1 Department of Obstetrics and Gynecology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-Ku, Tokyo 160-8582, Japan, 2 Unipath Ltd, Priory Business Park, Bedford, UK and 3 Mitsui Pharmaceuticals Inc., 122, Nihonbashi 3-Chome, Chuo-Ku, Tokyo 103-0027, Japan
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: fertile period/LH/LH surge/oestradiol/urinary metabolite
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The studies described above show that the measurement of LH alone will result in the prediction and detection of the two most potentially fertile days of the cycle. The evidence suggests that a test based on the monitoring of both urinary LH and E3G could be used to delineate the potentially fertile period and provide additional warning days of ovulation, on which intercourse may lead to pregnancy, compared with the use of LH alone. A new system has been developed to identify those days on which a couple should have intercourse if a woman is to maximise her chances of conception. The Clearview Primera Fertility Monitor (CPFM) (Mitsui Pharmaceuticals Inc., Tokyo, Japan), which has been designed for home-use, identifies the potentially fertile period of a woman's cycle by monitoring changes in the levels of LH and E3G in urine. (the CPFM is marketed in the USA as ClearPlan Easy® Fertility Monitor, Unipath Diagnostics Co., Princeton, NJ, USA). The aim of this study was to test whether CPFM could provide information about changes in cycle fertility comparable with that deduced from laboratory measurements. In order to exclude, at this stage, potential errors resulting from use of the system by ordinary women at home, CPFM testing was performed in real time in a laboratory. The monitor LH and E3G measurements and corresponding fertility status were compared with serum oestradiol, serum LH, urinary E3G and urinary LH measurements in a population of normal healthy women.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The system will delineate three levels of fertility according to changes detected in the concentrations of LH and E3G. Low fertility is displayed when the probability of conception is low and these hormones are at a baseline concentration. Low fertility will be displayed from day 1 of a woman's cycle until rises above the baseline concentrations are detected. The change from Low fertility to High fertility is triggered by detection of elevated E3G concentrations, typically at concentrations between 2030 ng/ml. The display of High fertility indicates that the woman is approaching a period of maximum fertility. High fertility is also displayed for one day after Peak fertility. The change from High fertility to Peak fertility is triggered by the detection of an LH surge, typically with a concentration >30 IU/l. The display of Peak fertility indicates that ovulation is imminent. Peak fertility is displayed on the day of the LH surge (CPFM peak day) and on the following day. Subsequently High fertility will be displayed for 1 day prior to a return to Low fertility. The changes in fertility are displayed on the monitor's LCD.
The transition from Low to High to Peak fertility is indicated by an increasing number of solid bars on the display; one bar (Level I) for Low fertility, two bars (Level II) for High fertility and three bars (Level III) for Peak fertility. In addition an egg symbol is displayed on Peak fertility days. The %T units are not displayed by the monitor; the monitor uses a built in rule-set to convert the detected changes in LH and E3G %T into the fertility status.
To use the system, on the morning after the start of menses the woman presses a button on the monitor to indicate that this is day 1 of her cycle. She then simply looks at her monitor every morning to check whether she needs to do a test. To perform a test she holds a test stick in her urine stream for 3 s. She then inserts the test stick into the monitor which reads the test stick after 5 min. On completion of the test the monitor informs the woman of her fertility status through a simple display.
Study recruitment
Normal healthy women were recruited onto the study. A brief medical history was collected from the volunteers who were screened for the following selection criteria: Age 2040 years; regular menstrual cycles of length 2534 days; no history of ovulatory disorders; no use of medication which would interfere with ovarian function; not breastfeeding; not pregnant.
Prior to admission all volunteers gave their informed consent and it was explained that they were free to leave the study at any time.
Study protocol
Blood and early morning urine samples were collected from volunteers for one cycle according to the schedule presented in Table I.
|
In this study the volunteers did not test their urine themselves using the monitor, instead they provided early morning urine samples for testing in the laboratory on the day of collection. Two types of CPFM measurements were made. Firstly the fertility status on that day, Low, High or Peak, was determined by testing the collected urine with a test stick and reading the fertility status using a standard CPFM allocated to each volunteer. Secondly the corresponding %T value for LH and E3G was measured by completing a second test on each of the collected samples. A monitor linked to a computer and adapted to provide the %T readings via the computer was used for this purpose.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
For the purposes of this study the day of peak urinary LH concentration was used as the reference day. A peak in the urinary LH concentration was observed in 29/30 cycles. One cycle was monitored up until day 28 of a 31 day cycle and no urinary LH peak was recorded. In all 29 cycles with a urinary LH peak, the peak was accompanied by a corresponding peri-ovulatory rise in the concentrations of serum oestradiol. A mid-luteal phase peak in progesterone was observed in 28/29 of the cycles. A possible reason for the absence of the progesterone peak in one of the cycles was that sample collection had stopped only 5 days after the urinary LH peak day and therefore the peak was not observed.
Figure 1 shows, on the days relative to the urinary LH peak day, the changes in mean serum oestradiol, LH, and progesterone concentrations, urinary E3G and LH concentrations, urinary LH and E3G %T measurements (adapted CPFM monitors), and percentage of cycles displaying High or Peak fertility on each day (standard CPFM monitors). Samples were not collected on all the cycle days (Table I
) however the data in Figure 1
are plotted against cycle day relative to the urinary LH peak day and the mean values may not include measurements from all volunteers. Table II
lists the number of measurements included on each day relative to the urinary LH peak and the standard errors of the mean are included in Figure 1
.
|
|
Table III shows that there was 65.6% agreement between the CPFM Peak day and the urinary LH peak day. The CPFM Peak day was observed either 1 day or 2 days before the urinary LH peak day in 24.1 and 6.9% of cycles respectively. In one cycle the CPFM showed peak status on day 9, 7 days prior to the urinary LH peak observed on day 16. A corresponding small peak in the urinary LH concentration was observed on this day. Similarly Table IV
shows that there was 55.2% agreement between the urinary LH peak day and the serum LH peak day. The serum LH peak day as observed either 1 day or 2 days before the urinary LH peak day in 37.9 and 3.4% of cycles respectively. In one cycle the serum LH peak was observed on day 18, 4 days prior to the urinary LH peak observed on day 22. After day 18 samples were collected on alternate days. This may have affected accurate detection of the urinary and serum LH peak and is the likely reason for the greater difference observed.
|
|
An oestradiol increase to concentrations >100 pg/ml was considered as the periovulatory oestradiol rise (Leidenberger, 1992). Similarly an E3G rise day was assigned using a threshold of 20 ng/ml. The days on and after the serum oestradiol rise day up until the urinary LH peak day were considered as warning days and up to 5 days warning was detected in 96.6% of cycles (Table V
). Similarly, the number of days on and after the E3G rise day up until the urinary LH peak day were considered as warning and up to 5 days warning were detected in 82.8% of cycles (Table VI
). In 58.6% of cycles CPFM showed either High or peak fertility for up to 5 days prior to the urinary LH peak day (Table VII
).
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
This study has shown good agreement between the CPFM Peak day and the urinary LH peak as detected by laboratory assay. It is not suprising that in 24.1% of cycles CPFM displayed Peak fertility the day before the urinary LH peak. This is a result of the difference in days between the LH surge, detected by CPFM, and the actual peak in urinary LH concentrations assigned retrospectively. In two cycles urinary LH began to rise 2 days before levels peaked and CPFM detected the start of the rise in LH. Neither is it suprising to see that in 37.9% of cycles peak serum LH concentrations were reached 1 day before peak urinary LH concentrations. This is a result of the time taken for changes in serum hormone concentrations to be detected in the urine, particularly when measurements are taken once during a 24 h period. In one cycle (3.4%) CPFM detected a false positive LH surge declaring Peak fertility 7 days prior to the observed urinary LH peak.
Another study was recently undertaken comparing the home-use performance of CPFM against transvaginal ultrasound. Results show that in 123 out of 135 ovulatory cycles with a CPFM peak day, ovulation was correctly predicted within 2 days following the CPFM Peak day (Behre et al.2000). Detection of the LH surge can at best identify the two most potentially fertile days of the cycle and therefore has limited opportunities for the timing of intercourse. This study has shown that the rise in E3G closely follows the rise in serum oestradiol and the number of days warning of the urinary LH peak day provided by CPFM coincide well with the warning provided by the quantitative measurement of serum oestradiol and E3G concentrations. CPFM was able to show High fertility for up to 5 days prior to the urinary LH peak day in 58.6% of cycles and High fertility for up to 5 days prior to Peak fertility in 72.4% of cycles. It should be noted that, as the urinary LH peak is an indirect marker of ovulation, the 5 days of High fertility detected by the monitor cannot be compared exactly with the five potentially fertile days prior to ovulation estimated from analysis of the Wilcox data (Dunson et al., 1999
). Typically follicle rupture has been observed to occur 24 h after detection of the urinary LH surge (Collins, 1996
). These additional days of potential fertility identified by CPFM, compared with LH tests alone, increase the opportunities for maximising conception.
For 27.6% of subjects the number of High fertility days displayed by the system was greater than five. It remains to be seen whether experiencing more than 5 days of High fertility has any bearing on a couples ability to also have intercourse on Peak fertility days when the chances of conception are at a maximum.
Here we present the results of a study designed to test whether CPFM can provide information about changes in cycle fertility which is comparable with that deduced from laboratory measurements. Results of a home-use study (Behre et al., 2000) have shown that women can use the system at home to predict ovulation and therefore the days of highest potential fertility. These results demonstrate that the CPFM will detect changes in urinary levels of LH and E3G which coincide well with laboratory measurements in the definition of the potentially fertile period. The system, which has been designed for home use, will allow couples to use the information to time intercourse for the best prospects of natural conception. In addition the system shows potential for use in the evaluation and treatment of the infertile couple.
![]() |
Acknowledgements |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Barrett, J.C. and Marshell, J. (1969) The risk of conception of different days of the menstrual cycle. Pop. Studies, 23, 455461.[ISI]
Behre, H.M., Kuhlage, L., Gassner, C. et al. (2000) Prediction of ovulation by urinary hormone measurements with the home use ClearPlan Fertility Monitor: comparison with transvaginal ultrasound scans and serum hormone measurements. Hum. Reprod., 15, 24782482.
Bourne, T.H., Hagström, H.-G., Granberg, S. et al. (1996a) Ultrasound studies of vascular and morphological changes in the human uterus after a positive self-test for the urinary luteinising hormone surge. Hum. Reprod., 11, 369375.[Abstract]
Bourne, T.H., Hagström, H.-G., Hahlin, M. et al. (1996b) Ultrasound studies of vascular and morphological changes in the human corpus luteum during the menstrual cycle. Fertil. Steril., 65, 753758.[ISI][Medline]
Branch, C.M., Collins, P.O. and Collins, W.P. (1982) Ovulation prediction: changes in the concentrations of urinary estrone-3-glucuronide, estradiol-17ß-glucuronide and estriol-16-glucuronide during conceptional cycles. J. Steroid. Biochem., 16, 345347.[ISI][Medline]
Burger, H.G. (1989) Estradiol: The physiological basis of the fertile period. Int. J. Gynaecol. Obstet., 1, 59.
Catalan, R., Castellanos, J.M., Palomino, T. et al. (1989) Correlation between plasma estradiol and estrone-3-glucuronide in urine during the monitoring of ovulation induction therapy. Int. J. Fertil., 34, 271275.[ISI][Medline]
Collins, W.P. (1996) Indicators of potential fertility: scientific principles. In Bonnar, J. (ed.) Natural Conception Through Personal Hormone Monitoring. The Parthenon Publishing Group, New York, pp. 1333.
Collins, W.P., Branch, C.M. and Collins, P.O. (1981). Ovulation prediction and detection by the measurement of steroid glucuronides. In Cortes-Prieto, J., Campos de Paz, A. and Neces-e-Castro, M. (eds.) Research on Fertility and Sterility. MPT Ltd., Lancaster, pp. 1933.
Dunson, D.B., Baird, D.D., Wilcox, C.R. et al. (1999) Day specific probabilities of clinical pregnancy based on two studies with imperfect measures of ovulation. Hum. Reprod., 14, 18351839.
Leidenberger, F. (1992) Clinical endocrinology for gynecologists. Springer, Berlin, pp. 160166.
Martinez, A.R., Zinaman, M.J., Jennings, V.H. et al. (1995) Prediction and detection of the fertile period: the markers. Int. J. Fertil., 40, 139155.[ISI]
Moghissi, K.S., Syner, F.N. and Evans, T.N. (1972) A composite picture of the menstrual cycle. Am. J. Obstet. Gynecol., 114, 405418.[ISI][Medline]
Pauerstein, C.J., Eddy, C.A., Croxatto, H.D. et al. (1978) Temporal relationships of estrogen, progesterone and luteinising hormone levels to ovulation in women and infra-human primates. Am. J. Obstet. Gynecol., 130, 876886.[ISI][Medline]
Royston, J.P. (1982) Basal body temperature, ovulation and the risk of conception, with special reference to the lifetimes of sperm and egg. Biometrics, 38, 397406.[ISI][Medline]
Schwartz, D., MacDonald, P.D.M. and Heuchel, V. (1980) Fecundability, coital frequency and the viability of ova. Pop. Studies, 34, 397400.[ISI]
Schiphorst, L.E.M., Collins, W.P. and Royston, J.P. (1985) An estrogen test to determine the times of potential fertility in women. Fertil. Steril., 44, 328334.[ISI][Medline]
WHO Task Force on Methods for Determination of the Fertile Period (1980a) Temporal relationships between ovulation and defined changes in the concentration of plasma estradiol-17ß, luteinising hormone, follicle stimulating hormone and progesterone. I. Probit analysis. Am. J. Obstet. Gynecol., 138, 383390.[ISI][Medline]
WHO Task Force on Methods for Determination of the Fertile Period (1980b) Temporal relationships between ovulation and defined changes in the concentration of plasma estradiol-17ß, luteinising hormone, follicle stimulating hormone and progesterone. II. Histologic dating. Am. J. Obstet. Gynecol., 139, 886895.[ISI]
WHO Task Force on Methods for Determination of the Fertile Period (1983) Temporal relationships between indices of the fertile period. Fertil. Steril., 39, 647655.[ISI][Medline]
Wilcox, A.J., Weinberg, C.R., O'Connor, J.F. et al. (1988) Incidence of early loss of pregnancy. N. Eng. J. Med., 319, 189194.[Abstract]
Wilcox, A.J., Weinberg, C.R. and Baird, D.D. (1995) Timing of sexual intercourse in relation to ovulation. N. Eng. J. Med., 333, 15171521.
Submitted on December 29, 2000; accepted on April 19, 2001.