Ovulation prediction by monitoring salivary electrical resistance with the Cue Fertility Monitor.

The purpose of this study was to investigate the potential relationship between the salivary electrical resistance, as measured by the Cue Fertility Monitor, and the time of ovulation. Twenty-seven cycles in 18 volunteers were analyzed. A slight correlation could be demonstrated between the day of salivary electrical resistance peak and the day of luteinizing hormone (LH) peak. However, the changes in salivary electrical resistance values, arranged to the day of LH peak, were not statistically significant. The days of salivary electrical resistance peak in relation to the day of LH peak were not reproducible in individual women. The apparent relationship between the day of salivary electrical resistance peak and the day LH peak might be explained by the methodology used. It is concluded that measuring the salivary electrical resistance is of no use in predicting the day of ovulation.

Use of the novel combined contraceptive vaginal ring NuvaRing for ovulation inhibition.

OBJECTIVE: To assess the effects of the combined contraceptive vaginal ring NuvaRing on ovarian function. DESIGN: Randomized, open-label, crossover study. SETTING: Clinical pharmacology unit. PARTICIPANT(S): Sixteen healthy female volunteers. INTERVENTION(S): Group 1: one cycle of combined oral contraceptive containing desogestrel (150 microg) and ethinyl estradiol (30 microg) (desogestrel/EE COC), followed by a NuvaRing treatment period. Group 2: NuvaRing treatment period followed by a cycle of desogestrel/EE COC. MAIN OUTCOME MEASURE(S): Follicular diameter, serum hormone concentrations (follicle-stimulating hormone, 17beta estradiol, luteinizing hormone, and progesterone), and endometrial thickness. RESULT(S): NuvaRing use for the recommended period of 3 weeks resulted in complete inhibition of ovulation, as assessed by vaginal ultrasound (follicular diameter) and by serum luteinizing hormone and progesterone concentrations. Inhibition of ovulation was maintained for an additional 2 weeks of NuvaRing use. Ovarian suppression between the groups was comparable. Furthermore, ovarian suppression after 3 weeks of NuvaRing use was comparable to that on day 21 of DGS/EE COC intake. NuvaRing was well tolerated. CONCLUSION(S): NuvaRing completely inhibited ovulation throughout the normal 3-week period and the extended period of use. Ovarian suppression was comparable to that with desogestrel/EE COC.

An oral contraceptive particularly suitable for women over 35.

PIP: Fertility control for women aged 35 and over is a concern that requires consideration of specific needs and technologies. Orally active steroids are considered the best method available among all the methods of contraception. The steroids are highly beneficial as they are effective and reversible. As well, they prevent the onset of osteoporosis and regulate menstrual bleeding. However, they do hide the symptoms of menopause and along with them come adverse side effects. A study of 434 women by 70 general practitioners and gynecologists was conducted to determine the cycle control and side effects of a combined oral contraceptives (OC). The women, aged 30 and older, were given one tablet containing 0.150 mg desogestrel and 0.020 mg ethinyl estradiol for 21 consecutive days. The results demonstrated the high effectiveness of this combination of desogestrel and ethinyl estradiol as a contraceptive (no pregnancies were recorded). It also proved an acceptable method of cycle control. Formerly, estrogens have been denounced for their side effects, but new compounds have proven effective, safe and beneficial.^ieng

Clinical acceptability of an ethylene-vinyl-acetate nonmedicated vaginal ring.

In an open study the acceptability of a newly designed vaginal ring was evaluated. The ring being developed for contraceptive purposes was made of ethylene-vinyl-acetate copolymer (EVA). In this study the ring did not contain active medication. Three groups of 20 healthy female volunteers were asked to use rings--with a diameter of 54 mm--for 21 consecutive days; each group was assigned rings with a different cross-sectional thickness of 3, 3.5, or 4 mm. Subjects were given diary cards to report on insertion and removal of the ring and on complaints. Of the 65 women who participated, 59 completed the study and used the ring for at least 21 days, giving an acceptability of 91% (59/65). No major differences were found between the three types of rings except for a sensation of expulsion, which was reported more often in the group assigned the smallest cross-sectional-thickness ring. Expulsion was reported once during intercourse in the 3.5-mm group. Insertion and removal of the rings were judged to be easy by the overall majority of the women. The ring was felt by the partner during intercourse in 35%-50% of couples. Further development of an active combined contraceptive EVA ring with a cross-sectional thickness of 4 mm seems a reasonable option. In future studies with the active ring, allowance for temporary removal of the ring during intercourse, if preferred, may be suggested.

PIP: The acceptability of a newly designed vaginal ring was evaluated in an open, randomized study conducted at Atrium Medical Center in Kerkrade, the Netherlands. 65 healthy women 18-45 years of age were assigned to use 1 of 3 types of nonmedicated vaginal rings made with ethylene-vinyl-acetate with the same diameter (54 mm) but varying cross-sectional thicknesses (3, 3.5, or 4 mm). Women were instructed to insert the ring on day 5 of the menstrual cycle and use the device for 21 days. Temporary removal of the ring was permitted during intercourse or for rinsing with water after vaginal bleeding. 59 women (91%) completed the study. 41 women (66.1%) reported at least 1 adverse effect, most frequently foreign body feeling (8 women) and vaginal discharge (15 women), but all side effects were mild. No major differences were recorded between the 3 types of rings other than a sensation of expulsion, which was more common in women assigned the ring with the smallest cross-sectional thickness. 1 woman in the 3.5 mm group experienced complete expulsion during intercourse. The ring was judged to be easy to insert and remove. The device was felt during intercourse by 5 women in the 3.5 mm group but by only 1 woman each in the 2 other groups. Although 35-50% of male partners could feel the ring during intercourse, only 11-15% cited this as a reason for disliking the device. Further development of an active combined contraceptive ethylene-vinyl-acetate ring with a cross-sectional diameter of 4 mm is recommended.

The effects of CTR-24, a biphasic oral contraceptive combination, compared to Diane-35 in women with acne.

One-hundred-and-eighty-three women were enrolled in an open, randomized, multicentre study in which the effects on acne of a low-dose biphasic oral contraceptive containing a daily dosage of 25 micrograms desogestrel and 40 micrograms ethinylestradiol (7 days) and a daily dosage of 125 micrograms desogestrel and 30 micrograms ethinylestradiol (15 days) were compared to Diane-35 containing a daily dosage of 2.0 mg cyproterone acetate and 30 micrograms ethinylestradiol (21 days) during four cycles of treatment. Clinical and photographic evaluation of acne plus laboratory assessments were done before treatment and at the end of cycle 4. A reduction with regard to the number of lesions and the degree of severity was observed in both groups. No differences were found between the two treatments in the clinical and photographic evaluation. In both treatment groups, a decrease in total testosterone and 3 alpha-17 beta-androstanediol glucuronide was observed and an increase in SHBG. The decrease in 3 alpha-17 beta-androstanediol was statistically significantly more pronounced in the Diane-35 group.

The effects of a combined contraceptive vaginal ring releasing ethinyloestradiol and 3-ketodesogestrel on vaginal flora.

Fifty nine women with documented normal ovulatory cycles and with no symptoms of vaginal infection were divided into four groups. Each group used a combined contraceptive vaginal ring (CCVR) with a mean daily release rate of 0.015 mg of ethinyloestradiol (EE) and 0.120 mg of 3-ketodesogestrel (3-KDG) per day, for one cycle of either 21, 28, 42, or 56 days. Cultures from the posterior vaginal fornix and from the endocervical canal were obtained immediately before insertion of the ring and on removal of the ring. Changes in the numbers of vaginal cells, aerobic and anaerobic bacteria, Chlamydia trachomatis, Gardnerella vaginalis, yeasts and Trichomonas vaginalis were documented at the end of each treatment. Intra- and inter- group changes in the vaginal flora were assessed at the end of each treatment. The comparison between the number and type of flora showed no significant change between the pre-treatment population and the post-treatment population. The results of this study suggest that the use of this CCVR for 21, 28, 42 and 56 days is not associated with an increase in inflammatory cells or pathogenic bacteria.

PIP: Researchers recruited 59 healthy volunteers from England and the Netherlands for a study to determine changes in the vaginal flora or inflammatory cells when a combined contraceptive vaginal ring (diameter of 6 cm) releasing .015 mg of ethinyl estradiol and .12 mg of 3-ketodesogestrel daily was in position for 21, 28, 42, or 56 days. They obtained cultures from the posterior vaginal fornix and the endocervical canal right before insertion of the ring and after its removal. Even though the researchers allowed sexual activity, they did not record data on sexual activity for this study. None of the volunteers had 1 sexual partner. The researchers specifically looked at vaginal cells, aerobic and anaerobic bacteria, Chlamydia trachomatis, Gardnerella vaginalis, yeasts, and Trichomonas vaginalis. No significant changes in vaginal flora or vaginal cells occurred between pretreatment and posttreatment for any of the 4 matched treatment groups (21, 28, 42, or 56 days insertion). Moreover there were no significant changes between treatment groups. The researchers suggested this vaginal ring performed so well in comparison to other rings such as those which release ethinyl estradiol and levonorgestrel because of its reasonable dimensions, its flexibility, and its low hormone release rate. They concluded that it can be used for extended periods.

Ovarian activity and bleeding patterns during extended continuous use of a combined contraceptive vaginal ring.

A combined contraceptive vaginal ring with a mean release rate of 0.015 mg of ethinyloestradiol and 0.120 mg of 3-ketodesogestrel per day was used by female volunteers, for either 28, 42, 56 or 84 days. Contraceptive efficacy was assessed by pelvic ultrasound scanning, endocrine monitoring and cervical mucus assessment. Menstrual diary cards were analysed to assess the effect on cycle control. Ovulation inhibition was seen in all treatment groups. Following removal of the ring, a return to an ovulatory cycle was observed in all volunteers. With extension of the treatment cycle beyond the recommended 21 days, there is an increase in the occurrence of bleeding and spotting episodes. This can be compared to patterns obtained during continuous use of combined oral contraceptives.

Bioavailability and bioequivalence of etonogestrel from two oral formulations of desogestrel: Cerazette and Liseta.

In a three-period cross-over study with 24 healthy young females (study part 1), the bioavailability of etonogestrel (3-ketodesogestrel) was determined after a single oral dose of two Cerazette tablets (each containing 75 microg desogestrel), one Liseta tablet (containing 150 microg desogestrel and 1.5 mg 17beta-estradiol), and an intravenous dose of 150 microg etonogestrel. Etonogestrel serum levels from 23 subjects could be analysed by radio-immunoassay. The geometric mean bioavailability of etonogestrel from Cerazette and Liseta tablets was 0.79 and 0.82, with 95% confidence intervals of 0.73-0.86 and 0.76-0.88, respectively. Also, the oral formulations were found to be bioequivalent. Subsequently, the single-dose pharmacokinetic parameters of etonogestrel from Cerazette tablets were compared with those after multiple dosing of one Cerazette tablet once daily for 7 days, in a subgroup of 12 subjects (study part 2). A steady state was observed from the fourth day of daily dosing onwards, with time-invariant parameters except for a 14% lower dose-normalised AUC. The least-squares geometric means of the elimination half-life of etonogestrel were approximately 30 h for the three single-dose treatments in study part 1, as well as for the single- and multiple-dose treatments of Cerazette in study part 2, without differences between groups.

Superior cycle control with a contraceptive vaginal ring compared with an oral contraceptive containing 30 microg ethinylestradiol and 150 microg levonorgestrel: a randomized trial.

BACKGROUND: This trial was conducted to compare cycle control with vaginal ring a combined contraceptive vaginal ring, and a combined oral contraceptive (COC) delivering 30 mug ethinylestradiol (EE) and 150 mug levonorgestrel. METHODS: This open-label, randomized, multi-centre, Phase III study involved adult women from 11 countries. Subjects were treated with either vaginal ring or a COC for 13 cycles (12 months). RESULTS: A total of 1030 subjects (vaginal ring, n=512; COC, n=518) comprised the intention-to-treat (ITT) population. The percentage of women in the ITT population who completed the trial was 70.9% for vaginal ring and 71.2% for the COC group. The incidence of breakthrough bleeding and spotting over cycles 2-13, the primary efficacy parameter, was lower with vaginal ring (range 2.0-6.4%) than the COC (range 3.5-12.6%), and for cycles 2 and 9 the lower incidence with vaginal ring was confirmed as statistically significant (P=0.003 and P=0.002 respectively). The incidence of intended bleeding was significantly higher over all cycles with vaginal ring (58.8-72.8%) than with the COC (43.4-57.9%). CONCLUSIONS: Cycle control with vaginal ring was excellent and superior to that of a COC containing 30 mug EE.

Desogestrel-containing oral contraceptives and blood pressure.

Oral contraceptives (OCs) containing 0.150 mg desogestrel plus 0.020 or 0.030 mg ethinylestradiol (Marvelon) were studied with respect to their effect on blood pressure. Data on 3,421 women were obtained covering 41,132 treatment cycles. The drop-out rate due to hypertension was 2.92 per thousand women-years (TWY). Mean changes in blood pressure were small, indicating that low doses of ethinylestradiol when combined with desogestrel do not adversely affect blood pressure.

Comparative study of the effects of a progestogen-only pill containing desogestrel and an intrauterine contraceptive device in lactating women.

OBJECTIVE: To evaluate the effects of desogestrel 75 microg/day, as a progestogen-only pill compared with a copper-bearing intrauterine contraceptive device (IUCD) on lactation and to study the safety of both treatments in mothers and children. Transfer of etonogestrel to breast milk was studied in a subgroup of desogestrel users. The children were to be followed up until 2.5 years of age. DESIGN: An open, non-randomised, group-comparative study in lactating women. SETTING: University Hospital, Reykjavik, Iceland. PARTICIPANTS: A total of 83 lactating women; 42 received desogestrel and 41 had an IUCD inserted for seven consecutive treatment cycles of 28 days. METHODS: Evaluation visits were planned at baseline and at the end of treatment cycles 1, 4 and 7. The amount of breast milk was determined by weighing the infants before and after feeding, at baseline and after treatment cycles I and 4. Milk samples were obtained at the same time for constituent measurements. Safety was studied by structured medical examinations and by recording adverse experiences in mothers and children. RESULTS: There were no significant differences between the desogestrel and IUCD groups in composition and quantity of breast milk nor in growth and development of the children followed up to the age of 2.5 years. In the desogestrel group a slightly higher incidence of mild adverse experiences of a hormonal nature was reported among both mothers and infants. Of the children 82% were followed until 1.5 years of age and 50% until 2.5 years. CONCLUSION: The use of desogestrel 75 microg/day did not change the amount and composition of breast milk nor did it affect growth and development of the breastfed children. It appears to be a safe and effective contraceptive method for lactating women

Long-term experience with Multiload intrauterine devices.

This paper reports the joint experience of three investigators who used three types of the Multiload (ML) IUD (MLCu250 Short, MLCu250 Standard, and MLCu375) in 1987 consecutive insertions during which an experience of 56,005 woman-months of use was accumulated. The material was analyzed using the life-table method and complemented with a case by case investigation, the main purpose of the study being the specific analysis of IUD-related complications. The authors also evaluated return of fertility whenever a device was removed because of wish of pregnancy. Results indicate that serious IUD-related complications were rare, continuation rate high, and reversibility of fertility unaffected by the device.

Multicentre study with a new biphasic oral contraceptive containing ethinylestradiol and desogestrel. Report on efficacy, cycle control and adverse experiences with special emphasis on blood pressure and weight.

In a multicentre study 882 women were treated during a total of 12850 cycles with a new biphasic oral contraceptive: CTR 24. The study period was 18 cycles. The biphasic preparation CTR 24 contains 25 micrograms desogestrel (CAS 54024-22-5) plus 40 micrograms ethinylestradiol (CAS 57-63-6) daily for the first 7 days followed by the combination of 125 micrograms desogestrel and 30 micrograms ethinylestradiol daily for the subsequent 15 days. One pregnancy occurred. The woman had forgotten one tablet on Day 6 of Cycle 12. The Pearl Index was 0.1 (0.0-0.5) for patient failure. The combination had a good cycle control and only few side effects were reported.

PIP: In a multicenter study, 882 women were treated during a total of 12,850 cycles with a new biphasic oral contraceptive (OC) CTR 24. The study period extended for 18 cycles. This biphasic OC contains 25 mcg desogestrel (CAS 54024-22-5) + 40 mcg ethinyl estradiol (CAS 57-63-6) daily for the 1st 7 days followed by a combination of 125 mcg desogestrel and 30 mcg ethinyl estradiol daily for the subsequent 15 days. 1 pregnancy occurred in a woman who had forgotten 1 tablet on day 6 of cycle 12. The Pearl Index was 0.1 (0.0-0.5) for patient failure. The combination thus had good cycle control and only a few side effects were reported. (author's modified)

The effects of two phasic oral contraceptives on hemostasis and platelet function.

OBJECTIVE: To compare the effects on hemostatic parameters of a combiphasic oral contraceptive containing desogestrel and ethinyl estradiol (DSG/EE) and a triphasic oral contraceptive containing levonorgestrel and ethinyl estradiol (LNG/EE). METHODS: In an open-label, randomized, group-comparative study in 10 healthy volunteers per treatment group, the effects on parameters of coagulation, anticoagulation, fibrinolysis, antifibrinolysis and platelet function were determined at baseline, after three treatment cycles, and after a post-treatment cycle. Changes from baseline were analyzed using a paired t-test, whereas between-group differences were analyzed by means of an analysis of co-variance. RESULTS: Both OC preparations induced modest changes of some coagulation, anticoagulation, fibrinolysis and antifibrinolysis parameters, although all mean values remained within the normal range. No significant effects were observed with either OC with respect to platelet function. Statistically significant differences between the two preparations could occasionally e observed: the concentrations of antithrombin II (AT-III) and Factor VII were higher with the DSG/EE preparation than with LNG/EE preparation at the end of treatment and AT-III activity, AT-III concentration, Factor X concentration, and plasminogen activity were higher with DSG/EE than with LNG/EE in the post-treatment cycle. CONCLUSIONS: Combiphasic DSG/EE and triphasic LNG/EE, both OCs with a comparable amount of EE per cycle, had no clinically significant effect on the overall hemostatic balance.

Effects of chlorhexidine-coated intrauterine device on the bacteriology of the uterine cavity.

Twenty-nine women, aged 31-53 years, scheduled for an abdominal hysterectomy, participated in this study. The patients were divided into three groups. The first received a Multiload MLCu250 intrauterine device (IUD); the second group received a chlorhexidine acetate medicated Multiload MLCu250 IUD; the third group acted as a control group receiving no IUD. Bacteriological cultures of the vagina and ectocervix were taken prior to insertion of the IUD. At hysterectomy, some 18 hours later, specimens were taken from the cervical canal, uterine cavity, and the device itself, for culture of anaerobic and aerobic organisms using a standardized previously validated technique. In three of the nine control patients, organisms were cultured from the uterine cavity. There were no differences between the bacteriological results of the two groups with medicated and non-medicated devices, with regard to the cultures from the cervical canal, uterine cavity or the devices themselves. Nor was there any difference between the control and the IUD group.

Efficacy, tolerability and acceptability of a novel contraceptive vaginal ring releasing etonogestrel and ethinyl oestradiol.

A novel contraceptive vaginal ring releasing etonogestrel 120 microg and ethinyl oestradiol 15 microg daily over a period of 3 weeks was tested. Each ring was used for one cycle, comprising 3 weeks of ring use followed by a 1 week ring-free period. This 1 year, multicentre study assessed the contraceptive efficacy, cycle control, tolerability and acceptability of the contraceptive. Altogether, 1145 women were exposed to the vaginal ring for 12,109 cycles (928 woman-years). Six pregnancies occurred during treatment, giving a Pearl Index of 0.65 (95% confidence interval 0.24--1.41). Cycle control was very good, since irregular bleeding was rare (2.6--6.4% of evaluable cycles) and withdrawal bleeding (mean duration 4.7--5.3 days) occurred in 97.9--99.4% of evaluable cycles. Compliance to the prescribed regimen was high with criteria being fulfilled in 90.8% of cycles. The ring was well tolerated. The majority of women considered this new contraceptive method easy to use, and it offers an effective, convenient, well-accepted and novel method for hormonal contraception.

A comparative study on the effects of a contraceptive vaginal ring NuvaRing and an oral contraceptive on carbohydrate metabolism and adrenal and thyroid function.

OBJECTIVES: To compare carbohydrate metabolism, adrenal and thyroid function during use of a combined contraceptive vaginal ring (NuvaRing, NV Organon, Oss, The Netherlands) with those of a combined oral contraceptive. METHODS: Healthy women aged 18-40 years used either the vaginal ring, delivering 15 microg ethinylestradiol and 120 microg of etonogestrel per day, or a combined oral contraceptive containing 30 microg ethinylestradiol and 150 microg levonorgestrel, for six cycles. Each cycle comprised 3 weeks of use of the ring or the pill followed by 1 ring- or pill-free week. The following parameters were measured at baseline and at the end of cycles 3 and 6: carbohydrate metabolism (glucose, insulin, glycosylated hemoglobin); adrenal function (total cortisol, cortisol binding globulin, dehydroepiandrosterone sulfate); thyroid function (thyroid stimulating hormone, free thyroxine). RESULTS: Small and similar increases in insulin were seen in both groups. Concentrations of cortisol binding globulin and total cortisol rose significantly less during ring use than during combined oral contraceptive use (cycle 3, p= 0.0002; cycle 6, p < 0.0001). Levels of dehydroepiandrosterone sulfate did not change in either group. Thyroid stimulating hormone levels increased significantly more in the ring group at cycle 3 (p = 0.0016) but free thyroxine levels were unchanged in both groups. CONCLUSIONS: Both the vaginal ring and the oral contraceptive have no clinically relevant effects on carbohydrate metabolism, adrenal or thyroid function.

Cycle control and side effects of a new combiphasic oral contraceptive regimen.

In a multicentre study 882 women were treated during a total of 12,850 cycles with a new combiphasic contraceptive: CTR 24. The study period was 18 cycles. The combiphasic preparation CTR 24 contains 25 micrograms desogestrel (CAS 54024-22-5) plus 40 micrograms ethinylestradiol (CAS 57-63-6) daily for the first 7 days followed by the combination of 125 micrograms desogestrel and 30 micrograms ethinyl-estradiol daily for the subsequent 15 days. The bleeding patterns were analysed over pill cycles and a comparison was made between starters and switchers. The cycle control of the combination was very good. The side effect profile was favourable.

PIP: Physicians recruited 882 women into a multicenter trial of a new biphasic oral contraceptive (OC) (25 mcg + 125 mcg desogestrel and 40 mcg + 30 mcg ethinyl estradiol). Trial sites were in Belgium, Denmark, Finland, France, Germany, Norway, Sweden, and the former Yugoslavia. After 3 cycles, women who had switched from using another OC in the 2 months before the study (switchers) were less likely to continue the new OC than were women who had not used any OC in the last 2 months (starters) (6 cycles = 87.2% vs. 90.6%, 12 cycles = 74.7% vs. 79.5%; and 18 cycles = 59.8% vs. 64.9%). Withdrawal bleeding did not occur in 3.2% of all cycles. Absence of withdrawal bleeding became less common over time (cycle 1 = 7.6%, cycle 3 = 5%, cycle 6 = 3.2%, and cycle 18 = 1.8%). Duration of withdrawal bleeding was no more than 5 days in 80% of all women. More and more women had no more than 5 days of withdrawal bleeding as time passed (cycle 1 = 81.7%, cycle 6 = 85.6%, and cycle 18 = 90.6%). Irregular bleeding was more common in the first cycles of the study than in subsequent cycles (e.g., spotting during cycles 1-3 = 8.5-4.8% vs. 3.7-3.1% during cycles 6-18). By cycle 18, 96% of all women had no irregular bleeding. The drop-out rate for irregular bleeding was 2.2% at the end of the study. In 5% of cycles, at least 1 tablet was forgotten. In the first cycles, starters were somewhat more likely to complain of nausea, headache, and breast tenderness than switchers (e.g., nausea, cycle 1 = 5.8% vs. 3.4%). The gap between the 2 groups disappeared after 3 cycles. Starters were more likely to have minor complaints before OC use than after OC use (e.g., 6.5% fewer frequencies of headaches at 18 months). These findings show that the new OC has very good cycle control and a agreeable side effect profile.

Recommendation for confidence interval and sample size calculation for the Pearl Index.

A new guideline on the clinical investigation of steroid contraceptives in women, which has been released by the European Agency for the Evaluation of Medicinal Products (EMEA), calls for the calculation of a confidence interval for the Pearl Index, a widely used measure to describe the effectiveness of a contraceptive method. However, the interpretation of the Pearl Index as a statistical parameter, for which a confidence interval can be calculated, needs further clarification. The guideline does not provide the necessary definitions. In this paper, two statistical models, the Bernoulli model and the Poisson model, are compared; both can be used for the calculation of the Pearl Index and its upper confidence limit. The Poisson model proved to be more suitable, because it can accommodate incomplete treatment cycles. Unambiguous definitions and statistical formulae for the calculation of overall Pearl Index and the Method Failure Pearl Index are given. Finally, the sample sizes required to fulfill the EMEA's guideline are given.

The cervico-vaginal epithelium during 20 cycles' use of a combined contraceptive vaginal ring.

The aim of the study was to evaluate the influence of a combined contraceptive vaginal ring (CCVR) made of Silastic on the cervico-vaginal epithelium during 20 cycles of use. A total of 76 volunteers used the CCVR releasing 0.120 mg etonogestrel and 0.015 mg ethinyloestradiol daily. Cytological samples were taken of the vaginal epithelium, the ectocervix and the endocervix before the start, at 4 and 12 months, and at the end of the study. Cytology, hormonal profiles, human papilloma virus (HPV) status, DNA-flow cytometry, bacterial flora, and morphometry was performed on these samples. Colposcopy and histopathology of biopsy specimens were performed at the end. No cytological changes of the squamous epithelium or the columnar epithelium were found. HPV was detected in three samples of three different women. At least two of them reverted to HPV negative during the rest of the study period. Aneuploidy was diagnosed in 11 women before the study. Seven of them changed to diploid during the study. No changes from diploid to aneuploid were seen. Aneuploidy was not seen in any of the HPV positive samples. Although bacterial flora showed considerable variation during the study, no significant influence of the CCVR could be established. Morphometrical analysis showed an increasing nucleus:cytoplasm ratio of the squamous cells during the study. Mild dysplasia was detected in one woman at the end of the study. It was concluded that no unfavourable cytological or bacteriological changes of the cervico-vaginal epithelium were demonstrated during 20 cycles of CCVR use. The vaginal epithelium became more progestogenic during the study.

PIP: A study of a combined contraceptive vaginal ring showed no unfavorable cytologic or bacteriologic changes of the cervico-vaginal epithelium during 20 cycles of use. A Silastic ring releasing 0.120 mg of etonogestrel and 0.015 mg of ethinyl estradiol daily was inserted in 76 healthy volunteers 18-35 years of age. Participants used the vaginal ring for 21-day periods interrupted by 7-day ring-free intervals. Squamous cells were detectable in 94 (98%) vaginal smears, 95 (99%) ectocervical smears, and 17 (18%) endocervical smears. No cytologic changes of the squamous or the columnar epithelium were noted, and atypical metaplastic cells were not diagnosed. The percentage of smears with a mixed estrogen-progestogenic pattern decreased from 83% at baseline to 63% during cycle 4; 50% of smears showed a progestogenic pattern by the end of the study (cycle 20). Half the women demonstrated aneuploidy at baseline, but two-thirds of these women reverted to diploid status during ring use; no changes from diploid to aneuploid were seen. The ring had no significant influence on the bacterial flora of the vagina or on human papillomavirus status. Further investigations involving larger sample sizes are urged to confirm that the combined contraceptive vaginal ring does not lead to cervical dysplasia or other lesions of the cervico-vaginal epithelium.