OBJECTIVE:This study aimed to determine the effect of oophorectomy on baseline serum levels of androgens and estrogens in premenopausal and postmenopausal women. METHODS: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 (E1), estradiol (E2), and sex hormone-binding globulin (SHBG) were measured by highly specific immunoassays prior to surgery and 2 weeks afterward. Free T and free E2 were calculated. Differences were determined between preoperative (preop) and postoperative (postop) samples, and between premenopausal and postmenopausal women. RESULTS:In premenopausal women, postop levels of total and free T, DHT, and total and free E2 decreased significantly from preop. Postop levels of DHEAS, A, 3α-diol G, and SHBG were decreased, but not significantly different from preop. In postmenopausal women, postop levels of total and free T and total and free E2 decreased significantly from preop, but there was little change in the other compounds. Significant differences in the mean change from baseline between premenopausal and postmenopausal women were observed only for E1 and total and free E2. CONCLUSION:The significant decrease in serum T in postmenopausal women following oophorectomy adds to the evidence that the postmenopausal ovary continues to produce T.

The selection committee picked three papers most deserving of this award.These articles included high-quality methodology, an excellent presentation of results, and a discussion that showed an exceptional understanding of

Unintended pregnancy is one of the main causes of maternal morbidity and mortality worldwide. Consequences of unintended pregnancy have an enormous financial and societal impact resulting in high medical costs, a reduction in the female workforce, and a threat to families and children. Empowering women to achieve their desired family size should be the focus of global public health policy in the 21st century. One of the major mechanisms toward achieving a desired family size is through enhanced contraceptive access and safe abortion. Currently there is an unmet global need for contraception in excess of 200 million women. This need can best be met by educating more women regarding all contraceptive options, development of diverse contraceptive options that address the needs of women from different cultural and ethnic backgrounds, and promotion of long-acting reversible contraception. Additionally, contraceptive methods that have additional medical benefits such as reducing the incidence of certain cancers and preventing the transmission of HIV are important considerations. The following themed section of this Women’s Health issue includes articles that provide the most current and evidence-based approaches toward achieving the goal of reducing the global burden of unintended pregnancy. ‘Addressing gaps in the contraceptive method mix: methods in development’ by Nanda et al. [1] highlights the importance of novel contraceptive development. New contraceptive methods aim to increase the number of contraceptive users through nontraditional approaches while maintaining or improving contraceptive efficacy. Another equally important strategy toward reducing unintended pregnancy is by reducing the incidence of teenage pregnancy. ‘Contraceptive counseling for adolescents’ by Potter and Santelli [2] focuses on key strategies for healthcare providers to increase the uptake of highly effective contraception for this patient population. ‘Oral steroid contraception’ by Sech and Mishell [3] aims to dispel certain myths attributed to the use of oral contraceptives that may prevent their current widespread global use. Oral steroid contraception continues to be a popular form of family planning with many additional and important health benefits. Knowledge of the true adverse event risk of oral steroid contraception will help to improve access to this highly desired form of contraception. The articles ‘Long-acting hormonal contraception’ (Benagiano et al.) [4] and ‘Intrauterine contraception’ (Whaley and Burke) [5] address the use of long-acting reversible contraception such as injectables, implants and IUDs, all of which can be used with safety in a wide variety of patient populations including adolescents. These forms of contraception have the highest contraceptive efficacy in addition to being completely reversible. ‘Permanent contraception for women’ by Micks and Jensen [6] addresses the available options for women who have definitively achieved their desired family size. It is important that these procedures are offered to women during pregnancy since the great majority of female permanent contraceptive procedures are performed in the immediate Contraception and its global public health impact

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.

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: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.

In Brief 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=1,504) were randomized to Patch (n=1,129) 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 Contraceptive efficacy and compliance between a new low-dose levonorgestrel and ethinyl estradiol patch and pill are comparable.

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 (D2O; 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 D2O 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.

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. (C) 2013 Elsevier Inc. All rights reserved.

Objectives To review the clinical experience with the contraceptive vaginal ring (CVR, NuvaRing (R)) 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.

Increased maternal mortality among women with Sickle Cell Disease (SCD) underscores the need for the use of effective contraceptives. Women with SCD have multiple health care providers potentially counseling them about contraception. This can create confusion and contribute to non-usage. The purpose of this study is to identify perceptions of counseling and reasons for contraceptive non-usage among women with SCD in the greater Los Angeles area.

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.

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.

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.