New and emerging contraceptives: a state-of-the-art review

Luis Bahamondes, M Valeria Bahamondes Human Reproduction Unit, Department of Obstetrics and Gynaecology, Faculty of Medical Sciences, University of Campinas and National Institute of Hormones and Women's Health, Campinas, SP, Brazil Background: The first hormonal contraceptive was introduced onto the market in several countries 50 years ago; however, the portfolio of contraceptive methods remains restricted with regards to their steroid composition, their cost, and their ability to satisfy the requirements of millions of women/couples in accordance with their different reproductive intentions, behaviors, cultures, and settings. Methods: A literature review was conducted using Medline, Embase, and Current Contents databases, up to September 1, 2013 to identify publications reporting new contraceptives in development using combinations of the search terms: contraception, contraceptives, oral contraceptives, patch, vaginal ring, implants, intrauterine contraceptives, and emergency contraception (EC). Also, several experts in the field were also consulted to document ongoing projects on contraception development. Additionally, the Clinicaltrial.gov website was searched for ongoing studies on existing contraceptive methods and new and emerging female contraceptives developed over the past 5 years. Information was also obtained from the pharmaceutical industry. Results: Early sexual debut and late menopause means that women may require contraception for up to 30 years. Although oral, injectable, vaginal, transdermal, subdermal, and intrauterine contraceptives are already available, new contraceptives have been developed in an attempt to reduce side effects and avoid early discontinuation, and to fulfill women's different requirements. Research efforts are focused on replacing ethinyl-estradiol with natural estradiol to reduce thrombotic events. In addition, new, less androgenic progestins are being introduced and selective progesterone receptor modulators and new delivery systems are being used. In addition, research is being conducted into methods that offer dual protection (contraception and protection against human immunodeficiency virus transmission), and contraceptives for use "on demand." Studies are also investigating non-hormonal contraceptive methods that have additional, non-contraceptive benefits. Conclusion: The most pressing need worldwide is, first, that the highly effective contraceptive methods already available should be affordable to most of the population and also that these methods should fulfill the needs of women of different ages and with different reproductive requirements. The development of new contraceptive methods should also take advantage of the knowledge obtained over the past 30 years on gamete physiology and gamete interaction to avoid the use of steroid compounds. Keywords: emerging contraceptives, patch, vaginal ring, intrauterine devices, spray, emergency contraceptive

Long-term assessment of forearm bone mineral density in postmenopausal former users of depot medroxyprogesterone acetate

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Background: There are many controversies on the association between depot medroxyprogesterone acetate (DMPA) and bone mineral density (BMD). This study reevaluated BMD in postmenopausal women who had used DMPA as a contraceptive until they reached menopause and compared them with non-users. BMD had previously been measured in these women either at 1 year or 2-3 years after menopause and was reassessed in these women 2 years later. Therefore, comparisons were made between the first and third years and between the second to third and fourth to fifth years after menopause. Study Design: BMD was reevaluated using dual-energy X-ray absorptiometry at two parts of the non-dominant forearm up to 5 years after menopause in 79 women between 46 and 61 years old: 24 former DMPA users and 55 former copper intrauterine device (IUD) users. Results: With respect to the former DMPA users, only the BMD measurement at the distal radius in the first year (mean SEM, 0.425 +/- 0.017) was significantly higher than the third-year measurement (0.406 +/- 0.017) (p<.015). No significant differences were found at the ultradistal radius. There were no significant differences between the groups of former DMPA and IUD users with respect to BMD measurements either at the distal radius or at the ultradistal radius. There was a direct relationship between higher body mass index (kg/m(2)) and higher BMD at the distal radius between the first and third years. At the ultradistal radius, there was an indirect relationship between older age and lower BMD between the first and third years in both groups. Conclusions: No statistically significant differences were found in forearm BMD measurements between postmenopausal women who had been long-term users of DMPA and those who had been long-term users of an IUD until menopause. Evaluation of BMD after the menopause showed slightly higher values in former DMPA users compared with non-users. (C) 2011 Elsevier Inc. All rights reserved.842122127Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)CNPq [573747/2008-3

Pain at insertion of the levonorgestrel-releasing intrauterine system in nulligravida and parous women with and without cesarean section

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Background: Despite the high contraceptive effectiveness and noncontraceptive benefits of the levonorgestrel-releasing intrauterine system (LNG-IUS) in nulligravidas, there are still concerns related to the use of this device. Pain at insertion is one of the limitations to the increased use of intrauterine contraceptives. The aim of the study was to evaluate the ease of insertion and occurrence of pain at insertion of the LNG-IUS in nulligravidas (women who never became pregnant) compared to parous women with and without cesarean section (c-section). We also assessed the difficulty at insertion in each group. Methods: Three groups of new acceptors of the LNG-IUS were studied: one with 23 nulligravida women, one with 28 parous women who had undergone at least one c-section and one with 23 parous women who had no previous c-section. Pain at insertion was evaluated by using a pain visual analogue score (VAS). The ease of insertion was defined as easy or difficult by health care providers (HCPs) and classified according to the cause of difficulty: tight cervix, anatomically distorted uterus or pain. Results: Almost all women reported pain at insertion, regardless of parity and form of delivery. The mean VAS was 6.6 for nulligravida women, 5.2 for parous women with c-section and 5.9 for parous women with no c-section. Although 93% of the women reported pain at insertion, they also reported a willingness to insert a new LNG-IUS again if needed. The most common difficulties were a tight cervix in nulligravidas, an anatomically distorted uterus in parous women with c-section and pain in parous women without c-section. There was no failure of insertion in any group. HCPs reported that it was easier to perform insertion in parous women who had undergone only vaginal deliveries than nulligravid women or parous women with a prior c-section. Conclusions: Although almost all women reported pain at insertion, they also reported a willingness to insert a new LNG-IUS if needed. This attitude reflects high satisfaction with the LNG-IUS. The type of difficulty at insertion was related to parity and type of delivery. The LNG-IUS was able to be inserted in all women; however, it was easier to do in parous women without c-section than nulligravid women or those with a prior C-section. (C) 2013 Elsevier Inc. All rights reserved.881164168Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)CNPq [573747/2008-3

Prospective study of the forearm bone mineral density of long-term users of the levonorgestrel-releasing intrauterine system

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)The levonorgestrel-releasing intrauterine system (LNG-IUS) induces amenorrhoea, and its effect on bone mineral density (BMD) may constitute a concern. This study evaluated BMD in long-term users of the LNG-IUS or intrauterine device (IUD). BMD was evaluated at the midshaft of the ulna and ultra-distal radius using dual-energy X-ray absorptiometry in 37 women at 7 or 10 years of use following placement of a second LNG-IUS. The groups were paired for duration of use, age, body mass index (BMI), ethnicity and number of pregnancies. The mean age of both LNG-IUS and IUD users at the 7th and 10th year was similar to 34 and 38 years, respectively. Mean BMI was similar to 25 in both groups, increasing to similar to 26 at the 10th year. Amenorrhoea occurred in 51.4 and 91.9% of LNG-IUS users at the 7th and 10th year, respectively. Estradiol levels in LNG-IUS users were normal at both evaluations. There were no differences in BMD (g/cm(2)) at the midshaft of the ulna nor ultra-distal radius between LNG-IUS and IUD users or between the 7th and 10th years of use in LNG-IUS users. A Z-score below -2SD at the ultra-distal radius was observed in only one LNG-IUS user and in none of the IUD users at the 10th year. Higher BMI and BMD at the seventh year and amenorrhoea were predictors of higher BMD at the 10th year. BMD at the midshaft of the ulna and ultra-distal radius in LNG-IUS users were similar to that of IUD users and remained unchanged between the 7th and the 10th years of use.25511581164Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP [03/083917]CNPq [573747/2008-3

Length of the endometrial cavity and intrauterine contraceptive device expulsion

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Objective: To evaluate the correlation between endometrial cavity length and expulsion rate in acceptors of the TCu380A intrauterine device (IUD) or the levonorgestrel-releasing intrauterine system (LNG-IUS). Methods: The study included 235 nulligravida and parous women who received a TCu380A IUD or LNG-IUS and who were observed for up to 1 year. The length of the uterine cavity was measured by uterine sounding and ultrasonography. Results: The endometrial cavity was shorter than 3.2 cm in 2 LNG-IUS users and at least 3.2 cm long in 87 LNG-IUS users, with expulsions occurring in 0 (0.0%) and 2 (2.3%) of these women, respectively (P > 0.999). Among the TCu380A IUD users, the endometrial cavity was shorter than 3.6 cm in 63 women and at least 3.6 cm long in 83 women, with expulsions occurring in 3 (4.8%) and 5 (6.0%) of these women, respectively (P > 0.999). The mean length of the endometrial cavity-evaluated via ultrasonography-among the 10 women whose devices were expelled was 3.9 +/- 0.3 cm, compared with 3.9 +/- 0.0 cm in those who retained their devices (P = 0.799). Conclusion: The present results do not support the hypothesis of an association between uterine length and risk of intrauterine contraceptive expulsion. (C) 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.11315053Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)CNPq [573747/2008-3

Body weight and composition in users of levonorgestrel-releasing intrauterine system

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Background: There is little information about body weight and body composition (BC) among users of the levonorgestrel-releasing intrauterine system (LNG-IUS). The aim of this study was to evaluate body weight and BC in LNG-IUS users compared to users of the TCu380A intrauterine device (IUD). Study Design: A prospective study was done with 76 new users of both contraceptive methods. Women were paired by age (+/- 2 years) and body mass index (BMI, kg/m(2), +/- 2). Body weight and BC (% lean mass and % fat mass) were evaluated by a trained professional at baseline and at 1 year of contraceptive use. The BC measurements were obtained using Lunar DXA equipment. Weight and BC were evaluated in each woman at baseline and at 12 months and analyzed as the mean change within each woman. Then, the changes in weight and BC for each woman were calculated and then compared between LNG-IUS and TCu380A IUD users (paired data for each woman). The central-to-peripheral fat ratio was calculated by dividing trunk fat by the upper and lower limb fat. Results: There were no significant differences at time of IUD insertion between LNG-IUS and TCu380A IUD users regarding age (mean +/- SD) (34.4 +/- 7.5 vs. 33.9 +/- 8.0 years), BMI (25.3 +/- 4.1 vs. 25.9 +/- 4.1) and number of pregnancies (1.9 +/- 0.2 vs. 1.7 +/- 0.2), respectively. Mean body weight gain of 2.9 kg was observed among LNG-IUS users at 12 months (p=.0012), whereas the body weight of TCu380A IUD users only increased by 1.4 kg (p=.067). There was no significant difference in body weight change between the two groups of users at 12 months. The variation in the central-to-peripheral fat ratio was the same between the two groups (-1.6% vs. -0.2%; p=.364). LNG-IUS users showed a 2.5% gain in fat mass (p=.0009) and a 1.4% loss of lean mass, whereas TCu380A IUD users showed a loss of 1.3% of fat mass (p=.159) and gain of 1.0% of lean mass (p=.120). TCu380A IUD users gained more lean mass than LNG-IUS users (p=.0270), although there was no significant difference between the two groups after 12 months of use. Conclusions: Although an increase in mean fat mass among LNG-IUS users at 12 months of use was observed, it should be noted that an increase of body weight was also observed in both groups after 1 year of insertion of the device. However, a study with a larger number of women and long-term evaluation is necessary to evaluate these body changes. (C) 2012 Elsevier Inc. All rights reserved.864350353Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP [2009/15595-4]CNPq [573747/2008-3

Length of the endometrial cavity as measured by uterine sounding and ultrasonography in women of different parities

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Background: In view of current controversies regarding the need for new, shorter intrauterine devices (IUDs) that would reduce expulsion rates in nulligravida, endometrial cavity length was measured in women of different parities using uterine sounding and ultrasonography. Study Design: A cross-sectional descriptive study was performed including 570 women of 17-52 years of age, 260 of whom were nulligravida and 310 parous. Results: The difference in mean length between measurements taken by uterine sounding and ultrasonography was 0.28 cm. Mean endometrial cavity length was 3.84 +/- 0.03 cm (mean +/- S.E.M.) in nulligravida and 4.25 +/- 0.03 cm in parous women according to uterine sounding (p3.6 cm, the length of the most common IUDs, the TCu380A and the levonorgestrel-releasing intrauterine system. Therefore, the issue appears controversial for developing new, shorter IUDs, since current models fit most women, including nulligravida, albeit one third of the women of our sample showed endometrial length shorter than 3.2 cm. (C) 2010 Elsevier Inc. All rights reserved816515519Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)National Research Council (CNN) [573747/2008-3]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [2003108391-7]National Research Council (CNN) [573747/2008-3

Resources and procedures in the treatment of heavy menstrual bleeding with the levonorgestrel-releasing intrauterine system (LNG-IUS) or hysterectomy in Brazil

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Background: Heavy menstrual bleeding (HMB) is the most common complaint of women seeking gynecological care. Treatments included surgical or medical options including hysterectomy and the levonorgestrel-releasing intrauterine system (LNG-IUS) due to the profound suppression of endometrial growth that intrauterine LNG exerts which results in amenorrhea or in a reduction of blood loss. Objective: The study was conducted to evaluate the resources and procedures involved in inserting an LNG-IUS compared to performing hysterectomy in women with HMB in a public sector hospital in Brazil. Study design: Two cohorts of women were studied: women who accepted an LNG-IUS (n=124) and matched women who underwent hysterectomy on the same day (n=122). We evaluate the number of procedures carried out in each group of women, including those performed before the decision was made to insert an LNG-IUS or to perform hysterectomy, the insertion of the device itself and the surgical procedure, in addition to the procedures and complications registered up to I year after LNG-IUS insertion or hysterectomy. Results: Age and the duration of HMB were significantly lower in the LNG-IUS acceptors than women at the hysterectomy group. The numbers of gynecological consultations and Pap smears were similar in both groups; however, women in the hysterectomy group also underwent laboratory tests, ultrasonography, chest X-ray and electrocardiogram. In the hysterectomy group, the main complications were hemorrhage (six), bladder/bowel perforation (four), complications with anesthesia (one), ureteral reimplantation required (one) and abdominal pain (two). At I year, HMB was controlled in 83.1% of women in the LNG-IUS group, and 106 women continued with the device. Conclusions: Both treatments were effective in HMB control. Fewer resources and complications were observed in LNG-IUS acceptors when compared to hysterectomy. The LNG-IUS represents a good strategy for reducing the number of hysterectomies and the resources required for women with HMB. (C) 2012 Elsevier Inc. All rights reserved.863244250Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)CNPq [573747/2008-3

Effect of hormonal contraceptives during breastfeeding on infant's milk ingestion and growth

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)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 (similar to 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.1002445450World Health OrganizationFundacao de Apoio a Pesquisa do Estado de Sao Paulo (FAPEP) [2010/09194-4]Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundacao de Apoio a Pesquisa do Estado de Sao Paulo (FAPEP) [2010/09194-4]CNPq [573747/2008-3