Development of a Cost-Effective Educational Tool to Promote Acceptance of the HPV Vaccination by Hispanic Mothers.

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.

Oral steroid contraception.

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.

A dose-finding, cross-over study to evaluate the effect of a Nestorone®/Estradiol transdermal gel delivery on ovulation suppression in normal ovulating women.

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 C(max) 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.

Safety and tolerability of a new low-dose contraceptive patch in obese and nonobese women.

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.

Comparison of serum and cervical mucus hormone levels during hormone-free interval of 24/4 vs. 21/7 combined oral contraceptives.

BACKGROUND: 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. STUDY DESIGN: 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. RESULTS: 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). CONCLUSION: 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.

Contraception technology: past, present and future.

Steady progress in contraception research has been achieved over the past 50 years. Hormonal and nonhormonal 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 and estradiol valerate 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. Although 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 nonhormonal methods is 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.

Ovarian activity in obese and nonobese women treated with three transdermal contraceptive patches delivering three different doses of ethinyl estradiol and levonorgestrel.

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 <30) women. 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.

Temporal changes in cervical mucus after insertion of the levonorgestrel-releasing intrauterine system.

BACKGROUND: The major contraceptive action of the levonorgestrel-releasing intrauterine system (LNG-IUS) is cervical mucus (CM) thickening, which prevents sperm penetration. No study to date has examined the temporal relationship between the insertion of the LNG-IUS and changes in CM quality and sperm penetration. STUDY DESIGN: Participants were enrolled in a clinically descriptive study to compare the quality of CM and three parameters of sperm penetration prior to insertion of the LNG-IUS and on Days 1, 3 and 5 after insertion. Measurements of estradiol, progesterone and levonorgestrel (LNG) in serum and LNG in CM were also carried out at these times. CM was analyzed using the World Health Organization CM grading criteria. Sperm penetration was determined using an in vitro sperm-CM penetration test. RESULTS: All 10 participants underwent LNG-IUS insertion during midcycle when CM quality was good and sperm penetration was excellent. On Day 1 after LNG-IUS insertion, the majority of participants demonstrated poor CM quality and poor sperm penetration. On Day 3, all participants had poor CM quality, and all but one subject had poor sperm penetration. By Day 5, all participants had poor CM quality and poor sperm penetration. LNG levels in CM peaked on the day after LNG-IUS insertion. CONCLUSION: Significant changes in quality of CM and sperm penetration were observed shortly after LNG-IUS insertion; however, CM can remain penetrable for up to 5 days when the LNG-IUS is inserted midcycle.

Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects.

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.

The contraceptive vaginal ring, NuvaRing(®), a decade after its introduction.

OBJECTIVES: To review the clinical experience with the contraceptive vaginal ring (CVR, NuvaRing(®)) since its introduction over ten years ago. METHODS: The literature was searched on efficacy, cycle control, safety, user preference and satisfaction of the CVR in comparison with combined oral contraceptives (COCs) and the patch, with special attention to recent developments. RESULTS: The ring has the same working mechanism and contraindications as COCs. Serum levels of steroids are steadier, whereas oestrogenic exposure is lower. Contraceptive efficacy is similar, as are metabolic changes. Cycle control is better, and compliance and continuation rates are equal or higher. Oestrogen-related adverse symptoms appear to be fewer, but reports on the incidence of venous thrombosis are conflicting. Expulsion of the ring is reported by 4% to 20% of women. Local adverse events are the main reason for discontinuation. Acceptability is as high as with COCs and, after structured counselling, the ring is preferred by many women to the pill or the patch. CONCLUSIONS: Efficacy of the CVR, and the metabolic changes and adverse events it elicits, are generally comparable to those of COCs, yet oestrogenic exposure is lower and cycle control superior. After counselling, the ring is preferred to the pill by many women.

Effects of a novel estrogen-free, progesterone receptor modulator contraceptive vaginal ring on inhibition of ovulation, bleeding patterns and endometrium in normal women.

BACKGROUND: Progesterone receptor modulators (PRMs) delivered by contraceptive vaginal rings provide an opportunity for development of an estrogen-free contraceptive that does not require daily oral intake of steroids. The objective of this proof-of-concept study was to determine whether continuous delivery of 600-800 mcg of ulipristal acetate (UPA) from a contraceptive vaginal ring could achieve 80% to 90% inhibition of ovulation. STUDY DESIGN: This was a prospective, controlled, open-labeled, multicenter international trial to examine the effectiveness and safety of this prototype vaginal ring. Thirty-nine healthy women, 21-40 years old and not at risk of pregnancy, were enrolled at three clinic sites. Volunteers participated in a control cycle, a 12-week treatment period and a post-treatment cycle. Pharmacodynamic effects on follicular function and inhibition of ovulation, effects on endometrium, bleeding patterns and serum UPA levels were evaluated. RESULTS: Mean UPA levels during treatment were nearly constant, approximately 5.1 ng/mL throughout the study. Ovulation was documented in 32% of 111 "4-week treatment cycles." A correlation was observed between serum UPA and degree of inhibition of ovarian activity. There was no evidence of hyperplasia of endometrium, but PRM-associated endometrial changes were frequently observed (41%). CONCLUSION: In this study, the minimum effective contraceptive dose was not established. Further studies are required testing higher doses of UPA to attain ovulation suppression in a higher percentage of subjects.

Randomized trial of estradiol vaginal ring versus oral oxybutynin for the treatment of overactive bladder.

OBJECTIVE: The aim of this study was to compare the efficacy of the ultralow-dose estradiol vaginal ring with that of oral oxybutynin in the treatment of overactive bladder in postmenopausal women. METHODS: Postmenopausal women with an overactive bladder were recruited from the general gynecology clinic. Participants were randomized to receive either the ultralow-dose estradiol vaginal ring or oral oxybutynin for 12 weeks. The primary outcome was a decrease in the number of voids in 24 hours. The secondary outcomes were quality-of-life questionnaires, vaginal pH levels, and vaginal maturation index. RESULTS: Fifty-nine women were enrolled. Thirty-one were randomized to receive oxybutynin, whereas 28 received the estradiol vaginal ring. Women who received oxybutynin had a mean decrease of 3.0 voids per day, and women who received the vaginal ring had a mean decrease of 4.5 voids per day, with no significant difference between the groups. There was a significant improvement in Urogenital Distress Inventory and Incontinence Impact Questionnaire scores in both groups, with no significant difference in improvement between the two groups. CONCLUSIONS: Ultralow-dose estradiol-releasing vaginal ring and oral oxybutynin seem to be similarly effective in decreasing the number of daily voids in postmenopausal women with overactive bladder.

Follicular development and ovulation in extremely obese women receiving depo-medroxyprogesterone acetate subcutaneously.

BACKGROUND: Subcutaneous depo-medroxyprogesterone acetate (DMPA-SC) has not been studied in the extremely obese population (BMI >or=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.

Breaking the cycle of pain in interstitial cystitis/painful bladder syndrome: toward standardization of early diagnosis and treatment: consensus panel recommendations.

Chronic pelvic pain (CPP) affects about 15% of female adults in the United States. The source of this pain in many women is the bladder, specifically interstitial cystitis/painful bladder syndrome (IC/PBS). Despite the frequent occurrence of IC/PBS as a cause of CPP, there currently are no universally accepted guidelines for diagnosis and treatment of this disorder, and, consequently, many patients do not receive appropriate treatment in a timely manner. In an effort to develop a rational way to diagnose and treat patients with CPP, a panel of leaders in urology, gynecology, urogynecology and general women's health met to review recent literature, reach consensus and formulate 2 algorithms, one for diagnosing and the other for managing IC/PBS. This article reflects the results of that meeting.

Follicular development in a 7-day versus 4-day hormone-free interval with an oral contraceptive containing 20 mcg ethinyl estradiol and 1 mg norethindrone acetate.

BACKGROUND: Combined oral contraceptive (COC) formulations with 20 mcg ethinyl estradiol (EE) have a greater incidence of ovarian hormone production and follicular development, which can be managed by shortening the number of hormone-free days per COC cycle. This study evaluates differences in follicular development during a 7-day versus 4-day hormone-free interval in a COC regimen with 20 mcg EE and 1 mg norethindrone acetate. STUDY DESIGN: Forty-one healthy women were randomized in an open-label fashion to this formulation in either a 24/4 or a 21/7 day regimen for three cycles. Estradiol, progesterone, follicle-stimulating hormone, luteinizing hormone and inhibin B were measured daily from Cycle 2, Day 21 to Cycle 3, Day 3 and on Day 7 of Cycle 3. Follicular diameter and Hoogland score were calculated on Cycle 2, Days 21, 24 and 28 and Cycle 3, Days 3 and 7. RESULTS: Sixty-six percent of subjects in the 21/7 group and 70% of the subjects in the 24/4 group developed a follicle greater than 10 mm diameter. Ovarian steroid hormone levels, Hoogland scores and bleeding patterns were not statistically significant between the groups. CONCLUSION: In contrast to prior studies, this analysis suggests no difference in follicle development or bleeding patterns among women receiving a 21/7 or 24/4 regimen of a 20-mcg EE/1-mg norethindrone acetate COC.

Evolving trends in the successful management of interstitial cystitis/painful bladder syndrome.

OBJECTIVE: To provide an overview of interstitial cystitis (IC), including the presentation of patients with the disorder, and to explore diagnostic and treatment options. STUDY DESIGN: Current literature concerning the history, etiology, diagnosis and treatment of IC was used to support expert recommendations regarding patient management. Experts discussed the literature surrounding IC, focusing on diagnostic tools and currently available treatment modalities. RESULTS: Diagnosis of IC may often be delayed or missed due to the similarity of symptoms with a number of other conditions. A detailed medical history and careful physical examination are key for diagnosis, and a variety of screening and diagnostic tools are also available. Once a patient is diagnosed with IC, multimodal treatment through pharmacological and nonpharmacological approaches is recommended. CONCLUSION: The involvement of both the patient and physician in determining the therapeutic approach, the use of multimodal therapies, regular follow-up and staff involvement in care can bring relief to a substantial number of patients with this condition.

The effect of transdermal and vaginal estrogen therapy on markers of postmenopausal estrogen status.

OBJECTIVE: 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. DESIGN: 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. RESULTS: Twenty women completed the study. The patch significantly increased serum E1 and E2 levels at 6 and 12 weeks (P < 0.01); 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 (P < 0.001) and 12 (P < 0.001) 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). CONCLUSIONS: 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.

Increased prevalence of interstitial cystitis in women with detrusor overactivity refractory to anticholinergic therapy.

OBJECTIVES: To estimate the prevalence of interstitial cystitis in women with detrusor overactivity refractory to anticholinergic medication using the potassium sensitivity test (PST). METHODS: Women with complaints of urinary frequency, urgency, and/or urge incontinence of 3 months' duration or longer were referred to the urogynecology clinic. Between October 2003 and June 2004, 47 consecutive women were diagnosed with phasic, idiopathic detrusor overactivity after evaluation by history, physical examination, urinalysis, urine culture, urodynamic testing, and cystoscopy. Refractory detrusor overactivity was defined as a 50% or less improvement in urinary urgency, frequency, and/or urge incontinence episodes while taking anticholinergic medications. All women were offered the PST. RESULTS: All 47 women were included in the study; 18 (38.3%) had only detrusor overactivity incontinence and 29 (61.7%) also had concomitant urodynamic stress incontinence. Additionally, 19 women (40.4%) had pelvic pain. Of the 47 women, 31 agreed to undergo the PST. Of the 31 women, 25 had positive and 6 had negative PST result. Of the 31 women, 25 did not respond to therapy with one or more anticholinergic medications, and 24 (96%) of these 25 had had a positive PST. The remaining 6 women responded to treatment with oxybutynin, and only 1 (16.7%) had had a positive PST (P = 0.0002). The odds ratio of a positive PST for women in whom anticholinergic therapy failed compared with women in whom it did not was 120.0 (95% confidence interval 6.4 to 2257.5; P = 0.0002). CONCLUSIONS: These preliminary findings suggest that there is a high prevalence of interstitial cystitis in women with detrusor overactivity that does not respond to anticholinergic medication.

Serum Nestorone and ethinyl estradiol levels, and ovulation inhibition in women using three different dosage combinations of a Nestorone progestogen-ethinyl estradiol contraceptive vaginal ring on a bleeding-signaled regimen.

OBJECTIVES: This trial tested the hypothesis that menstrually signaled use of contraceptive vaginal rings ("rings") releasing low-dose combinations of Nestorone (NES) and ethinyl estradiol (EE) would reliably suppress luteal activity and ovulation, and prevent unintended pregnancy, while controlling the incidence of menstrual bleeding episodes and bleeding days. METHODS: Nestorone/ethinyl estradiol rings releasing 50/10, 50/20 and 150/15 mug/day were studied through 6 months. A ring was to be used continuously, until its removal was signaled by menstrual bleeding. Reinsertion was required 96 h after removal. Serum for NES, EE and progesterone were collected and assayed, and vaginal ultrasound scans were performed in three 5-week periods to examine luteal activity, follicular growth, ovulation and their correlates. In 10 subjects using the 150/15 ring, six samples were drawn in the 24-h period after ring removal to examine serum levels of NES and EE. RESULTS: One hundred sixty subjects at three doses provided blood samples. Median serum concentrations of NES and EE demonstrated dose ratios slightly below the nominal dose ratios expected. Serum NES concentrations declined 19-22% from weeks 3 to 25. Changes in EE levels depended on dose. Nestorone levels fell 81% by 24 h after ring removal and EE levels fell by 50%. Luteal activity was completely suppressed in 94-95% of cycles and in 90% of subjects. Three pregnancies occurred in subjects participating in this serum sampling study. CONCLUSION: Satisfactory serum levels of NES and EE, and a high level of ovulation suppression were achieved. Irregular ring use, however, permitted pregnancies to occur.