-reported and verified compliance question reliability of patient diaries.This paper, based on an analysis of a phase 3 trial, shows that compliance was significantly greater with a new weekly transdermal CP than with a once-daily COC in obese as well as nonobese participants. Discrepancies between self-reported compliance and laboratory-verified compliance raise questions regarding the reliability of patient diaries.

OBJECTIVE: To compare a new low-dose levonorgestrel and ethinyl estradiol contraceptive patch (Patch) with a combination oral contraceptive (Pill; 100 micrograms levonorgestrel 20 micrograms ethinyl estradiol) regarding efficacy safety compliance and unscheduled uterine bleeding. METHODS: Women (17-40 years; body mass index 16-60) were randomized in a 3:1 ratio to one of two groups: Patch only (13 cycles) or Pill (six cycles) followed by Patch (seven cycles). Investigators evaluated adverse events during cycles 2 4 6 9 and 13. Participants recorded drug administration and uterine bleeding on daily diary cards. Compliance was assessed by measuring levonorgestrel and ethinyl estradiol plasma levels. Pearl Index (pregnancies per 100 woman-years) was calculated to evaluate efficacy. RESULTS: Participants (N=1504) were randomized to Patch (n=1129) or Pill (n=375). Approximately 30% were obese more than 40% were racial or ethnic minorities and more than 55% were new users of hormonal contraceptives. Laboratory-verified noncompliance (undetectable plasma drug levels) was 11% of Patch and 12.6% of Pill users at cycle 6. Pearl Indices (95% confidence intervals) for the intention-to-treat population (cycles 1-6) were 4.45 (2.34-6.57) for Patch and 4.02 (0.50-7.53) for Pill; excluding laboratory-verified noncompliant participants Pearl Indices were 2.82 (0.98-4.67) for Patch and 3.80 (0.08-7.52) for Pill (differences not statistically significant). Incidence of unscheduled bleeding and incidence and severity of adverse events were similar for both contraceptives (no statistically significant difference). CONCLUSIONS: Efficacy and safety of the new contraceptive Patch are comparable to those of a Pill. Laboratory-verified noncompliance and bleeding profile are similar between the two treatments. The Patch was well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov www.clinicaltrials.gov NCT01181479. LEVEL OF EVIDENCE: I.

Objective: Pharmacokinetic interactions exist between combined oral contraceptives and protease inhibitors (PI). However, such information is lacking for progestin-only oral contraception. We sought to define the steady-state pharmacokinetic interaction between norethindrone (NET) and PI in HIV-infected women. Methods and Design: We conducted an open-label, prospective, nonrandomized trial to characterize the steady-state pharmacokinetics of serum NET in HIV-infected women receiving PI compared with a control group of HIV-infected women receiving other noninteracting drugs. After 21 days of 0.35 mg of NET ingestion once daily, serial serum samples were obtained at 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours. The area under the curve between 0 and 72 hours after ingestion was calculated by trapezoidal approximation. Results: Thirty-five women were enrolled, 2 withdrew. Sixteen women in the PI group and 17 controls completed the study. NET half-life and maximum concentration were not significantly different between the 2 groups. Minimum concentration of NET was significantly higher in the PI group (P = 0.01). The ratio of the geometric mean NET area under the curve in the PI group compared with controls was 1.5 (90% confidence interval: 1.21 to 1.86). NET serum concentrations were significantly higher in HIV-infected women taking a PI compared with controls (P = 0.004). Conclusions: Coadministration of PI inhibits NET metabolism as shown by higher serum NET area under the curve levels, a surrogate marker for therapeutic contraceptive efficacy. This study supports the increased utilization of progestin-only pills in HIV-infected women receiving certain PI regimens.

Background The metabolic effects of progestin-only long-acting reversible contraception [levonorgestrel-releasing intrauterine system (LNG-IUS) and etonogestrel implant (ENG-I)] have been studied in normal-weight women but not in obese [body mass index≥30kg/m2] women. Study Design A nonrandomized open-label prospective trial of healthy obese, reproductive-age women desiring to use long-acting reversible contraception (LARC) or nonhormonal contraception (NHC). At baseline, 3 months and 6 months, homeostasis model assessment insulin resistant (HOMA-IR) score, insulin sensitivity (HOMA-%S) and β-cell function (HOMA-%B) were calculated based on fasting insulin and glucose values. In addition, components of metabolic syndrome [fasting glucose (FG), high density lipoprotein cholesterol and triglycerides, systolic and diastolic blood pressure, abdominal circumference] were measured. Twenty-four subjects total (8 in each arm) were needed to detect a 1.0 difference in HOMA-IR with 80% power and a two-sided alpha of 0.05. Results We present data on eight NHC, eight ENG-I and nine levonorgestrel intrauterine system (LNG-IUS) users. FG increased, and insulin sensitivity decreased over time among ENG-I users to a greater extent than among LNG-IUS users when compared to women using a nonhormonal method [FG change over 6 months=9.4mg/dL, 4.6mg/dL and − 2.1mg/dL, respectively; p=.01); (HOMA-%S change over 6 months=−29.9%, − 14.8% and 19.3%, respectively; p=.02)], while β-cell function and insulin resistance did not change significantly (p>.05). Conclusion While changes in FG and insulin sensitivity were seen in the present study among obese progestin-only contraceptive users, either progestin-only LARC method may be safely used clinically.

Objective To measure infants' breast milk intake and infant growth when their mothers initiated either combined oral contraceptive (COC), levonorgestrel-releasing intrauterine system, or etonogestrel-releasing implant, or copper intrauterine device (IUD) as a reference group. Design Prospective trial. Setting University-based hospital. Patient(s) On postpartum day 42, 40 women initiated a contraceptive method according to their choice. Intervention(s) Deuterium (D 2 O; 0.5 g/kg mother's weight) was ingested by mothers on postpartum days 42, 52, and 63 as a marker of total body fluid. Main Outcome Measure(s) Infants' milk intake from 42 to 63 postpartum days was assessed by measurement of D 2 O levels in infants' saliva and infant growth by measuring their body weight, height, and tibia length. Women recorded all infant feed and changes of diapers wet with urine. Breastfeeding continuation was assessed at 6 months postpartum. Result(s) Infant mean milk intake, mean growth increase, mean number of breastfeeding episodes, daily wet diaper changes, and mean duration of exclusively breastfeeding (∼5 months) were similar in the four groups. Conclusion(s) Use of a COC, the two progestin-only contraceptives, or copper IUD did not affect the amount of infant milk intake and growth up to 9 weeks of age. The incidence of full breastfeeding and breastfeeding continuation was similar with contraceptive hormonal use and no use. Clinical Trials Registration Number NCT01388582.

This study analyzes levels of progesterone, estradiol, norethindrone (NET) and ethinyl estradiol (EE) in serum and levels of NET in cervical mucus on the last day of the hormone-free interval (HFI) in users of 24/4 [norethindrone acetate (NETA)/EE-24] vs. 21/7 (NETA/EE-21) regimens.This was a randomized controlled, crossover, equivalency trial. Subjects were randomized to receive NETA/EE-24 or NETA/EE-21 for 2 months and then switched between study drugs. Blood and cervical mucus samples were obtained on Days 12-16 and on the last day of the HFI.From April 2010 to November 2011, 32 subjects were enrolled with 18 subjects completing all study visits. There were no statistically significant differences in either day 12-16 (p=.54) or last hormone-free day (p=.33) cervical mucus NET concentrations between the regimens. On the last day of the HFI, median serum progesterone levels did not differ significantly; however, users of NETA/EE-24 had higher levels of serum NET (p.001) and users of NETA/EE-21 had higher levels of serum estradiol (p=.01).This data supports the fact that inhibition of the pituitary-ovarian axis occurs during oral contraceptive use and during the HFI. We demonstrated that a reduced HFI of 4 days resulted in better suppression of the ovarian hormone production, thereby reducing the risk of ovulation and potential contraceptive failure.

Steady progress in contraception research has been achieved over the past 50 years. Hormonal and non-hormonal modern contraceptives have improved women’s lives by reducing different health conditions that contributed to considerable morbidity. However the contraceptives available today are not suitable to all users and the need to expand contraceptive choices still exists. Novel products such as new implants, contraceptive vaginal rings, transdermal patches and newer combinations of oral contraceptives have recently been introduced in family planning programs and hormonal contraception is widely used for spacing and limiting births. Concerns over the adverse effects of hormonal contraceptives have led to research and development of new combinations with improved metabolic profile. Recent developments include use of natural compounds such as estradiol (E2) and estradiol valerate (E2V) with the hope to decrease thrombotic risk, in combination with newer progestins derived from the progesterone structure or from spirolactone, in order to avoid the androgenic effects. Progesterone antagonists and progesterone receptor modulators are highly effective in blocking ovulation and preventing follicular rupture and are undergoing investigations in the form of oral pills and in semi long-acting delivery systems. Future developments also include the combination of a contraceptive with an antiretroviral agent for dual contraception and protection against sexually transmitted diseases, to be used before intercourse or on demand, as well as for continuous use in dual-protection rings. Alhough clinical trials of male contraception have reflected promising results, limited involvement of industry in that area of research has decreased the likelihood of having a male method available in the current decade. Development of non-hormonal methods are still at an early stage of research, with the identification of specific targets within the reproductive system in ovaries and testes, as well as interactions between spermatozoa and ova. It is hoped that the introduction of new methods with additional health benefits would help women and couples with unmet needs to obtain access to a wider range of contraceptives with improved acceptability.

Background The effect of obesity on ovarian follicular suppression in women using low-estrogen dose contraceptive patches has not been determined. Study Design A Phase II, parallel-group, multicenter, three-cycle study evaluated three patches containing different ethinyl estradiol (EE) and levonorgestrel (LNG) doses. Serum levels of EE, LNG, sex hormone-binding globulin and progesterone were compared in 41 obese [body mass index (BMI) ≥ 30] and 75 nonobese (BMI Results Suppression of ovulation during the luteal phase was dose dependent, with the highest dose (AG200-15) preventing progesterone increases in all women (cycles 2–3). In the follicular phase, the lowest-dose patch had the highest rate of increased progesterone in nonobese subjects. Progesterone levels ≥ 3.0 ng/mL in the follicular phase were more common in obese than nonobese women. Conclusions AG200-15 suppresses ovulation in obese and nonobese women. All three patches found increased progesterone in the follicular phase, albeit more in obese versus nonobese women.

The safety of progestogens as a class has come under increased scrutiny after the publication of data from the Women's Health Initiative trial, particularly with respect to breast cancer and cardiovascular disease risk, despite the fact that only one progestogen, medroxyprogesterone acetate, was used in this study. Inconsistency in nomenclature has also caused confusion between synthetic progestogens, defined here by the term progestin, and natural progesterone. Although all progestogens by definition have progestational activity, they also have a divergent range of other properties that can translate to very different clinical effects. Endometrial protection is the primary reason for prescribing a progestogen concomitantly with postmenopausal estrogen therapy in women with a uterus, but several progestogens are known to have a range of other potentially beneficial effects, for example on the nervous and cardiovascular systems. Because women remain suspicious of the progestogen component of postmenopausal hormone therapy in the light of the Women's Health Initiative trial, practitioners should not ignore the potential benefits to their patients of some progestogens by considering them to be a single pharmacological class. There is a lack of understanding of the differences between progestins and progesterone and between individual progestins differing in their effects on the cardiovascular and nervous systems, the breast, and bone. This review elucidates the differences between the substantial number of individual progestogens employed in postmenopausal hormone therapy, including both progestins and progesterone. We conclude that these differences in chemical structure, metabolism, pharmacokinetics, affinity, potency, and efficacy via steroid receptors, intracellular action, and biological and clinical effects confirm the absence of a class effect of progestogens.

Background Few studies have examined the action of combined oral contraceptives (COCs) on cervical mucus. We hypothesized that midcycle cervical mucus of women taking COCs is of poor quality when compared to their own midcycle mucus prior to initiating COCs. We sought to compare the effect upon quality and sperm penetration of the cervical mucus on the last hormone-free day with a 24/4 regimen to a 21/7 regimen. Methods This is an open-label, investigator-blinded, randomized, controlled, crossover equivalency study. All subjects received, in random order, 2 months of a 21/7 regimen and 2 months of a 24/4 regimen, each containing 20 mcg ethinyl estradiol and 1 mg norethindrone acetate. Analysis of cervical mucus quality (CMQ) and sperm penetration took place midcycle and on the last day of the hormone-free interval during the second month of each COC treatment. Results From April 2010 to November 2011, 18 subjects completed all study visits. Mean midcycle CMQ was poor (mean CMQ=1) and did not differ between 24/4 and 21/7 regimens (p=.92). On the last day of the pill-free interval, the quality and sperm penetration were poor with both regimens. Conclusion This study indicates that thickening of cervical mucus is a major mechanism of contraceptive action of COCs and that both 21/7 and 24/4 regimens result in poor quality and impenetrable mucus on the last day of the pill-free interval.

The type of estrogen and progestin as well as their doses, route and regimens of administration may each affect the benefit-risk profile of postmenopausal hormone therapy. The aim of this study was to evaluate the endometrial effect of progesterone released continuously from a vaginal ring, combined with transdermal estradiol in postmenopausal women.Forty-four postmenopausal women participated in a randomized, double-blind, dose-finding study evaluating two hormonal treatments, combining 50 microg/day of estradiol delivered by transdermal patches and either 0.5-g or 1-g progesterone vaginal rings (PVR) given for 12 weeks. The effect on the endometrium was assessed by histology and the detection of the proliferative marker Ki-67. We also measured the serum concentration of estradiol and progesterone, the tissue concentration of progesterone and the immunolocalization of estradiol and progesterone receptors in the endometrium.Endometrial thickness was increased after both treatments, although endometrial histology appeared atrophic in most biopsies. A circulating dose-response of serum progesterone levels was observed from the first to the 12th week of PVR use. In the high-progesterone-dose group, the scarce presence of Ki-67 and hormone receptors reflected the predominant action of progesterone in endometrial glands and stroma, in parallel with a lower tissue concentration of progesterone in this group.The PVR appears to be a promising method of administering natural progesterone to postmenopausal women treated with estrogen. Estradiol levels corrected the menopausal symptoms, as expected, and the presence of atrophic endometrium in the majority of women indicated that both doses of progesterone oppose the stimulatory estradiol effects, although the percentage of proliferative tissue was not negligible in both groups.

Background Subcutaneous depo-medroxyprogesterone acetate (DMPA-SC) has not been studied in the extremely obese population (BMI ≥40 kg/m 2 ). The purpose of this 26-week prospective experimental study was to determine incidence of ovulation and follicular development among women with Class 1, 2 and 3 obesity after receiving DMPA-SC. Methods Five normal-weight, five Class 1-2 obese, and five Class 3 obese women received subcutaneous injections of 104 mg DMPA-SC at baseline and 12 weeks later. Weekly progesterone levels, bimonthly estradiol (E 2 ), and monthly medroxyprogesterone acetate (MPA) levels were measured by immunoassay methods for a total of 26 weeks in each subject. Results Ovulation did not occur in any subject more than 1 week after the first injection. There was large intersubject and intrasubject variability in E 2 levels, and fluctuating E 2 levels were more frequent among obese women than normal-weight women. Median MPA levels remained above the level needed to prevent ovulation but, compared with normal-weight subjects, were lower among Class 1-2 obese and lowest among Class 3 obese subjects. Conclusion Fluctuating E 2 levels reflective of follicular development occurred more often among Class 1, 2 and 3 obese women than normal-weight women after DMPA-SC injections. Median MPA levels were consistently lowest among Class 3 obese women but remained above the level needed to inhibit ovulation. Further studies should more fully address the pharmacokinetics of DMPA-SC in extremely obese women.

OBJECTIVE: To examine breastfeeding and contraceptive use after the lactational amenorrhea method (LAM) criteria were no longer met. METHODS: Two hundred and thirty-three parous Egyptian women with unplanned pregnancies less than 2 years after delivery completed a questionnaire examining breastfeeding practice and contraceptive use. RESULTS: The majority of women (81.5%) with unplanned pregnancies within 2 years of delivery were breastfeeding at conception. Of these women 36.3% had used a method of contraception other than LAM compared with 60.5% of women who had weaned (P

In countries where levonorgestrel-releasing IUD use has increased the incidence of female surgical sterilization procedures has decreased. Will the same inverse relationship appear in the United States and if so what would be the medical implications of such a transition in long-term contraception? A recent UK review compared long-term contraception with IUDs vs. surgical sterilization; here we compare these two approaches from a US perspective. We focus on interval tubal sterilization by laparoscopy or laparotomy and will not consider postpartum sterilization. (excerpt)

To compare serum 17beta-estradiol (E2), estrone (E1), estrone sulfate, follicle-stimulating hormone, luteinizing hormone, sex hormone-binding globulin, vaginal pH, and the vaginal maturation indices in women using a low-dose transdermal patch releasing 14 microg of E2 per day and a vaginal ring releasing 7.5 microg of E2 per day.Twenty-four postmenopausal women were randomly assigned to either the patch (n = 12) or the ring (n = 12) for a 12-week study period. Serum E2, E1, estrone sulfate, follicle-stimulating hormone, luteinizing hormone, and sex hormone-binding globulin were measured by immunoassay at baseline and 6 and 12 weeks. Vaginal pH was determined at baseline and 6 and 12 weeks. Vaginal cytologic examinations for vaginal maturation index were done at baseline and 12 weeks.Twenty women completed the study. The patch significantly increased serum E1 and E2 levels at 6 and 12 weeks (P0.01); there was no significant increase in serum E1 and E2 levels with the ring. Both the patch and the ring significantly reduced vaginal pH at 6 (P0.001) and 12 (P0.001) weeks and significantly reduced the percentage of vaginal parabasal cells at 12 weeks with no significant difference between the two groups. Both preparations increased the proportion of superficial cells; the increase was significant only with the patch (P = 0.04).A transdermal E2 skin patch releasing 14 microg of E2 per day had an effect on vaginal pH and vaginal maturation indices similar to that of a vaginal E2 ring releasing 7.5 microg of E2 per day. Therefore, this patch is likely to relieve symptoms of vulvovaginal atrophy.

Initially approved for use in the United States nearly 50 years ago, oral hormonal contraceptives containing both estrogen and progestin have undergone steady improvements in safety and convenience. Concurrent with improvements in safety associated with decreasing doses of both steroids, there has been an increased incidence of unscheduled bleeding and spotting. There exist no standards regarding data collection techniques and methods, and reporting and analysis of bleeding and spotting events during combined hormonal contraceptive (CHC) trials. For the regulatory review of hormonal contraceptives, data regarding the incidence of bleeding and spotting events are not included in either of the traditional categories of efficacy and safety. Standardization of methods for collecting and analyzing data about cycle control in all clinical trials of CHCs is long overdue. Until such standards are developed and implemented, clinicians need to familiarize themselves with the techniques used in each study in order to provide correct information to their patients about the frequency of bleeding and spotting associated with different formulations and delivery systems.

This is the second of a two-article series describing the outcomes of the Hormonal Contraceptives Trial Methodology Consensus Conference held in Philadelphia, PA, on September 23, 2005. The first manuscript, "Hormonal Contraceptive Trials: Variable Data Collection and Bleeding Assessment Methodologies Influence Study Outcome and Physician Perception," provided a description of methodologies applied in the US Food and Drug Administration medical officer's review of clinical trial data as contained in the Summary Basis of Approvals of New Drug Applications, results of the review and general conclusions. This manuscript provides recommendations regarding best practices in trial design, data collection and analysis regarding bleeding data in combined hormone contraception trials.

Oral steroid contraception is a popular method of family planning worldwide. Over the past several decades, this method of contraception has changed significantly by decreasing the estrogen dose, changing the progestin component, and reducing the hormone free interval. Despite the popularity of oral steroid contraception, there has been much criticism regarding the associated risks of venous thromboembolism and stroke. Despite these established, yet uncommon risks, oral steroid contraception has many important health benefits. This review highlights the available formulations of oral contraceptives along with their evidence-based associated risks and benefits. Highlights regarding future directions for development of novel oral contraceptives are also addressed.

The primary objective is to examine activation of food motivation centers in the brain before and 8 weeks after depo medroxyprogesterone acetate (DMPA) administration.This prospective experimental pilot study examined the effects of DMPA on food motivation centers utilizing functional magnetic resonance imaging (fMRI) in eight nonobese, ovulatory subjects. fMRI blood oxygen level dependent (BOLD) signal was measured using a 3-Tesla Scanner while participants viewed images of high-calorie foods, low-calorie foods and nonfood objects. fMRI scans were performed at baseline and 8 weeks after participants received one intramuscular dose of DMPA 150 mg. fMRI data were analyzed using the FMRIB Software Library. Changes in adiposity and circulating leptin and ghrelin levels were also measured.There was a greater BOLD signal response to food cues in brain regions associated with food motivation (anterior cingulate gyrus, orbitofrontal cortex) 8 weeks after DMPA administration compared to baseline (z2.3, p.05 whole-brain analysis clustered corrected). No statistically significant change was detected in circulating leptin or ghrelin levels or fat mass 8 weeks after DMPA administration.Analysis of differences in food motivation may guide the development of interventions to prevent weight gain in DMPA users.These data support a neural origin as one of the mechanisms underlying weight gain in DMPA users and may guide future research examining weight gain and contraception.

Objective: We examined the clinical performance of contraceptive vaginal rings (rings) delivering Nestorone (NES) progestin and ethinyl estradiol (EE). Ring removal times were signaled by menstrual events. Bleeding patterns adverse events patterns of use and continuation rates were the principal parameters evaluated. Methods: In a two-stage 6-month trial subjects were randomized to use rings releasing 50 µg/day of NES and either 10 (50/10) or 20 (50/20) µg/day of EE. Subjects were to keep rings continuously in situ until menstrual bleeding or prolonged spotting-signaled removal. Reinsertion was to occur 96 h later. After the randomized stage an open-label 6-month trial of rings releasing 150 µg/day of NES and 15 µg/day of EE (150/15) began with the same menstrually signaled regimen. Results: Two-hundred forty-six subjects participated in the trial. Six-month pregnancy rates ranged by ring dose from 1.3 to 3.9 per 100. For each ring dose combination 6-month continuation rates were above 80 per 100. Bleeding and spotting (B+S) days in women with the 50 µg/day NES rings were similar in number to those experienced by cycling women not using contraception. Nevertheless in the initial 90 days fewer B+S days were reported by subjects with the 50/20 ring than by subjects with the 50/10 ring (p

Objectives The safety and efficacy of a single-rod implantable contraceptive containing etonogestrel (Implanon���) were investigated in a multicenter clinical trial. Study Design Sexually active American women ( N =330) with apparently normal menstrual cycles used the implant for up to 2 years. All subjects recorded bleeding and/or spotting daily in a diary. Safety was assessed through adverse experiences (AEs), laboratory tests and physical and gynecologic examinations. Results Total exposure was 474 woman-years (6186 cycles), and 68% of subjects had at least 1 year of exposure. No pregnancies occurred. The most common bleeding pattern observed throughout the study was infrequent bleeding, defined as less than three episodes of bleeding in a reference period (excluding amenorrhea). The least common pattern was frequent bleeding, defined as more than five episodes of bleeding in a reference period. Infrequent, prolonged and frequent bleeding patterns were most common early in the study and declined thereafter. During the 3-month Reference Periods 2���8 (Months 4���24), the incidence of amenorrhea ranged from 14% to 20%. Forty-three subjects (13%) withdrew from the study because of bleeding pattern changes and 76 subjects (23%) discontinued because of other AEs. Other common AEs leading to discontinuation, besides bleeding irregularities, were emotional lability (6.1%), weight increase (3.3%), depression (2.4%) and acne (1.5%). Use of Implanon (etonogestrel subdermal implant, referred to herein as ENG implant) for up to 2 years had no clinically significant effects on laboratory parameters, physical and pelvic examinations, vital signs or body mass index. The average length of time required for ENG implant insertion and that for removal were 0.5 and 3.5 min, respectively, and all the procedures were uncomplicated. The return to normal menstrual cycles and fertility was rapid after removal. Conclusions Implanon is a safe, highly effective and rapidly reversible new method of contraception.

Objectives To translate the previously described Pelvic Pain and Urgency/Frequency (PUF) questionnaire into Spanish using a back-translation technique and to validate the Spanish version in a group of bilingual women with symptoms consistent with interstitial cystitis or painful bladder syndrome. Methods Bilingual women with complaints of urinary urgency/frequency and/or pelvic pain were randomized to complete initially either the Spanish version or the original English version of the PUF questionnaire followed by the questionnaire in the other language. To evaluate retest reliability, subjects completed the Spanish version a second time 1 week later. Demographic information, including age, ethnic origin, and primary language, was obtained. Paired t tests and Wilcoxon signed rank tests for total PUF score, its two domain scores, and each item were used to assess the difference between the Spanish and English versions. Test and retest reliability of the Spanish version was similarly assessed. Agreement between the Spanish and English versions was assessed by weighted kappa statistics and 95% confidence intervals for each item. P values less than 0.05 were considered significant, and kappa values greater than 0.7 were considered to indicate good agreement. Results No statistically significant difference was found in the mean or median scores (ie, item, symptom, bother, total) between the English and Spanish versions. Good agreement between English and Spanish versions in all eight items was demonstrated by weighted kappa statistics. The Spanish version demonstrated retest reliability among total scores and seven of eight items when administered 1 week later. Conclusions The Spanish PUF questionnaire is a valid and reliable instrument for the evaluation and treatment of patients with interstitial cystitis or painful bladder syndrome.

Female hormonal contraceptive methods have undergone slow change over the past four decades. Due to social, political and legal reasons, as well as medical complications, several new methods have been removed from the contraceptive armamentarium almost as quickly as they have been added. With worldwide unintended pregnancy rates approaching 50% of all pregnancies, there is an increased need for the development of new methods of effective, safe, acceptable hormonal contraception. Pharmacological methods of contraception are reversible and contraceptive steroids are now formulated in pills, patches, intravaginal rings, subdermal implants and injections. All currently marketed formulations are made from synthetic steroids and contain no natural oestrogens or progestins. This article reviews the current state of female contraception and explores future directions.

Interstitial cystitis (IC) remains a challenging disease to treat, but increased awareness, better diagnostic tools, and effective pharmacologic agents can help non-urologists successfully manage this condition. Interstitial cystitis is much more prevalent than previously thought and is often misdiagnosed. Left untreated, IC can have a deleterious effect on the quality of life of the affected individual. In-office symptom-based techniques have been developed to screen for the presence of IC in both women and men presenting with symptoms of chronic pelvic pain (CPP) or chronic prostatitis (CP), and effective pharmacologic treatments exist that can provide acute and long-term symptom relief. Individual patient response to therapy varies, with some patients taking up to several months to achieve an optimal therapeutic response. To optimize patient response, a comprehensive algorithm for the diagnosis and management of IC should be utilized. Symptoms and progress should be assessed at each follow-up visit and changes in therapy made accordingly. Patients should be encouraged to learn as much as possible about IC and to take charge of the management of symptoms using their physician for guidance in decision making. The importance of this aspect of therapy should be reinforced at each subsequent visit. The entire office staff also has an important role in understanding and acknowledging each patient's pain and frustration as well as in providing support and education about IC.This paper presents recommendations from a multidisciplinary panel for the evaluation, diagnosis, treatment, and follow-up care of patients with IC or CPP of bladder origin.

C disease (CVD) is the leading cause of death among US women. Despite this fact, CVD is perceived mainly as a disease of middle-aged men. Female patients often seriously underestimate the risk of CVD faced by themselves and other women, focusing instead on other causes of morbidity and mortality, such as cancer.1 At the same time, physicians may underdiagnose heart disease in women because of a lack of awareness. Women often present differently from men, with atypical chest pain and less specificity for exercise stress testing. Perhaps, because of missed diagnoses, women tend to have more advanced disease at the time of diagnosis and less favorable outcomes after first or subsequent myocardial infarctions.2 The risk of CVD in women increases substantially after menopause. This finding is believed to be caused in part by the loss of estrogen, which has multiple protective effects on the vascular system (reviewed by Mendelsohn and Karas).3 Numerous observational studies have shown a cardioprotective benefit when estrogen replacement therapy/hormone replacement therapy (ERT/HRT) is given to healthy women after menopause. However, recent randomized trials (Heart and Estrogen/ progestin Replacement Study [HERS], Estrogen Replacement and Atherosclerosis [ERA] trial) have suggested that in women with well established CVD, ERT and HRT do not have a protective effect, and they may even lead to an increased risk of coronary events in their first year of use.4,5 It is important to emphasize that these trials were for secondary CVD prevention in older postmenopausal women with established CVD only, and that they included only a single combination HRT regimen. The results obtained in these trials are therefore not relevant to the potential effect of primary prevention of CVD in healthy women or to use of the newer HRT formulations that are now available. Unfortunately, these studies have been extensively overinterpreted as well as misinterpreted.6 Because of the misinterpretation of these studies, there is considerable confusion in the medical community about the use of HRT and its potential effects on CVD risk. Table 1 lists some of the most common misconceptions. These issues were addressed at a roundtable discussion held in Los Angeles on June 21, 2001, attended by a multidisciplinary panel of physicians with expertise in the fields of cardiology, obstetrics and gynecology, and epidemiology. The objecFrom the Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA; and Tufts University School of Medicine, Molecular Cardiology Research Institute, Tufts–New England Medical Center, Boston, Massachusetts, USA. Address for reprints: Daniel R. Mishell, Jr., MD, Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Mail Code 999, Building WCH L-1009, 1240 North Mission Road, Los Angeles, California 90033.

Objective This study aims to determine the lowest effective of three Nestorone (NES)/estradiol (E2) transdermal gel doses to ensure ovulation suppression in 90–95% of cycles. Methods This was a randomized, open-label, three-treatment-period cross-over study to evaluate the effects of NES/E2 transdermal gel on ovulation inhibition, suppression of follicular growth and pharmacokinetic parameters. The doses were low (1.5 mg NES/0.5 mg E2), medium (3.0 mg NES/1.0 mg E2) and high (4.5 mg NES/1.5 mg E2). Participants applied gel daily to a fixed area on the abdomen for 21 consecutive days. They were interviewed regarding their experiences using the gel. Results Eighteen participants were randomized; 16 completed the study. Median NES Cmax values for low, medium and high dose groups at day 21 were 318.6 pmol/L, 783.0 pmol/L and 1063.8 pmol/L, respectively. Median maximum follicular diameter was higher with the lowest dose with 16.2 mm versus 10.0 and 10.4 mm with the medium and high doses, respectively. Among adherent participants, ovulation was inhibited in all dose groups, except for one participant in the medium dose (6.7%) that had luteal activity and an ultrasound image suggestive of a luteinized unruptured follicle. There were few reports of unscheduled bleeding, with more episodes reported for the lower dose. Adverse events were mild, and no skin irritation was reported from gel application. Conclusion While all three doses blocked ovulation effectively and were evaluated as safe and acceptable, the medium dose was considered the lowest effective dose based on a more adequate suppression of follicular development. Further development of this novel contraceptive delivering NES and E2 is warranted and has potential for improved safety compared to ethinyl-estradiol-based methods.

Objective The safety and tolerability of a new low-dose levonorgestrel/ethinyl estradiol (LNG/EE) contraceptive patch was compared with 2 combination oral contraceptives in 2 clinical studies in which approximately 30% of enrolled participants were obese. Study Design Two phase 3, open-label, randomized, parallel-group, multicenter trials compared the LNG/EE contraceptive patch (n = 1579) with combination oral contraceptives (n = 581) in healthy women 17–40 years of age. Combination oral contraceptives were LNG 100 μg per EE 20 μg (combination oral contraceptive 20; n = 375) or LNG 150 μg per EE 30 μg (combination oral contraceptive 30; n = 206). Safety and tolerability data from the 2 trials were evaluated in integrated safety analyses. Results Treatment-emergent adverse events of 2% or greater in the LNG/EE contraceptive patch were nasopharyngitis (5.2%), nausea (4.1%), upper respiratory infection (3.5%), headache (3.4%), sinusitis (2.9%), cervical dysplasia (2.3%), and urinary tract infection (2.1%). Including skin reaction–related treatment-emergent adverse events, the proportion of women who experienced any treatment-emergent adverse event was similar among women randomized to the contraceptive patch (47.5%), the combination oral contraceptive 20 (47.4%), or the combination oral contraceptive 30 (46.8%). The incidence of treatment-emergent adverse events was similar in obese vs nonobese participants in all groups. Serious adverse events occurred in less than 1% of participants in any of the treatment groups. Conclusion The LNG/EE contraceptive patch and combination oral contraceptives were well tolerated and associated with similar treatment-emergent adverse event incidences in obese and nonobese women.

Objective: To compare the effect of mifepristone with placebo on cervical ripening before labor induction in prolonged pregnancies. Methods: One hundred eighty women with pregnancies beyond 41 weeks and undilated, uneffaced cervices were assigned randomly to receive mifepristone 200 mg or placebo and observed for 24 hours. We then gave intravaginal misoprostol 25 μg every 4 hours or intravenous oxytocin. We expected 60% of placebo-treated and 80% of mifepristone-treated women to deliver vaginally within 48 hours. Results: Among 180 subjects, 97 received mifepristone and 83 received placebo. The mean interval (± standard deviation [SD]) from start of induction to delivery was 2209 ± 698 minutes for mifepristone-treated subjects and 2671 ± 884 minutes for placebo-treated subjects (P < .001, log-transformed data). Twelve (13.6%) mifepristone-treated women and seven (10.8%) placebo-treated women delivered vaginally on day 1 (P = .60). After 24 hours, the median Bishop score for both groups was 3 (0–11) (P = .51). One hundred thirty-one subjects required misoprostol, 65 (67.0%) were mifepristone-treated women, and 66 (79.5%) placebo-treated women (P = .06). The median (range) oxytocin dose was 871.5 (0–22,174) mU for mifepristone-treated women and 2021.0 (0–24,750) mU for placebo-treated women (P = .02). Seventy-seven (87.5%) mifepristone-treated women and 46 (70.8%) placebo-treated women delivered vaginally 48 hours after the start of treatment (P = .01). There were nine cesareans in the mifepristone group and 18 in the placebo group (P = .02). More nonreassuring fetal heart rate patterns and uterine contractile abnormalities occurred in mifepristone-treated subjects. There were no statistically significant differences in neonatal outcomes between groups. Conclusion: Mifepristone had a modest effect on cervical ripening when given 24 hours before labor induction, appearing to reduce the need for misoprostol and oxytocin compared with placebo.

Vaginal inspections using colposcopy before insertion of contraceptive vaginal rings and at 2-month intervals during ring use were conducted on 169 users of four different formulations. The rings studied released Nestorone alone (50, 75, 100 g daily over 6 months); ethinyl estradiol: Nestorone (30:100 and 15:150 g daily over 6 months); ethinylestradiol:norethindrone acetate (20:1000 and 15:1000 g daily over 4 months); and ethinyl estradiol:norethindrone acetate (20:1000 g daily over 12 months). A total of 88 altered or atypical conditions of the vaginal surface appearance were recorded in 507 inspections (17.4% of inspections). Many of these atypical appearances were quite subtle. The incidence was significantly higher (p0.01) than in the single pretreatment examinations (11 in 158 inspections; 7.0%), but closely matched that of a "control group" of sexually active women who were the subject of an earlier study by the same investigators. In that study, the incidence was 18% (57 atypical conditions in 317 inspections). In all, 83% of atypical conditions identified in the vagina during ring use had disappeared by the next scheduled colposcopy despite continued ring use. Findings of potential significance were conservatively defined as all ulcerations, those abrasions and ecchymoses that were0.5 cm in any direction, and fields of five or more petechiae. Findings fitting those criteria comprised 30% of atypical conditions in ring users, 33% in the control group, and 27% pretreatment. The corresponding incidence as a percentage of inspections were 5.3%, 6. 0%, and 2.5% in the ring users, control groups, and pretreatment groups, respectively. These differences were not statistically significant. The findings suggest that the vaginal rings included in the studies contributed little, if at all, to clinically significant lesions or to total lesion incidence. Further definition would require a larger and longer-term study with matched controls.

Objective: The purpose of this study was to compare the abortifacient effect of intravaginally administered moistened misoprostol tablets with that of the combination regimen of mifepristone and oral misoprostol. Study Design: One hundred women at ≤56 days' gestation received 800 μg misoprostol intravaginally in the form of sodium chloride solution–moistened tablets. The dose was repeated 24 hours later if a gestational sac persisted on ultrasonographic examination. These 100 subjects (group 1) were then matched with 100 subjects who had received 600 mg mifepristone followed by 400 μg misoprostol orally as part of a large multicenter American trial (group 2). Subjects were monitored for abortion success, adverse side effects, and bleeding characteristics. Abortion failure was defined as persistence of an intrauterine sac or the need to perform a surgical evacuation of the uterus for hemorrhage, for incomplete abortion, or at the subject's request. Results: In 88 of the 100 women in group 1 and 94 of the 100 women in group 2, abortion occurred and a surgical procedure was not required. Abortion rates were not influenced by gestational age in either group. Prostaglandin-related side effects of fever and chills, vomiting, diarrhea, and uterine pain were all significantly higher in group 1. Excessive uterine bleeding was uncommon in both groups, and no subjects received blood transfusions. Conclusion: The abortion rate with intravaginally administered moistened misoprostol tablets is similar to that with the combination of mifepristone and oral misoprostol. However, intravaginal administration of misoprostol is associated with significantly more prostaglandin-related side effects. (Am J Obstet Gynecol 1999;181:1386-91.)

A total of 107 sexually active women, aged 18-35 years, was recruited through family planning clinics in four centres in different countries. Each woman underwent two or three gentle but thorough and systematic vaginal inspections using a consistent technique with colposcopic magnification over a 4-6 month period to look for changes in vaginal and cervical appearance which might be related to sexual intercourse, tampon use, contraceptive method used, cigarette smoking or other environmental factors. Obvious changes in appearance were photographed at x10 magnification. These 'appearances' or 'conditions' were classified according to a modification of the recommendations of a workshop sponsored by the World Health Organization, the Population Council and the Conrad Program. Most of these alterations in the appearance of the vaginal epithelium were judged to be of such minor clinical importance that they have been termed 'conditions' or 'changes in appearance' rather than 'lesions'. In all, 56 'conditions' or 'appearances' were noted in 314 inspections, the commonest being petechiae (53.6%). Potentially significant conditions justifying the term 'lesions' (three microulcerations, two ecchymoses, five abrasions and one mucosal tear; 3.5% of inspections) usually healed spontaneously and disappeared rapidly. The incidence of these conditions was highest when the inspections followed intercourse in the previous 24 h (25.2 versus 14.2%; P < 0.0008), or tampon use (32.4 versus 15.9%; P < 0. 0001). These processes may be regarded as a reflection of regular minor trauma to the vaginal epithelium.

In 1988, the Department of Obstetrics and Gynecology of the University of Southern California School of Medicine; created its own Breast Diagnostic Center for training resident physicians and providing breast care for outpatients and inpatients of Women's and Children's Hospital, Los Angeles, California. The structure and function of the Breast Diagnostic Center allow residents to be directly involved in and responsible for evaluation and care of benign breast problems and allow comprehensive breast-care education and integration of referral breast services for residents and patients. Direct faculty supervision, uniform history and physical records on printed forms, fine-needle aspirations and breast biopsies, and staff assistance with follow-up and patient tracking maximize resident physician education and experience. This departmental approach to resident physician training in breast care can be adapted to the resources and logistics of any department of obstetrics and gynecology.

Objective: To compare the effectiveness of misoprostol administered intravaginally every 6 versus every 12 hours for termination of second-trimester pregnancies. Methods: One hundred pregnant women at 12–22 weeks’ gestation were randomized to receive 200 μg of misoprostol intravaginally either every 6 or every 12 hours for up to 48 hours. Results: The incidences of abortion within 48 hours after initial drug administration were 87.2 and 89.2%, the complete abortion rates 43.9 and 33.3%, and the mean abortion intervals 13.8 and 14.0 hours in the 6- and 12-hour groups, respectively. Side effects were similar between groups. Conclusion: Misoprostol administered vaginally is effective for terminating second-trimester pregnancies. Shortening the dosing interval from 12 to 6 hours produced no significant benefit.

The high estrogen doses in the original oral contraceptive (OC) formulations were associated with an increased risk of cardiovascular events. Since then the steroid doses in OC have been reduced steadily, so that current low-estrogen-dose (or = 35 micrograms) combination OC are associated with a lower risk of arterial and venous events than occurs with higher-estrogen-dose formulations. Based on the currently available epidemiologic evidence, the following conclusions can be made regarding the cardiovascular disease risks associated with use of low-dose OC by healthy, nonsmoking women: there is no increased risk of myocardial infarction (MI) or hemorrhagic or ischemic stroke; and there is a three- to fourfold increased risk of venous thrombosis and embolism (VTE). This risk is about half that associated with pregnancy. Smoking is the most important independent risk factor for MI, and is synergistic with OC use. Women smokers should be advised strongly to stop smoking, but those aged35 years may use any OC containingor = 35 micrograms of estrogen. Women smokers agedor = 35 years should be advised to use a nonestrogen or nonhormonal contraceptive method.

The interaction between smoking and oral contraceptive (OC) use with respect to thrombogenesis was investigated by studying the effects of OC and smoking on urinary prostacyclin (PGI 2 ) and thromboxane A 2 (TxA 2 ) metabolite levels in smokers and nonsmokers. Sixty healthy women, aged 19–32 years, who were not taking any hormonal treatment for at least 3 months before initiating the study, were divided into three equal groups: OC users who smoked (N = 20), OC users who did not smoke (N = 20), and a control group of 10 smokers and 10 nonsmokers. Each OC treatment group was randomized to receive either norethindrone (NET) acetate (1 mg)/ethinyl estradiol (EE 2 ) (35 μg) (N = 10) or NET acetate (1 mg)/EE 2 (20 μg) (N = 10) daily for 3 months. Overnight urine collections and fasting blood samples were obtained at baseline and at the end of the 3-month study. Serum levels of NET and EE 2 , as well as urinary levels of cotinine and the stable metabolites of PGI 2 and TxA 2 , namely 6-keto-prostaglandin F 1α (6-keto-PGF 1α ) and thromboxane (TxB 2 ), respectively, were measured by specific immunoassays. Analysis of pre- to posttreatment changes in mean urinary 6-keto-PGF 1α and TxB 2 levels for each subgroup, as determined by smoking status and EE 2 dose, showed no statistically significant differences. Also, no significant differences were found in each subgroup with respect to changes in the 6-keto-PGF 1α /TxB 2 ratios. Large intersubject variability in urinary 6-keto-PGF 1α and TxB 2 levels were observed in all subgroups. The results of this study indicate that both low-estrogen–dose compounds, when used by smokers or nonsmokers, did not significantly alter the ratio of PGI 2 to TXA 2 metabolites, compared with pretreatment. However, the small number of subjects and the large intersubject variability in this study make it difficult to determine if there is a significant difference between the 20- and 30-μg EE 2 doses.

A 5-year trial of a two-rod contraceptive implant, which releases the progestin levonorgestrel (LNG rod), was conducted at four clinics with 594 women. Mean age and weight at admission were 25.5 years and 62.4 kg, respectively. Consent to continue through 5 years was sought and obtained when the 3-year cumulative pregnancy rate proved to be 0.8 per 100. No pregnancies occurred in the fourth or fifth years. The 5-year cumulative pregnancy rate was, therefore, 0.8 per 100 with an annual average pregnancy rate below 2 per 1000 women. Prolonged bleeding/spotting (8.2% of subjects) and irregular bleeding (5.6%) were the most frequently cited medical reasons for removal. Removals for headache (4.7%) and weight change (4.0%) were the next most frequent medical reasons. Between 1% and 2% of subjects during the 5-year trial sought removals for each of the following conditions: mood changes, lower abdominal pain, depression, or pain at the implant site. The mean annual continuation rate during the study was 77 per 100. Use per woman averaged 2.96 years. Mean removal time was 5.9 +/- 0.6 min. These data indicate that, for a 5-year period, the two LNG rod implants are equivalent to the six Norplant capsule implants with respect to safety and efficacy parameters, but permit easier and more rapid implant removal.

Forty-two healthy women volunteered to have blood samples drawn at 2, 4, 8, 24, 48, and 168 h (7 days) following placement of levonorgestrel-releasing rod (LNG rod) or of Norplant capsule implants to permit measurement of drug concentrations. Three clinics recruited 10 women each, half of whom used each type of implant. Twelve additional subjects were later enrolled at one site to provide greater detail for the capsule implants. Throughout the week, women with Norplant implants had apparently higher mean drug concentrations than did women with LNG rod implants, but the differences were significant only in the first 48 h after placement (p0.05). Maximum levels for capsule implants were found at the 24-h sample (mean, 1358 to 1474 pg/mL) and for the LNG rod implants at 48 h (772 pg/mL). Body weight was negatively correlated with levonorgestrel concentrations at all times (p0.05). For several sampling times, differences between clinics in mean concentrations were statistically significant after weight adjustment. Despite differences by implant type, weight, or clinic location, drug concentrations compatible with contraceptive effect were attained within 24 h in users of LNG rod or of Norplant implants, insofar as all women had levonorgestrel concentrations above 250 pg/mL at the 24-h sample.To establish the minimum times required for contraceptive implants to achieve serum concentrations compatible with contraceptive action, drug concentrations were measured in blood samples collected from 42 women at 2, 4, 8, 24, and 168 hours after implant insertion. 15 volunteers from three centers (US, Chile, and the Dominican Republic) were fitted with a levonorgestrel (LNG)-releasing rod and 27 received Norplant implants. An LNG concentration of 250 pg/ml and above was considered indicative of contraceptive action. By 8 hours, all Norplant subjects but only 40% of the LNG rod subjects had achieved this serum level. By 24 hours, however, all women in both groups had LNG concentrations above 250 pg/ml. The maximum mean LNG level was recorded in the 24-hour sample (1358 pg/ml) in the Norplant group and at 48 hours (772 pg/ml) in the LNG rod group. Consistent with earlier investigations, LNG concentrations demonstrated strong and significant negative correlations with body weight at all time points. The paucity of pregnancies recorded in large-scale clinical trials in the first month of use of contraceptive implants supports the rapid attainment of effective LNG concentrations. It remains unclear, however, precisely how late in the menstrual cycle implants can be inserted and still prevent follicular development or halt ovulation. Until more information is available, continuation of the policy of implant placement in the first few days after the onset of menstruation is recommended.

Our purpose was to determine whether intracervical placement of laminaria tents would improve the effectiveness of the prostaglandin analog misoprostol for the elective termination of pregnancies in the second trimester.Sixty-eight women between 12 and 22 weeks of gestation with either an intrauterine fetal death (n = 40) or medical or genetic indications for pregnancy termination (n = 30) were randomized to receive 200 micrograms of misoprostol administered vaginally every 12 hours with or without intracervical placement of laminaria concurrently with the first dose of misoprostol.The rate of abortion 24 hours after initiation of treatment was 69.7% in the 33 women receiving misoprostol alone and 68.6% in the 35 women treated with misoprostol and laminaria. The abortion rates 48 hours after initiation of treatment were 84.8% and 91.4%, respectively, an insignificant difference. The complete abortion rate was also similar between women receiving misoprostol alone (39.3%) and the group receiving misoprostol and laminaria (37.5%). There were no significant differences in the incidence of fever, vomiting, diarrhea, or pain. The mean interval from initiation of treatment to abortion was also similar, 15.7 hours in those receiving misoprostol alone and 17.4 hours in those treated with misoprostol and laminaria. In both groups women who had live fetuses at the start of the procedure had a higher failure rate of abortion and a longer time interval to abortion than women whose fetus was dead.Laminaria tents inserted concurrently with the first dose of misoprostol do not significantly improve the abortifacient effect of vaginal misoprostol in the second trimester of pregnancy.The authors conducted a study to determine whether the intracervical placement of laminaria tents would improve the effectiveness of the prostaglandin analog misoprostol for the elective termination of pregnancies in the second trimester. 68 women at 12-22 weeks of gestation with either an intrauterine fetal death or medical or genetic indications for pregnancy termination were randomized to receive 200 mcg of misoprostol administered vaginally every 12 hours with or without the intracervical placement of laminaria concurrently with the first dose of misoprostol. There was a 69.7% rate of abortion 24 hours after the initiation of treatment in the 33 women who received misoprostol alone and 68.6% in the 35 women treated with both misoprostol and laminaria. Abortion rates 48 hours after the initiation of treatment were 84.8% and 91.4%, respectively, an insignificant difference. The complete abortion rate was 39.3% among women who received misoprostol alone and 37.5% among women who received both misoprostol and laminaria. There were no significant differences between the two groups in the incidence of fever, vomiting, diarrhea, or pain. The mean interval from the initiation of treatment to abortion was 15.7 hours among women who received misoprostol alone and 17.4 hours among women who received both misoprostol and laminaria. In both groups, women who had live fetuses at the start of the procedure had a higher failure rate of abortion and a longer time interval to abortion than women whose fetus was dead. These findings indicate that the insertion of laminaria tents concurrent with the first dose of misoprostol does not significantly improve the abortifacient effect of vaginal misoprostol during the second trimester of pregnancy.

To compare the clinical performance of the TCu380A, the most widely used copper IUD in the world today, and a new frameless device, the Cu-Fix, we report results from a randomized international two-year clinical trial involving 874 parous women followed for an average of fourteen months. Event rates at the end of two years (per 100 women) for pregnancy were 0.0 for the TCu380A and 1.5 for the Cu-Fix. Termination due to expulsion was significantly less for TCu380A as compared with Cu-Fix users (2.0 and 11.4 per hundred women, respectively); other medical reasons for termination (bleeding/pain, pelvic inflammatory disease (PID), and other) did not differ significantly. PID incidence rates at two years were 1.0 per hundred women for the TCu380A and 1.6 for the Cu-Fix (equivalent to 6.0 and 8.3 per 1,000 woman-years, respectively). The net cumulative continuation rates at two years per hundred women were 78.8 for TCu380A, and 71.9 for the Cu-Fix. Both IUDs provide highly effective protection against pregnancy, but the TCu380A has a lower expulsion rate. The low rate of PID indicates that it is an in-frequent occurrence in appropriately selected candidates.

Misoprostol is a prostaglandin analogue which has uterotonic properties. Administered vaginally, it is an effective agent for induction of second trimester abortions. This study was undertaken to determine if the vaginal administration of misoprostol is effective for inducing first trimester abortions. Fifty-eight women with pregnancies less than 10 weeks gestation who desired pregnancy termination received varying dosages of vaginal misoprostol, either alone or in combination with laminaria or tamoxifen. The overall success rate for a complete abortion was 61%. The use of laminaria or tamoxifen did not affect success rates. Abortions occurred within 24 hours of administration of misoprostol. Side effects were minimal. There were no significant differences in any of the following between those who had a successful abortion and those who did not: gravidity, parity, prior elective abortion, age, gestational age of the pregnancy, and level of human chorionic gonadotropin. Although not as successful as other combination regimens, misoprostol alone is readily available, easy to administer, and without major side effects. The use of this agent could eliminate the need for about two-thirds of surgical abortions in the first 10 weeks of gestation.