Contraception
46:269-278,
1992
OVARIANACTIVMYANDBLEED~PA~SIxlRINGMTENDED KNTmSUSEOFAmINEDmVAGINALm Gmham C.Bwies,
MRXG
Li Xiao Ferg JohnR.Nmton,FRCCG The Acadmic Bt of &&etrics and Gynaecolcgy, university of 3&&7c@m, l&T&q&n, m Than O.M. Dieken HerjanJT.Coelirgh-&mink
OrganOn InternationalB-V., Oss, ?"ne Nether1e
A combined contraceptive vaginal ring with a mean release rate and 0.120 mg of 3of 0.015 mg of ethinyloestradiol 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 diary cards were cervical mucus assessment. Menstrual 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.
Submitted for publication April 2, 1992 Accepted for publication July 7, 1992
Copyright 0 1992 Butterworth-Heinemann
270
Contraception
INTRODUCTION The ability to delay the onset of menses by extended use of the oral contraceptive pill has allowed many women flexibility in their use of the method but has frequently led to a sacrifice in cycle control (1). The development of the combined contraceptive vaginal ring (CCVR) has permitted independently programmable steroid release akin to oral preparations but with the advantage of a lower daily release of steroids and improved user compliance. CCVR The releasing 3-ketodesogestrel (3-KDG) and ethinyloestradiol (EE) is presently being developed to be used for three or four 21-day cycles interspersed with seven-day ring-free intervals. This regimen is the method originally described for oral contraceptive preparations (2). The ease of use may be improved by reducing the number of ring changes. Extending the length of use from 21 days onwards could lead to such a reduction. The preference by women for a longer bleeding-free interval within reversible hormonal methods has been documented (3). The success of prolonging the treatment cycle is not only dependent on the contraceptive efficacy but also the acceptability of the method,which is closely aligned to good cycle control and the effect on the vaginal bacteriological environment (4). In the present study, we therefore investigated the extended use of the CCVR beyond 21 consecutive days and studied women using the CCVR for 28, 42, 56 and 84 days, respectively.
MATERIALS
AND METHODS
The CCVR, developed by Organon International, Oss, the Netherlands, is a flexible, off-white,two-compartment ring system with an overall diameter of 6 cm and a cross-sectional diameter of 5 mm. The outer part of the ring consists of two medical grade Silastic tubes joined by glass connectors and medical grade adhesive. The larger Silastic tube contains a fibre of approximately 10 cm, consisting of an ethylene vinyl acetate (RVA) core containing 3-ketodesogestrel. The smaller Silastic tube contains a fibre of approximately 1.5 cm, consisting of an EVA core with both 3-KIX and ethinyloestradiol . The mean daily release rate is 0.120 mg 3-KDG and 0.015 mg of ethinyloestradiol. After obtaining ethical committee approval and obtaining informed consent, volunteers with a cycle length of 27 - 32 days were considered for the study. Following a physical examination, the volunteers underwent a cycle of screening. This entailed performing ultrasound scans (USS) from day 10 of
Contraception
the cycle and ovarian follicle size was measured until rupture or disappearance. Venepuncture was performed at every USS for oestradiol and progesterone assay. All blood samples related to one cycle were measured in one radioirrununoassay series. If no evidence of ovulation was observed by USS, the subject was not considered eligible. Following instruction, the ring was inserted between days one and five of the menstrual cycle by the investigator. In group 1 the ring was in situ for 28 days. If results were satisfactory, group 2 was commenced with the ring in situ for 42 days. Following completion of group 2, group 3 used the ring for 56 days. A final group (84 days) was planned if the results from the previous groups were favourable. From day 19 onwards, USS measurement endometrial thickness was performed removal of the ring.
of follicle size and twice per week until
A Sonoline SLl scanner with a 3.5 megahertz (MHz) sector probe calibrated at 1540 m/s was employed for all ultrasound measurements. Ultrasound measurements were abdominal. The technique utilising the full bladder was used to ensure the ovaries lay outside the zone of reverberation emanating from the abdominal wall and to bring them within the focused range of the transducer (2.5-12 cm) * Follicles were measured with the calibrated electronic calipers in three perpendicular planes and the mean follicle diameter (MFD) calculated from the mean of these three measurements. The endometrium was visualized as the dull echogenic area either side of the mid-line cavity. The endometrium was measured as the sum of the echogenic widths either side of the mid-line. Venepuncture was performed in conjunction with the USS measurements. Oestradiol and progesterone assays were performed on the samples at the West Midland's Hospital for women using a standard radioimmunoassay technique. The coefficient of variation (CV) for the oestradiol assay ranged from 6.6% to 8.9% (at a oestradiol level of 1770 pmol/l). The CV for the progesterone assay ranged between 26% (at a progesterone level of 2 nmol/l) to 4.2%
46:269-278,
1992
OVARIANACTIVMYANDBLEED~PA~SIxlRINGMTENDED KNTmSUSEOFAmINEDmVAGINALm Gmham C.Bwies,
MRXG
Li Xiao Ferg JohnR.Nmton,FRCCG The Acadmic Bt of &&etrics and Gynaecolcgy, university of 3&&7c@m, l&T&q&n, m Than O.M. Dieken HerjanJT.Coelirgh-&mink
OrganOn InternationalB-V., Oss, ?"ne Nether1e
A combined contraceptive vaginal ring with a mean release rate and 0.120 mg of 3of 0.015 mg of ethinyloestradiol 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 diary cards were cervical mucus assessment. Menstrual 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.
Submitted for publication April 2, 1992 Accepted for publication July 7, 1992
Copyright 0 1992 Butterworth-Heinemann
270
Contraception
INTRODUCTION The ability to delay the onset of menses by extended use of the oral contraceptive pill has allowed many women flexibility in their use of the method but has frequently led to a sacrifice in cycle control (1). The development of the combined contraceptive vaginal ring (CCVR) has permitted independently programmable steroid release akin to oral preparations but with the advantage of a lower daily release of steroids and improved user compliance. CCVR The releasing 3-ketodesogestrel (3-KDG) and ethinyloestradiol (EE) is presently being developed to be used for three or four 21-day cycles interspersed with seven-day ring-free intervals. This regimen is the method originally described for oral contraceptive preparations (2). The ease of use may be improved by reducing the number of ring changes. Extending the length of use from 21 days onwards could lead to such a reduction. The preference by women for a longer bleeding-free interval within reversible hormonal methods has been documented (3). The success of prolonging the treatment cycle is not only dependent on the contraceptive efficacy but also the acceptability of the method,which is closely aligned to good cycle control and the effect on the vaginal bacteriological environment (4). In the present study, we therefore investigated the extended use of the CCVR beyond 21 consecutive days and studied women using the CCVR for 28, 42, 56 and 84 days, respectively.
MATERIALS
AND METHODS
The CCVR, developed by Organon International, Oss, the Netherlands, is a flexible, off-white,two-compartment ring system with an overall diameter of 6 cm and a cross-sectional diameter of 5 mm. The outer part of the ring consists of two medical grade Silastic tubes joined by glass connectors and medical grade adhesive. The larger Silastic tube contains a fibre of approximately 10 cm, consisting of an ethylene vinyl acetate (RVA) core containing 3-ketodesogestrel. The smaller Silastic tube contains a fibre of approximately 1.5 cm, consisting of an EVA core with both 3-KIX and ethinyloestradiol . The mean daily release rate is 0.120 mg 3-KDG and 0.015 mg of ethinyloestradiol. After obtaining ethical committee approval and obtaining informed consent, volunteers with a cycle length of 27 - 32 days were considered for the study. Following a physical examination, the volunteers underwent a cycle of screening. This entailed performing ultrasound scans (USS) from day 10 of
Contraception
the cycle and ovarian follicle size was measured until rupture or disappearance. Venepuncture was performed at every USS for oestradiol and progesterone assay. All blood samples related to one cycle were measured in one radioirrununoassay series. If no evidence of ovulation was observed by USS, the subject was not considered eligible. Following instruction, the ring was inserted between days one and five of the menstrual cycle by the investigator. In group 1 the ring was in situ for 28 days. If results were satisfactory, group 2 was commenced with the ring in situ for 42 days. Following completion of group 2, group 3 used the ring for 56 days. A final group (84 days) was planned if the results from the previous groups were favourable. From day 19 onwards, USS measurement endometrial thickness was performed removal of the ring.
of follicle size and twice per week until
A Sonoline SLl scanner with a 3.5 megahertz (MHz) sector probe calibrated at 1540 m/s was employed for all ultrasound measurements. Ultrasound measurements were abdominal. The technique utilising the full bladder was used to ensure the ovaries lay outside the zone of reverberation emanating from the abdominal wall and to bring them within the focused range of the transducer (2.5-12 cm) * Follicles were measured with the calibrated electronic calipers in three perpendicular planes and the mean follicle diameter (MFD) calculated from the mean of these three measurements. The endometrium was visualized as the dull echogenic area either side of the mid-line cavity. The endometrium was measured as the sum of the echogenic widths either side of the mid-line. Venepuncture was performed in conjunction with the USS measurements. Oestradiol and progesterone assays were performed on the samples at the West Midland's Hospital for women using a standard radioimmunoassay technique. The coefficient of variation (CV) for the oestradiol assay ranged from 6.6% to 8.9% (at a oestradiol level of 1770 pmol/l). The CV for the progesterone assay ranged between 26% (at a progesterone level of 2 nmol/l) to 4.2%
