Search

The Natural Cycles app employs daily basal body temperature to define the fertile window via a proprietary algorithm and is clinically established effective in preventing pregnancy. We sought to (1) compare the app-defined fertile window of Natural Cycles to that of CycleProGo, an app that uses BBT and cervical mucus to define the fertile window and (2) compare the app-defined fertile windows to the estimated physiologic fertile window.Daily BBT were entered into Natural Cycles from 20 randomly selected regularly cycling women with at least 12 complete cycles from the CycleProGo database. The proportion of cycles with equivalent (±1 cycle day) fertile-window starts and fertile-window ends was determined. The app-defined fertile windows were then compared to the estimated physiologic fertile window using Peak mucus to estimate ovulation.Fifty seven percent of cycles (136/238) had equivalent fertile-window starts and 36% (72/181) had equivalent fertile-window end days. The mean overall fertile-window length from Natural Cycles was 12.8 days compared to 15.1 days for CycleProGo (p0.001). The Natural Cycles algorithm declared 12% to 30% of cycles with a fertile-window start and 13% to 38% of cycles with a fertile-window end within the estimated physiologic fertile window. The CycleProGo algorithm declared 4% to 14% of cycles with a fertile-window start and no cycles with a fertile-window end within the estimated physiologic fertile window.Natural Cycles designated a higher proportion of cycles days as infertile within the estimated physiologic fertile window than CycleProGo.Use of cervical mucus in addition to BBT may improve the accuracy of identifying the fertile window. Additional studies with other markers of ovulation and the fertile window would give additional insight into the clinical implications of app-defined fertile window differences.

Objectives Cervical mucus varies in response to both natural and artificial hormonal changes. It is commonly believed that cervical mucus thinning is associated with normal fertility and that progestogen-induced thickening is an essential contraceptive mechanism. This review aims to broadly summarize our current knowledge about cervical mucus from both a clinical and basic research perspective. Study design We reviewed published literature pertinent to cervical mucus and contraception across scientific disciplines. We first present the most current understanding of the composition of cervical mucus, how it is hormonally regulated, and examine the role of mucus as an immune barrier. We then critically assess the current clinical tests used as surrogate markers for a contraceptive effect. Finally, we review contraceptive studies that have specifically focused on cervical mucus changes. Results Existing research suggests that cervical mucus has potential to be a contraceptive target with unique, multipurpose characteristics. However, methodologic limitations associated with clinical assessments of cervical mucus complicate our understanding of contraceptive treatment effects. Key pathways involved in cervical mucus production with potential as novel nonhormonal contraceptive targets have been identified. Conclusions More research is needed to clarify the role of cervical mucus in current hormonal contraceptives and to support the development of novel nonhormonal cervix-based methods.

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.

Background The estrogen step-down/progestogen step-up 28-day estradiol valerate/dienogest (E 2 V/DNG) oral contraceptive effectively inhibits ovulation; however, limited data are available regarding its effects on estradiol (E 2 ), progesterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) or its additional extraovarian contraceptive effects. Study Design In this secondary analysis, 100 women received E 2 V 3 mg on days 1���2, E 2 V 2 mg/DNG 2 mg on days 3���7, E 2 V 2 mg/DNG 3 mg on days 8���24, E 2 V 1 mg on days 25���26 and placebo on days 27���28 for one treatment cycle. Measures included the presence/absence of cervical mucus; endometrial thickness; and serum E 2 , progesterone, and gonadotropin levels. Results E 2 , progesterone, LH and FSH levels did not exhibit the typical ovulatory increase and remained relatively stable during the cycle. E 2 V/DNG reduced mean maximal endometrial thickness and proportion of women with visible cervical mucus. All parameters returned to pretreatment levels during the posttreatment cycle. Conclusion E 2 V/DNG provides extraovarian contraceptive effects (reducing endometrial thickness and cervical mucus production) in addition to inhibiting ovulation, assuring contraceptive efficacy.

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 Mifepristone alone or in combination with ethinyl estradiol (EE) can effectively stop an episode of uterine bleeding in women using the etonogestrel-releasing contraceptive implant, Implanon® but could impair contraceptive efficacy. Aim To examine the effects of administration of mifepristone alone or with EE on ovarian function and cervical mucus consistency in women using Implanon. Study Design Women using Implanon were randomized to mifepristone 25 mg twice daily on day 1 plus placebo 1 daily for 4 days or plus EE 20 mcg daily for days 2–5. Measurements of serum estradiol (E2), progesterone (P4), luteinizing hormone (LH), follicle-stimulating hormone (FSH), cervical mucus examination and maximal follicle size (by vaginal ultrasound) were carried out at various times. Results Following mifepristone intake, there was a dramatic increase in E2 levels ranging from 543 to 1183 pmol/L (p=.000), which was not correlated with maximal follicle size or preceded by LH or FSH increase. The increase in E2 triggered an LH increase resulting in development of a luteinized follicle in four women with no evidence of ovulation. One of these women had estradiol and progesterone levels suggestive of ovulation, but no corpus luteum was seen. Almost all women had very low mucus scores, which did not correlate with E2 levels. Discussion Despite a transient increase in E2 levels after mifepristone, there was no evidence of subsequent ovulation irrespective of whether they also received EE. The mechanism by which mifepristone in the presence of etonogestrel results in a rapid increase in E2 levels remains unclear and could not be related to any significant changes in FSH, LH, ovarian follicle dynamics or subsequent possible ovulation. Conclusion Pregnancy is very unlikely to occur if mifepristone and EE are given during use of Implanon to stop an episode of bleeding.

Background Requiring that women wait until the onset of menses to initiate a family planning method is a medical barrier that can result in unintended pregnancies. In the efficacy study of the TwoDay Method, a new fertility awareness-based method of family planning, women were taught the method in the first seven days of their cycles. This study tested a quick-start approach (providing the method at any time in the cycle) to TwoDay Method delivery. Study Design In Peru, 167 women were counseled in TwoDay Method use (regardless of cycle day) and followed for up to 7 months. They were interviewed periodically to assess their use of and satisfaction with the method. Simulated clients gauged providers' ability to correctly counsel in method use at different times of the cycle. Results No significant differences were observed in correct use, continuation rates, and acceptability of the method among women who were counseled at different points in the cycle; quality of counseling was not undermined by the quick-start approach. Conclusions There is no need to limit delivery of the TwoDay Method to the first seven days of the menstrual cycle.

Background This study was conducted to compare the effectiveness of a new, single-size silicone contraceptive diaphragm used with either spermicide [2% nonoxynol-9 (N-9)] or lubricant in preventing sperm from penetrating midcycle cervical mucus. Study design A crossover postcoital test (PCT) in healthy, sexually active women not at risk for pregnancy due to tubal occlusion was conducted. Couples had a baseline PCT without a device to verify normal fertility parameters. Qualified couples underwent up to two test cycles using the SILCS diaphragm with a metal spring. A subgroup of couples underwent a third test cycle with the SILCS polymer spring diaphragm used with N-9 gel. Results Fifteen couples completed a baseline cycle and were randomized to order of study gel. Of these, 14 couples completed a baseline cycle and at least one test cycle, 12 couples completed a baseline cycle and two test cycles and 8 couples completed a third test cycle with the polymer spring prototype. Sperm was detected in the vaginal pool in all completed test cycles. The SILCS metal spring diaphragms used with N-9 gel reduced the average number of progressively motile sperm per high power field in the cervical mucus from a baseline of 12.5 to 0, while use of this device with lubricant reduced the number to 0.5. The SILCS polymer spring diaphragm used with N-9 performed the same as the metal spring used with N-9. Conclusion The SILCS diaphragm used with N-9 gel performed well. It is likely that the SILCS diaphragm will give acceptable results in a contraceptive effectiveness study but that adjunctive use of a chemical barrier such as N-9 gel will be necessary for it to be most effective.

All intrauterine devices (IUDs) that have been tested experimentally or clinically induce a local inflammatory reaction of the endometrium whose cellular and humoral components are expressed in the tissue and the fluid filling the uterine cavity. Depending on the reproductive strategy of the species considered and the anatomical features and physiologic mechanisms that characterize their reproductive system, the secondary consequences of this foreign body reaction can be very localized within the uterus, as in the rabbit, or widespread throughout the entire genital tract as in women or even systemic as in some farm animals. Levonorgestrel released from an IUD causes some systemic effects, but local effects such as glandular atrophy and stromal decidualization, in addition to the foreign body reaction, are dominant. Copper ions released from an IUD enhance the inflammatory response and reach concentrations in the luminal fluids of the genital tract that are toxic for spermatozoa. In the human, the entire genital tract appears affected due to luminal transmission of the noxa that accumulates in the uterine lumen. This affects the function and viability of gametes, decreasing the rate of fertilization and lowering the chances of survival of any embryo that may be formed, before it reaches the uterus. The bulk of the data indicate that if any embryos are formed in the chronic presence of an IUD, it happens at a much lower rate than in non-IUD users. The common belief that the usual mechanism of action of IUDs in women is destruction of embryos in the uterus is not supported by empirical evidence.

Objective Ulipristal acetate (UPA) 30mg is safe and effective for emergency contraception (EC). This prospective open-label exploratory study was conducted to obtain additional data on the pharmacodynamic effects of repeated dose of UPA 30mg during an 8-week period (effects on ovulation inhibition, hormonal levels, endometrium and cervical mucus). Safety and tolerability data of repeated use of UPA EC were also collected. Study design A total of 23 healthy female, healthy sterilized women participated in two substudies receiving UPA for 8 consecutive weeks. In substudy 1, UPA 30mg was administered every 7days (Q7D n =12); while in substudy 2, every 5days (Q5D n =11). Subjects were monitored three times a week in a baseline cycle and during treatment with transvaginal ultrasounds, hormonal measurements and cervical mucus evaluation. Laboratory safety measurements and standard surrogate thrombosis risk markers were measured at baseline and within a few days of the last tablet. A luteal phase endometrial biopsy was taken in the baseline cycle and posttreatment. Results A total of 11/12 (91.7%) and 8/11 (72.7%) of the subjects ovulated at least once in substudy Q7D and Q5D, respectively, with similar, normal hormonal profiles. No effect on cervical mucus was observed. All biopsies were classified as benign in both substudies; 5/11 biopsies on Q5D posttreatment were classified as nonphysiological with some of typical progesterone receptor modulator-associated endometrial changes. UPA was well tolerated in both treatment arms while clinical laboratory results and surrogate thrombosis markers were reassuring. Conclusions Repeat use of 30mg oral UPA every 5 or 7days for 8weeks initially delays follicular rupture but ovulation eventually occurs with time in most subjects. Safety data indicate that UPA 30mg could be safely administered if needed more than once for EC in a given menstrual cycle. Implications These data demonstrate that repeated use of UPA 30mg is safe. However, ovulation eventually occurs in a high proportion of women in spite of repeated treatments in both studied regimens. Nevertheless, since the stage of follicular development of women seeking initial or repeat EC use is generally unknown, the repeated use of UPA may still delay follicular rupture and prevent an unintended pregnancy in the event of further unprotected intercourse.

C31G is a broad-spectrum antibacterial agent that shows contraceptive properties in vitro. This postcoital testing study evaluated the ability of three C31G concentrations, 0.5%, 1.0% and 1.7%, administered as a 3.5-mL dose of a vaginal gel to prevent sperm from entering mid-cycle cervical mucus. Irritation of the genitalia and acceptability were also assessed.At baseline, a mid-cycle cervical mucus test and a postcoital test were performed within 24 h of each other without use of any study products to establish normal mid-cycle cervical mucus and sperm penetration. Subjects then completed up to three test cycles using one of the three concentrations of study product during intercourse.Twenty-two of the 61 women enrolled completed a baseline cycle and at least one test cycle. An average of 14.6 progressively motile sperm per high power field was seen at baseline. This was reduced to 0.3 after use of 0.5% C31G, 0.5 after use of 1.0% C31G, and 0.4 after use of 1.7% C31G. There was no significant difference between test products (p/= 1.000) but each test product was significantly different from baseline (p0.002). Very little genital irritation was observed. There were more reports of leakage and messiness with increasing C31G concentration.This study suggests that all three concentrations of C31G are likely to give reasonable results in a contraceptive effectiveness trial. Based on the results of this and other trials, the 1.0% concentration has been selected for further development, including Phase III trials of contraceptive effectiveness.

The purpose of this study was to compare the fertile phase of the menstrual cycle as determined by the Clearplan Easy Fertility Monitor (CPEFM) with self-monitoring of cervical mucus. One-hundred women (mean age = 29.4 years) observed their cervical mucus and monitored their urine for estrogen and luteinizing hormone metabolites with the CPEFM on a daily basis for 2-6 cycles and generated 378 cycles of data; of these, 347 (92%) had a CPEFM peak. The beginning of the fertile window was, on average, day 11.8 (SD = 3.4) by the monitor and day 9.9 (SD = 3.0) by cervical mucus (r = 0.43, p < 0.001). The average first day of peak fertility by the monitor was 16.5 (SD = 3.6) and by cervical mucus 16.3 (SD = 3.7) (r = 0.85, p < 0.001). The mean length of the fertile phase by the monitor was 7.7 days (SD = 3.1) and by cervical mucus 10.9 days (SD = 3.7) (t = 12.7, p < 0.001). The peak in fertility as determined by the monitor and by self-assessment of cervical mucus is similar but the monitor tends to underestimate and self-assessment of cervical mucus tends to overestimate the actual fertile phase.

The (PD) peak day of cervical mucus is an important biologic marker for the self-determination of the optimal time of fertility in a woman's menstrual cycle. The purpose of this article is to provide evidence (literature and empiric) for the accuracy of the PD of cervical mucus as a biologic marker of peak fertility and the estimated day of ovulation. An analysis of data from four published studies that compared the self-determination of the PD of cervical mucus with the urinary luteinizing hormone (LH) surge was conducted. The four studies yielded 108 menstrual cycle charts from 53 women participants. The 108 cycles ranged in length from 22 to 75 days (mean 29.4 SD 6.0). Ninety-three of the 108 cycles had both an identified PD and LH surge. Data charts showed that 97.8% of the PD fell within +/-4 days of the estimated day of ovulation. Use of a standardized mucus cycle scoring system indicated that the peak in cervical mucus ratings was highest on the day of the LH surge. Self-determination of the PD of cervical mucus is a very accurate means of determining peak fertility and a fairly accurate means of determining the day of ovulation and the beginning of the end of the fertile time.

A synthetic formulation has been developed with viscosity, spinnbarkeit, and pH comparable to that reported for human cervical mucus. The formulation contains guar gum crosslinked with borate ion, mucin (dried porcine gastric), and a mixed preservative system in pH 7.4, 0.1M phosphate buffer. The guar gum source, mucin concentration, and method of preparation were shown to be critical factors in the performance of the formulation.

As an ongoing effort to elucidate the mechanisms involved in the calcium-dependent fertility regulation process, the viscoelastic properties of the mucus obtained from lamb cervix and human semen, as well as their water and total protein contents after exposure to EDTA, a chelating agent, or Nonoxynol-9 (N-9), a spermicidal agent, were examined. The viscosity was measured using a Cone Plate Digital Viscometer, while the water and total protein contents were determined by the lyophilization process and the Lowry method, respectively. The significant changes in the rheological properties of mucus, such as its viscosity and the water content, upon exposure to EDTA were demonstrated. The viscosity of cervical mucus and human semen were significantly increased by EDTA treatment (as compared to the controls): lamb cervical mucus (2.9 +/- 0.3 vs. 2.2 +/- 0.3 cps) and human semen (5.0 +/- 0.3 vs. 4.3 +/- 0.3 cps), respectively. The hydration rate was decreased by EDTA treatment as compared with the control (93.6 +/- 0.7 vs. 96.8 +/- 0.8%). Among tested samples, the reduction in the percentage of sperm penetration through the cervical mucus was the highest in the mucus containing EDTA, which had the lowest water content (93.6 +/- 0.7%), indicating that there is a positive relationship between the hydration rate of the cervical mucus and its ability to permit the penetration of spermatozoa. This result indicates that spermicidal activity exerted by high concentrations of EDTA is in part due to its effect on the rheological properties of cervical mucus or semen.

The aim of this study was to evaluate the effectiveness of lactational amenorrhoea and to determine the relationship between extended breastfeeding and the return of fertility. Breastfeeding pattern, basal body temperature, cervical mucus, salivary ferning, vaginal blood discharge, frequency of sexual intercourse, and the presence of ovulation in the first cycle after the resumption of menses with ultrasonography were evaluated in 40 women. All subjects completed the study with only one case of incomplete breastfeeding. No pregnancies were observed. The mean number of feeding sessions and mean interval between sessions decreased significantly (p0.01) during the first six months postpartum (7.5 +/- 1.3 after 60 days postpartum vs. 5.7 +/- 2.1 after 180 days, and 3.6 +/- 0.8 vs. 5.1 +/- 0.9, respectively). Eight women (20%) menstruated before weaning, but none had an adequate thermal shift, while 32 (80%) had their first vaginal bleeding after weaning with 12 (37.5%) registering an adequate thermal shift. Both basal body temperature and salivary ferning proved to be suggestive of ovarian activity, while mucus characteristics were not reliable in identifying fertile periods. Our study showed that breastfeeding associated with lactational amenorrhoea proved to be a good method of postpartum fertility control. Since the importance of supplementation is still debated, it is recommended that a "complete" breastfeeding program be used.

Small hand-held microscopes have been developed for self-observation of salivary ferning patterns to detect the fertile time of a woman's menstrual cycle. The purpose of this study was to evaluate one such microscope, the Lady Free Biotester, by comparing it with the self-observation of cervical-vaginal mucus and with the self-detection of luteinizing hormone (LH) in the urine. Twelve natural family planning teachers (average age 34.6 years) observed their cervical-vaginal mucus, tested their urine for LH, and observed salivary and cervical-vaginal mucus ferning patterns (with the Lady Free Biotester) for two menstrual cycles. Data indicated that there was a strong correlation between the LH in the urine and the peak in self-observed cervical-vaginal mucus ferning (r = 0.99, por = 0.001) and salivary ferning (r = 0.98, por = 0.001). However, it was difficult to assess the beginning and end of the fertile time based on the salivary ferning patterns. Further testing of salivary ferning patterns is recommended before widespread use of these devices for family planning.Several small, hand-held microscopes have been developed and marketed for self-observation of ferning patterns in either saliva or cervical-vaginal mucus to detect the fertile period of a woman's menstrual cycle. This study evaluated the Lady Free Biotester microscope, which detects salivary ferning patterns, by comparing its performance with that of self-observation of cervical-vaginal mucus through the Creighton model vaginal discharge recording system and self-detection of luteinizing hormone (LH) in urine with an OvuQuick kit. 12 US natural family planning teachers (mean age, 36.7 years) practiced all three methods for two menstrual cycles. There was a strong correlation between urinary LH and the peak observed in cervical-vaginal mucus ferning (r = 0.99; p 0.001) and salivary ferning (r = 0.98; p 0.001). However, there was no discernible beginning or end to fertility as determined by salivary or cervical-vaginal ferning. In many cases, ferning days were found throughout the cycle. Until more definitive tests with salivary ferning patterns are conducted, it is recommended that the hand-held microscopes be used only in connection with other tested markers of fertility.

Gramicidin, a linear polypeptide with antiviral and antimicrobial properties, was compared in vitro with a commonly used spermicidal detergent-nonoxynol-9 (N9). The inhibition of sperm functions was evaluated by computer-assisted semen analysis (CASA) for sperm motility, in cervical mucus penetration assay, and by colorimetric tetrazolium salt and lactate dehydrogenase release assays routinely employed for testing the toxicity of drugs. The effective 100% inhibitory concentration (IC100) of gramicidin in a 2-min sperm immobilization assay by CASA was equal to 4 micrograms/ml, whereas IC100 of N9 was equal to 200 micrograms/ml. The presence of 0.1% of chelating agent, EDTA, reduced IC100 of gramicidin to 10 ng/ml, while less than a twofold enhancement in N9 activity was observed upon combination with EDTA. Likewise, the gramicidin/EDTA combination was 100,000 times more potent than N9/EDTA in the sperm penetration assay. Quantitative toxicity tests confirmed that gramicidin is a potent spermostatic rather than spermicidal agent. Further development of a gramicidin/EDTA formulation is warranted as a nontoxic topical contraceptive with activity against viral and microbial sexually transmitted diseases (STDs).The possibility of enhancing the anti-fertility potential of gramicidin with low doses of ethylenediaminetetraacetic acid (EDTA) was investigated in an in vitro study. The inhibition of sperm functions was evaluated by computer-assisted semen analysis for sperm motility, cervical mucus penetration assay, and colorimetric tetrazolium salt and lactate dehydrogenase release assays. Gramicidin, nonoxynol-9, and EDTA all were found to immobilize sperm, although their effective doses diverged by orders of magnitude. Gramicidin abolished sperm motility within 2 minutes at 4 mcg/ml, but a 50 times higher dose of nonoxynol-9 and 1250 times more EDTA were required to achieve a comparable effect. The combination of 10 ng/ml of gramicidin with 0.1% of EDTA resulted in activity that was four orders of magnitude higher than the optimal combination of nonoxynol-9 with EDTA; sperm penetration into mucus was completely prevented. Moreover, gramicidin inhibited sperm motility without affecting mitochondrial respiratory function or disrupting cell membrane integrity. Quantitative toxicity tests confirmed that gramicidin is a potent spermostatic agent rather than a spermicidal agent. Further development of a gramicidin-EDTA formulation is urged given its potential as a non-toxic topical contraceptive with activity against viral and microbial sexually transmitted diseases.

The aim was to compare the efficacy and acceptability of two Internet-supported fertility-awareness-based methods of family planning.Six hundred and sixty-seven women and their male partners were randomized into either an electronic hormonal fertility monitor (EHFM) group or a cervical mucus monitoring (CMM) group. Both groups utilized a Web site with instructions, charts and support. Acceptability was assessed online at 1, 3 and 6 months. Pregnancy rates were determined by survival analysis.The EHFM participants (N=197) had a total pregnancy rate of 7 per 100 users over 12 months of use compared with 18.5 for the CMM group (N=164). The log rank survival test showed a significant difference (p.01) in survival functions. Mean acceptability for both groups increased significantly over time (p.0001). Continuation rates at 12 months were 40.6% for the monitor group and 36.6% for the mucus group.In comparison with the CMM, the EHFM method of family planning was more effective. All users had an increase in acceptability over time. Results are tempered by the high dropout rate.

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.

In levonorgestrel intrauterine system (LNG-IUS) users, the prevention of sperm penetration through cervical mucus has not been demonstrated.Subjects were enrolled in an investigator-blinded study to compare quality and sperm penetrability of mid-cycle cervical mucus between LNG-IUS users and hormone-free controls. Cervical mucus was microscopically examined using World Health Organization (WHO) cervical mucus analysis (CMA). CMA score ≥10 of 15 points indicated cervical mucus favoring sperm penetration. Mucus was incubated with sperm using the WHO simplified slide test (SST) and Kremer sperm cervical mucus penetration test (SCMPT).Data from 14 LNG-IUS users and 16 controls showed 14% of LNG-IUS users had CMA score ≥10% vs. 69% of controls (p=.004). SST showed no sperm penetration for LNG-IUS users, significantly less than controls (0% vs. 64.3%, p.001). SCMPT demonstrated no sperm mucus penetration for LNG-IUS users at 2 and 6 h (0% vs. 85% in controls with 2-h score ≥6, p.001; 6 h 0% vs. 79% in controls, p.001).Mid-cycle cervical mucus of LNG-IUS users is poor quality and prevents endocervical sperm transport in vitro.

The rate of diffusion of [125I]-nonoxynol 9 into mid-cycle human cervical mucus was measured and found to be negligible compared with D-glucose (used as an uncharged small molecule for comparison with nonoxynol 9). These data were confirmed by observation of the lack of inhibition of the movement of spermatozoa in mucus that had been in surface contact, for 3 hours, with a concentration 30 times greater than the ED100 of nonoxynol 9. These results show that the entry of nonoxynol 9 into mucus could be minimal under conditions that would exist in vivo and highlights a limitation of this compound as a vaginal contraceptive.Obstetrician-gynecologists and chemists analyzed data on midcycle cervical mucus samples from normally cycling women attending the infertility clinic at the University Hospital of South Manchester, England, to determine the ability of nonoxynol-9 to diffuse into the mucus, thereby testing its spermicidal activity. They used the double diffusion test. They compared diffusion depths of radiolabelled nonoxynol-9 at 120 minutes with those of D-glucose, an uncharged small molecule. They compared the depths of these 2 methods with those of controls containing Tyrode's solution. Migration of spermatozoa in 6 nonoxynol-9 rectangular capillaries was greater than the Tyrode controls, lower in 5 capillaries, and the same in 9 capillaries. Thus, no difference in spermatozoal penetration into midcycle cervical mucus existed between nonoxynol-9 and Tyrode's solution. Further, a 62% concentration of D-glucose was evident in the 1st 5 mm of the cervical mucus column at 2 hours and the concentration fell exponentially. The chemists cold still detect D-glucose at 30 mm at 2 hours. On the other hand, they detected nonoxynol-9 at a 6 times lower concentration than D-glucose in the 1st 5 mm at 2 hours, but could not detect it beyond 5 mm. This meant that, in vivo, only 10% of nonoxynol-9 would be in the interfacial zone of the cervical mucus and not at greater depths. If these results hold true, the ability of nonoxynol-9 to act as a contraceptive and a means to destroy HIV would be limited in the upper genital tract and the cervix. In conclusion, nonoxynol-9's spermicidal activity in midcycle cervical mucus is considerably lower than it is in free solution.

Ovarian function was studied for two complete menstrual cycles in 9 regularly menstruating women and for 8 weeks in three amenorrhoeic women who had used levonorgestrel-releasing IUDs (LNG-IUD) for more than four years. Nine patients using copper IUDs (Nova-T) were studied for two complete menstrual cycles as controls. According to progesterone levels, 15/17 cycles in women using LNG-IUDs were ovulatory, whereas only 8/17 cycles showed normal follicular growth and rupture as judged by ultrasound. In ovulatory cycles, the peak progesterone levels were lower than in the controls. The preovulatory estradiol and LH peak levels were also lower than in control subjects. SHBG levels were lower in LNG-IUD users than in copper IUD users. It is concluded that, although the dose of levonorgestrel released from the IUD is very low, it probably exerts an effect on the gonadotrophin secretion, which disturbs follicular development in many of the women studied, which in addition to the local effect on the endometrium, contributes to its high contraceptive efficacy.

Objectives Construction of vaginal rings to deliver nonhormonal contraceptives and 3���-Azido-3���-deoxythymidine (AZT) as an anti-HIV agent and determination of their daily release and efficacy in vitro. Materials and Methods Intravaginal rings of 0.5���0.7 cm rim and 5���5.5 cm in diameter were cast in the molds. The rings were composed of biosoluble acacia gum or nonbiodegradable hydrogel of 2-hydroxyethyl methacrylate (HEMA) and sodium methacrylate (SMA) [P(HEMA-co-SMA)]. The rings were impregnated with nonhormonal contraceptives such as ferrous gluconate to cause spermiostasis, l-ascorbic acid to increase the viscosity of the cervical mucus, and pharmalytes of pH 4���5 or AZT. Results The daily release rate of nonhormonal contraceptives as well as AZT from the rings was efficacious in vitro. Cumulative effect of nonhormonal contraceptives showed complete spermiostasis within 30 s up to 10 and 28 days, respectively. Daily release of AZT from both rings was also likely to be efficacious to inhibit HIV proliferation in vitro for 10 and 28 days, respectively. Conclusion The data indicate that the rings described here can be developed for intravaginal delivery of nonhormonal contraceptives and/or anti-HIV agents.

Objective This study aimed to evaluate the pharmacokinetics, pharmacodynamics and safety of the nonsteroidal progesterone receptor agonist, tanaproget. Methods A randomized, double-blind, placebo-controlled, sequential-group study of ascending single doses of tanaproget was conducted in healthy, 25- to 45-year-old women on cycle days 8 to 12. Eight subjects (six active, two placebo) per cohort received a dose of 0.1, 0.3, 1, 3, 7 (��high-fat meal) or 15 mg. Results The maximum concentration ( C max ) of tanaproget occurred approximately 2 to 3 h after administration. The elimination half-life ( t 1/2 ) ranged from 12 to 30 h, and the oral clearance was approximately 70 L/h. The pharmacokinetics of tanaproget was not noticeably altered with a high-fat meal. All doses of tanaproget decreased cervical mucus scores (using a modified Insler method), indicating poor production and poor quality of cervical mucus. The most frequent treatment-emergent adverse events were vaginal bleeding/spotting, abdominal cramping and vomiting; their incidence was not dose related and most events were mild. Conclusions Tanaproget was safe and well tolerated, decreased cervical mucus scores and had a pharmacokinetic profile acceptable for use as a once-daily oral contraceptive.

Context: Fertility awareness-based (FAB) methods of family planning estimate the fertile days of the menstrual cycle whether by observing fertility signs such as cervical secretions and basal body temperature or by monitoring cycle days. The efficacy and acceptability of these methods are unclear. Methods: We retrieved and analyzed all randomized controlled trials that examined any FAB method used for contraception. Results: Because of poor methods and reporting, pregnancy rates could not be determined. A trial in Colombia found similar numbers of pregnancies among women randomized to the ovulation and symptothermal methods, but a trial in Los Angeles observed more pregnancies in the group assigned to the ovulation method. In the two American trials, recruitment of participants was unexpectedly difficult. Continuation rates were poor. Conclusion: Despite intensive training and ongoing support, most participants in these trials discontinued prematurely. The comparative efficacy of these methods remains unknown. However, with the ovulation and symptothermal methods, pregnancies appear to be common; method continuation rates are low.

The purpose of this study was to identify compounds that could potentially be useful for vas irrigation at the time of vasectomy. We studied the in vitro effects of a group of membrane-active and ion-channel blocking agents on human sperm motility, viability and cervical mucus penetration. Diltiazem, an anti-arrhythmic drug, and methylene blue, an agent commonly used in vasography, showed the most promising effects with marked reduction of sperm motility and cervical mucus penetration after incubation with sperm for a short period of 15 min. Diltiazem was more effective than methylene blue in inhibiting the motility and viability of sperm. Furthermore, unlike methylene blue, diltiazem significantly compromised sperm viability. Other compounds studied, such as lidocaine, nicardipine and Neosporin((R)), showed only partial inhibitory activity. Based on the data reported herein, both diltiazem and methylene blue appear to be suitable candidates to be developed for vas irrigation at the time of vasectomy.

In this study, the feasibility of a carbopol 934P-HPMC-based gel formulation as a vaginal drug delivery system was evaluated. A vaginal fluid simulant (VFS) was utilized to simulate human vaginal mucus. The viscosity of the carbopol-HPMC gel system and VFS was examined using a cone and plate viscometer. The surface tension of VFS was measured using a capillary rising method. Differential scanning calorimetry (DSC) was employed to investigate the effect of carbopol gel on the conformational changes of rat vaginal membrane. The viscosity of carbopol gel increased as the pH of the system increased from 4.0 to 6.0. The viscosity of HPMC gel remained the same irrespective of pH of the system. The viscosity of the carbopol gel significantly increased, when HPMC (0.5–1.5%) was added to the system. The optimal viscosity value (1.5∼2.0 poises) was achieved at 1.0∼1.5% carbopol (pH 4.0) with the presence of 1.0∼1.5% HPMC. There were mucin concentration dependent changes in viscosity and surface tension of VFS. The results of DSC analysis of rat vaginal membrane showed that the profiles of thermal stability for both carbopol-treated and the untreated control at the temperature ranging from 40 to 90°C were almost identical. The thermal denaturation temperatures (Td) of the carbopol-treated membrane and the untreated control were not significantly different from each other. The combination of carbopol and HPMC seems to be an ideal formulation as a vaginal delivery system. Mucin played an important role in the regulation of viscosity and surface tension of VFS. DSC study demonstrated that carbopol gel showed good biocompatibility and did not cause any conformational changes in rat vaginal membrane.

This study was undertaken to investigate the role of cytokines in intrauterine contraception. Cervical mucus samples were obtained from 20 women with proven fertility 7, 14, 30, and 120 days after insertion of copper-T380 intrauterine devices (IUDs) for the determination of interleukin-2 (IL-2) soluble receptor (IL-2SR) and granulocyte macrophage colony stimulating factor (GM-CSF) concentrations. Both levels of IL-2SR and GM-CSF were significantly elevated after insertion of copper-releasing IUDs. This elevation remained significant through 6 months post-insertion. The mean-fold rise of GM-CSF compared to pre-insertion mean values amounted to 12.4, 11.8, 2.1, and 1.5 at 7, 14, 30, and 120 days post-insertion, respectively. The corresponding values for IL-2SR were 10.4, 8.8, 2.6, and 2.5, respectively. These results demonstrate enhanced local cytokines production in IUD users indicating local inflammatory reaction in the endometrium. This inflammatory reaction together with the cytotoxic effects of these cytokines may produce an environment which adversely affect embryo pre-implantation. This may explain the antifertility effect of copper IUDs.

The objectives of this study were to assess whether women who were administered the first injection of the once-a-month contraceptive containing estradiol cypionate and 25 mg depot-medroxyprogesterone acetate (MPA+E 2 C) on Day 7 of their menstrual cycle (delayed injection) exhibit the same degree of cervical mucus changes as women who receive it on Day 5 of their menstrual cycle. This was a multicenter, randomized, controlled clinical trial. A total of 158 women, aged between 18 and 38 years (inclusive), who, were willing to use MPA+E 2 C as their contraceptive method participated in the trial. Participants received a MPA+E 2 C injection on Day 5 (control group, n = 41) or Day 7 (delayed-injection group, n = 117) of their menstrual cycle. Participants who received MPA+E 2 C on Day 5 of their menstrual cycle (control group) exhibited fair or poor mucus quality and poor sperm penetration. Of those women who received MPA+E 2 C on Day 7 of their menstrual cycle (delayed-injection group), 3 (3%) showed good mucus or good sperm penetration at some time point during follow-up. It is possible to conclude that the first injection of MPA+E 2 C given on Day 7 of a menstrual cycle does not provide the same degree of inhibition of mucus quality and sperm penetration as that observed if it is administered on Day 5. However, the theoretical risk of pregnancy after receiving MPA+E 2 C on Day 7 would be expected to be low.

This study was designed to describe an accurate and consistent microscopic technique for the assessment of sperm number and motility in sperm–cervical mucus samples, such as those of postcoital tests (PCTs), and to identify a suitable method to extract functional spermatozoa from cervical mucus (CM). Sperm–CM preparations containing various sperm concentrations were counted using three different microscopic illuminations. The dark field-Makler technique was compared with the more classical bright field-slide technique currently used by our clinicians. Several sperm extraction techniques were applied first to bovine (BCM) and then to human (HCM) cervical mucus. Dark field microscopic illumination provided accurate, fast, and easy sperm identification. Counting variability was significantly greater with bright field-slide than with dard field-Makler, while sperm motility was always higher with this latter methodology. A high degree of agreement (intraclass correlation coefficient = 0.965) among three raters, i.e., low interobserver variability, was obtained only with dark field-Makler. Extraction procedures based on “swim-out,” Percoll, trypsin, an enzyme cocktail, and mercaptoethanol resulted in small sperm yields in BCM. Mercaptoethanol and trypsin also showed poor sperm recovery in HCM. Among the protocols with the largest yields, the mechanical technique had the largest amount of residual CM, and bromelain reduced sperm motility. The extraction with dithiothreitol (DTT) showed the best results with a mean sperm recovery of 76% and enhanced sperm motility. Sperm viability as well as spontaneous and induced acrosome reaction were conserved in all techniques. In conclusion, use of the dark field-Makler counting technique in combination with DTT extraction of spermatozoa from CM samples, such as those of PCTs, would allow accurate and functional assessment of spermatozoa for preliminary contraceptive efficacy or infertility evaluation.

To elucidate the mechanism of sterility induced by gossypol, we studied the relationship between the activities of acrosomal enzymes and their fertilizing capacity in the hamster. The results showed that the ability of spermatozoa to penetrate into bovine cervical mucus, hyperactivated motility (HAM) and fertility in vivo were significantly inhibited when spermatozoa were exposed to gossypol (2.5 μg–60 μg/mL) for 15 min in vitro. Also, following administration of gossypol (12.5 mg/kg/day) for 6 weeks, sperm motility, HAM and rate of fertilization in vitro by the hamster cauda epididymal spermatozoa were significantly decreased and the extracts of testis delayed dispersion of the cumulus oophorus cells, suggesting that hyaluronidase and other acrosomal enzymes might be inhibited by gossypol. In addition, acrosin and arylsulfatase activities were also markedly inhibited. These data show that the inhibition of acrosin and arylsulfatase activities is the main cause of gossypol-induced infertility. The inhibition was dependent upon gossypol dose and the duration of administration. Thus, the assay of acrosin and arylsulfatase activities may provide a useful tool for monitoring sterility induced by gossypol.

Little is known about the effects of contraceptive vaginal rings on the vaginal surface epithelium, although most studies have not demonstrated any significant deleterious effect. However, one study found that some medium-to-long-term levonorgestrel-releasing ring users developed chronic erythematous and ulcerative lesions in the posterior vaginal fornix. Subsequently, this ring was completely redesigned (IVR-2) with different dimensions and much greater flexibility. The first version of IVR-2 was designed as a placebo ring to explore effects on the vagina and cervix without addition of a progestogen. One-hundred-sixty-six healthy sexually active women volunteers were recruited in four centers and randomly assigned for 6 months to either placebo ring use or control (non-use) using a predetermined randomization code generated by WHO in a 2:1 ratio. Careful inspections of the vaginal and cervical epithelium were performed with a colposcope at admission and at 2-month intervals. No clinically significant lesions were detected in any center either among ring users or controls. However, a number of minor changes in appearance of the vaginal and cervical epithelium (erythema, petechiae, ecchymosis, and minor aceto-white changes) were described from the Sydney Center, some of which were present on admission and some of which were found on subsequent examination. Ten of eleven "red" changes on the cervix and vagina were noted in IVR-2 users, and only one in the controls, suggesting a contribution by the IVR-2 to minor epithelial surface changes. Five of ten resolved completely with continued ring use. There was no correlation in this study between epithelial changes and cigarette smoking or frequency of intercourse in the 14 days prior to colposcopic examination but a significant relationship between tampon use in the last 7 days and all epithelial changes (p = 0.05) and especially red changes (p = 0. 027) was noted. Red changes were significantly less likely to be found among condom users (p = 0.007). The IVR-2 placebo ring did not produce clinically significant changes in the vaginal epithelium and cervical mucosa and a carefully controlled and randomized study should be considered to compare the epithelial appearances in women using a placebo IVR-2 and one releasing 20 microg levonorgestrel.

The objectives of the study were to assess the ability of the Femcap, a new vaginal contraceptive device made of silicone and designed to fit snugly around the cervix to prevent the penetration of sperm into midcycle cervical mucus when used with and without spermicide; and to compare it with the standard contraceptive diaphragm used with spermicide. Eight women underwent two baseline cycles of postcoital testing in which no device was used, followed by three test cycles in which Femcap with spermicide, Femcap with nonspermicidal lubricant (K'Y gel) or the Ortho All-Flex diaphragm with spermicide was used. The sequence of testing cycles was randomized. In each cycle, condoms were used prior to midcycle, then a midcycle cervical mucus specimen was examined to ensure midcycle characteristics and the absence of sperm. Each woman then had intercourse using either no device (baseline cycles) or the prescribed device (test cycles) and returned 2-3 h afterwards. Cervical mucus was again assessed for adequacy and the presence of spermatozoa. The average number of progressively motile sperm seen per high power field was as follows: first baseline cycle, 18.0; second baseline cycle, 17.8; test cycle with Femcap used with nonspermicidal lubricant, 0.1; test cycle with Femcap used with spermicide, 0.2; and test cycle with the diaphragm used with spermicide, 0.0. There was no significant difference between baseline cycles or among test cycles in the average number of progressively motile sperm seen (p0.05). The average number of progressively motile sperm seen in each test cycle did, however, differ significantly from the average number seen in either baseline cycle (p0.05). Femcap, used with either a spermicidal lubricant or a nonspermicidal lubricant, appears to be comparable with the diaphragm used with spermicide in preventing sperm from entering midcycle cervical mucus.A Phase I postcoital study assessed the capability of Femcap, a new vaginal contraceptive device made of silicone, to prevent sperm from entering midcycle cervical mucus. After 2 baseline cycles of postcoital testing in which no device was used, 8 US women underwent 3 test cycles in which Femcap with spermicide, Femcap with a nonspermicidal lubricant (KY gel), or the Ortho All-Flex diaphragm with spermicide was used. The sequence of testing cycles was randomized. The average number of progressively motile sperm seen per high power field was as follows: first baseline cycle, 18.0; second baseline cycle, 17.8; test cycle with Femcap used with nonspermicidal lubricant, 0.1; test cycle with Femcap used with spermicide, 0.2; and test cycle with the diaphragm used with spermicide, 0.0. These findings indicate that Femcap, used with either a spermicide or a nonspermicidal lubricant, is comparable to the diaphragm in terms of its ability to prevent the penetration of sperm into midcycle cervical mucus.