CZ596A3 - Method of monitoring fertility stage, a testing set and reserve package - Google Patents

Abstract

A method of monitoring the status of a current ovulation cycle of an individual female mammalian (generally human) subject, involving repeated testing of the body fluid concentration of at least one analyte, preferably estrone-3-glucuronide (E3G) of significance in relation to the status of the ovulation cycle, during at least the pre-ovulation phase of the current ovulation cycle of the individual subject, wherein testing for said analyte concentration during the current ovulation cycle conducted at least once during the interval spanning days 1 to 7 inclusive following the onset of menses, to establish a reference concentration value for analyte in the current cycle, and then testing is conducted repeatedly during a plurality of days, preferably commencing at least 5 numerical days in advance of the mean numerical day on which actual ovulation has occurred over one or more previous ovulation cycles in the same individual subject, analyte concentration values obtained during said repeated testing being compared with the reference concentration value to determine whether a concentration change indicative of imminent ovulation is occurring or has occurred since the previous test. The method can be based solely on E3G measurements.

Description

The method of monitoring the fertility stage, the test bag and the avyo storage container

Technical field

6 .111 θ ²

The present invention relates to methods, devices, and test kits for controlling the low / low blood cycle in female ss, and in particular in women. i I L K θ θ • f-q

In particular, although not exclusively, the invention relates to a simple practice which can be easily performed by untrained persons, eg at home, to provide reliable fertility status data to aid contraception. An important object of the invention is to provide such information without the need to perform tests on a frequent (i.e., daily) basis during each ovulation cycle. The need for regular, eg daily cycle testing, has been characterized by many previously proposed ovulation cycle monitoring systems.

The invention may also be used by persons wishing to increase the probability of conception by providing an indication of the time during the ovulation cycle when fertilization is most likely to occur.

BACKGROUND OF THE INVENTION

In order to provide reliable information on the fertility stage, the user must be given adequate notice of the onset of the fertile phase of the cycle. A number of procedures have been proposed in the art, some of which involve monitoring one or more parameters that differ as cases of ovulatory approaches. Typical parameters that have been used are the concentrations of the analyte in body fluids such as estradiol and its metabolites, for example estrone-3-glucuronide (E3G). Other parameters that have been used are basal body temperatures (which can only provide predictable information for use in subsequent cycles) and various physiological changes, such as vaginal mucosa characteristics.

Many excellent academic studies have been performed using these parameters. These studies have determined how these parameters can be correlated with the fertility status of the average ankle of a broad population sample. An example is Collins et al. (1981), Proc. Xth International Congress on Fertility and Sterility, edited by MTP Ltd., pp. 19-33.

The accentuated crazato in the amoha of such stages is to support the conception of previously seen as infertile.

idmců,

However, when developing a practical monitoring system suitable for use by an individual, it is found that many individual subjects do not correspond to the average in terms of cycle length and / or duration and timing of the fertile phase. The extent of individual variation between individuals and of course one cycle from others in the same individual makes average population data too unreliable for consistent practical use.

Obviously, since an undesirable pregnancy may be a serious consequence of an imperfect warning about the fertility stage, there has been a tendency to exercise extreme caution and require testing of the appropriate parameter (s) during the cycle and particularly from the beginning of the cycle (onset of menstruation). From the individual user's point of view, it would be advantageous to avoid the need for such continuous testing and instead to perform testing during a comparatively short portion of each cycle. This can benefit the user not only in terms of convenience, but can also reduce the cost of the method if a disposable test device is used and only a few such disposable test devices are needed each month.

An example of a system for determining the onset of ovulation using water-swellable polymer pellets to measure the water content of vaginal mucosa that apparently rises at the time of ovulation is described in US 4151833 (Polishuk). It is determined that the difference in maximum pellet size, as a result of the absorption of water from cervical mucosa, is closely related to a sudden increase in luteinizing hormone (LH) and changes in basal body temperature.

From the experimental data reported in US 4151833 (Figure 8), it appears that the pellet diameter is indeed closely related to the timing of LH rise; consequently, the proposed system cannot in practice provide any reliable warning of the onset of ovulation earlier than this warning obtained from the knowledge of LH concentration.

EP-A-385621 (Coley et al. / Uailever) describes disorders of the ovulation cycle monitoring systems which primarily consist of a change in basal body temperature (BBT) to estimate ovulation time and the authors propose a system that uses regular (conventional) measurements. BBT in conjunction with the knowledge of other parameters, particularly the measurement of certain hormone levels in the urine. A specific suggestion is that BBT is measured daily during each cycle and is used to estimate changes in the fertility stage in the next cycle. During this closest (predictable)? During the cycle, hormone levels in the urine are checked at certain times to confirm that cycle development, as predicted from prior BBT knowledge, is consistent. The particular hormones selected are E3G, P3G (pregnandiol-3-glucuronide) and LH. Urine E3G levels are expected to be measured at least for a day interval from Day 5 to Day 7 of the predicted cycle and again at least one day, during the interval from Day 10 to Day 15 of the predicted cycle. According to the example in EP <385621, it is sufficient for the hormone level to be either high or low relative to the threshold. The emphasis in EP 385621 is that occasional hormone level measurements are used to complement the BBT monitoring system. There is no mention that hormonal measurement alone could provide the basis for a reliable fertility monitoring system personified.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a method for monitoring the fertility stage of an individual subject which provides sufficient notice of the onset of the fertile stage to enable contraceptive counseling to be provided and which can be personified for an individual subject.

- 4 can thereby be avoided nespoHHivdstrm substantial "^ rnezénárp ^- oužitelnO" šrjÍnyclr measuring systems (such as BBT). Another objective is to exclude the use of average data obtained from population studies, with their substantial risk that the individual parameter tested may differ significantly from the norm in the population.

A further object is to provide the possibility to base an effective tracking method only on the measurement of one body fluid analyte, such as estradiol or a metabolite thereof. Other advantages of the invention will be apparent from the following description.

Another object of the invention is to provide a test regime that would be a good compromise between the desire to minimize the user's test load and the need to provide the user with valid information about the fertility stage.

By way of illustration only, the invention will be described in relation to the measurement of urinary analytes, in particular E3G (estron-3-glucuronide) and LH (luteinizing hormone).

In addition to the aforementioned estrone-3-glucuronide, estradiol metabolites which can also be determined for the purposes of the invention include estradiol-3-glucuronide, estradiol-17-glucuronide, estriol-3-glucuronide, estriol-16-glucuronide and (essentially for others) than human subjects) estrone-3-sulfate. As will be apparent from the following description, the invention can readily be applied to data obtained by measuring the concentration of other analyte substances relevant to the ovulation cycle stage in body fluids. In general, hormones and their metabolites are the most suitable substances to be analyzed. One example is follicle stimulating hormone (FSH). Examples of other useful body fluids that are relatively available are saliva, crevicular fluid, sweat, sebum, tears, and vaginal fluid. In principle, internal fluids such as blood can also be used, but are generally not preferred as they can only be achieved by invasive methods.

The skilled person will also appreciate that the concentration of the analyte (s) selected in the body fluid need not be measured in absolute terms, although this is possible if desired. It will generally be sufficient to assay an analyte in a manner which yields a signal, convertible to numerical data, related to the actual concentration, so that such data can be compared with T »<5 dcbnÝnxi Udai obtained ^1» '! In různ.ýcb. cycle stages to determine if there was a significant change in current concentration. Thus, if the description or the claims below indicate the concentration of the analyte, this term should be interpreted broadly. ·. . ·

The invention provides a method of monitoring the fertility stage of an individual female subject in a mammal which comprises testing the concentration of the analyte in a body fluid, particularly estradiol and its metabolites. In this method, said testing is performed at least once during an interval comprising days 1 to 7 (inclusive) of the running cycle to determine a reference or concentration value for the current cycle, and this testing is also performed later during the running cycle and obtained by it the concentration value or signal is compared to a reference value or signal.

An important aspect of the invention is a method of monitoring the current fertility status of an individual woman, comprising testing the concentration of estradiol or its metabolites in a body fluid and comparing the test result to a comparative value or signal to determine whether an elevated ovulation concentration is present. The current ovulation cycle is determined by testing the concentration in the body fluid of the same individual at least once during an interval comprising days 1 to 7 inclusive of the running cycle.

More particularly, the invention provides a method for monitoring the current fertility status of an individual woman, comprising testing the concentration of estradiol or its metabolites in body fluid and comparing the test result to a comparative value or signal to determine whether an elevated ovulation concentration is present. the ovulatory cycle is determined by testing the concentration in the body fluid of one individual at least once during an interval comprising days 4 to 7 inclusive, preferably on days 5 and / or 6 of the running cycle, and testing is recommended on day 9 of the running cycle and continues thereafter at least daily, at least until a significantly elevated concentration is detected and the stage of the on-going cycle is indicated as DIVE at an interval beginning at the measurement of significant elevated concentration and at least 12 immediately following days, or until evidence of the end of the cycle (eg the onset of menstruation), however later. Unless a significantly elevated concentration is detected on day 15 or earlier, the cycle is, as an optional refinement of this method, considered fertile for an interval lasting at least 14 and preferably 15 days immediately after day 15, or until evidence of termination of the cycle occurs previously.

Another important aspect of the invention is a human contraceptive method, comprising:

(a) testing the concentration of estradiol or its metabolite in the female urine at least once in an interval, including days 4 to 7 inclusive, and preferably at days 5 and / or 6 of an ongoing cycle to determine a comparative value or signal for the current cycle;

b) retesting the urine concentration at least daily from day 9 of the ongoing cycle until day 15 (preferably day 14) of the ongoing cycle; and

(c) avoidance of unprotected contact during a period of at least 12 days immediately following the date on which a significant increase in urine concentration was observed, or, if no significant increase in urine concentration was observed by day 15 (preferably on day 14), , lasting at least 14, preferably 15 days immediately after day 15 (preferably day 14), in both cases, the interval is optionally terminated earlier if evidence of cycle termination (onset of menstruation) is obtained.

In a first embodiment, the invention provides a method of controlling the fertility stage of an individual female subject in a mammal, comprising testing the body fluid concentration of at least one analyte significant to the ovulation cycle stage during the pre-ovulation phase, wherein testing said analyte is performed at least once. an interval comprising days 1 to 7 (inclusive) of an ongoing cycle, calculated from the onset of menstruation (day 1 is the day on which menstruation was first recorded), to determine a comparative concentration or signal of said analyte in the ongoing cycle. Thereafter, testing is performed at least once (generally repeated, e.g., daily) during a period of at least 5 and preferably at least 6 serial days. before the average order day on which actual ovulation occurred in one or more of the preceding ovulation cycles in the same individual subject. The concentration values or signals obtained during that period are compared with a concentration reference value or signal to determine whether it occurs? concentration change, indicating incoming ovulation or whether it has occurred since the last testing. Generally, retesting may not be initiated earlier than about 9 days before the average ovulation day. /

The concentration comparative value is preferably determined from a test (s) performed during an interval comprising days 4 to 7 inclusive, more preferably from a test (s) performed on days 5 and / or 6, and most preferably from a single test performed on day 6.

A significant change in the concentration of the analyte indicating upcoming ovulation, particularly appropriate when the analyte is estradiol or a metabolite thereof, will generally be noted if the ratio of the reference concentration [r] to the test concentration [i] meets the following relationship:

w

1.5 <[rj <2.5

More specifically, in particular if the analyte is E3G and the benchmark is determined on day 6:

. 8 -

If the chosen adjustment of the assay through which concentration data is obtained provides a signal that is inverted relative to the current concentration, as may be the case with a competitive assay, experienced in that relationship.

It is generally assumed that there will be a delay of at least one day, and more usually 1 day, between the determination of the comparative concentration value and the start of retesting, during which no testing is required. Thus, in an ideal situation, the user performs only a single test at an early stage of the cycle, e.g., on Day 6, and a few days thereafter begins a relatively short pattern of repeated, e.g., daily measurements, ending after obtaining sufficient information to determine fertile phase the end of the fertile phase in this cycle. Typically, the end of the assays will be on the day of LH ascension, or a few days thereafter so that the rest of the cycle is not tested.

Preferably, the body fluid will be urine. Thus, a highly suitable analyte is estradiol or a metabolite thereof, such as estrone-3-glucuronide.

In one embodiment of the invention, the average day of ovulation is preferably derived from data obtained from at least 3, and more preferably from at least 5 consecutive previous cycles.

A particularly suitable method involves determining the average day of ovulation from data obtained from a moving repetitive comparative base composed of a fixed number of consecutive cycles prior to the close of the cycle in progress. Preferably, this movable base consists of 3-12 immediately preceding cycles and more preferably of the preceding 5 to 6 cycles. Due to such a recurrent benchmark, any progressive ovulation shift in the subject can be recorded and taken into account for the layout of the next initial day of retest.

The invention encompasses a test kit comprising one or more test devices for determining the concentration (in relative or absolute data) of said at least one analyte in said body fluid, together with instructions that advise the user to begin the test within a given time interval and / or on the exact start day of testing according to the knowledge of the serial day. in which the current run-ovulation and at least one previous ovulatory cycle of the user has occurred.

Another independent aspect of the invention, which may nevertheless be combined with any of the methods mentioned above for convenience, includes:

(a) providing the user with a plurality of disposable body fluid testing devices, the amount preferably being 7, but preferably no more than 12; and '4

b) focusing the user on the use of all said provided test devices during a single ovulation cycle, according to a predetermined test scheme, regardless of whether the determination of the upcoming ovulation was obtained before using all of the provided test devices.

The user is preferably encouraged to perform one test on day 6 and to use all remaining test devices daily during the retest period.

The invention also provides a kit for use in any of the foregoing methods, comprising a plurality of disposable body fluid testing devices, together with means for reading and explaining the results of tests performed using the testing devices.

The invention also encompasses a replacement package of disposable body fluid testing devices for use in any previously determined method, with instructions to the user to use all said disposable testing devices contained in the present invention.

Preferably, the package comprises at most T2 testing devices and more preferably at least 7 but at most 10 devices.

The requirement for the user to use all devices from a single batch or a set of disposable test devices within one cycle is beneficial for both the user and the management of the process, as the monthly test scheme is simplified - there is no need to make decisions when to retry testing, or to use the test equipment remaining in earlier cycles for subsequent cycles. For the manufacturer, there is confidence that the data for each cycle is obtained from one set (batch) of test equipment, eliminating the standardization difficulties that may otherwise occur and reducing the complexity of any monitor required to interpret the test data. No user activity is required to ensure calibration of the assay. Disposable testing devices can be refilled in standard monthly replacement packaging, rationalizing the packaging process. By eliminating the problem of test device dwelling, the possible cause of customer questions is also eliminated.

An advantage of the method of the present invention is that effective monitoring of the ovulation cycle can be achieved using data obtained only from measuring the concentration (s) of the analyte in the body fluid. It is not necessary to combine these data with other parameters. In particular, there is no need to supplement these data with routine basal body temperature measurements.

By using comparative concentration values from the early part of the running cycle, the methods of the invention avoid the need for calibration and ensure that the comparative background is intrinsic to the test subject. This leads to a clearer indication of the significant preovulatory concentration change compared to previously proposed methods based on daily measurements.

The analyte selected to provide an alert for emerging ovulation is not critical to the invention, provided that the analyte exhibits a detectable concentration change in the time interval between the start of testing (as

- 11 established here) and a safe time before actual ovulation in the ongoing cycle.

The invention may be applied to any method of monitoring the ongoing ovulation cycle stage of an individual female subject, which comprises measuring an analyte that is significant relative to the ovulation cycle stage and that exhibits a detectable change during the pre-ovulatory phase of the click, occurring at least 2 and preferably at least 3 days before day of actual ovulation, in body fluid.

The following description is provided, by way of example only, in relation to urinary hormones E3G, luteinizing hormone (LH) and pregnanediol-3-glucuronide (P3G), although it will be readily apparent that the principles of this method may be used in relation to other biochemical markers , for example the estradiol and progesterone hormones found, for example, in blood or saliva. Method according to? The invention can be used in combination with observation of other physiological symptoms of fertility levels in a woman of which she is self-aware or which are easy to make aware, eg with markers in other body fluids.

The day of ovulation can be determined by any of the known chemical or physiological parameters, although the preferred method is to measure the LH level. Once a sudden increase in LH is observed, ovulation follows. Also, the day of the cycle in which ovulation occurs can be recorded for future comparison. If a sudden increase in LH is detected and therefore the day of ovulation is precisely defined, the user with a very high degree of certainty may be indicated that the subject will not be fertile for more than 4 days thereafter (3 days after ovulation). For practical purposes, a urinary LH concentration of 20 mlU / ml can be considered as a universal threshold, indicating a sudden increase in LH in virtually all circumstances.

The term sudden increase in LH is used herein to mean a dramatic increase in LH concentration that precedes ovulation. There is also reference in the art to LH max, i.e., peak (maximum) LH concentration. For most individuals, for all practical purposes, this data is current when the cycle is tracked on a per-cycle basis

- 12 daily measurements. However, in a small proportion of individuals, about 20% of the population, the actual concentration of LH is not observed until the day after the main concentration increase. For the purposes of the invention, the authors prefer an observable rise as a key parameter.

In addition, the © asbo alternative may be declared end of the fertile phase and based on the knowledge of the concentration of estradiol (or its metabolite) in the ongoing cycle. Advantageously, this can be declared on the day of determination following the peak concentration value. Since peak E3G concentration in urine, for example, appears to be less easily detectable than a sudden increase in LH, the peak E3G may be defined in relation to a threshold, determined for example by:

[rj> 2.5, preferably> 3, taking into account that the peak occurs on the day on which this relationship is met for the first time during the test regimen received in the ongoing cycle. The inverse relationship will be used in the case of the E3G signal in inverse ratio to the current concentration. In some cases, it may be on the same day as a significant increase in E3G is determined, indicating upcoming ovulation. After determining the peak of E3G, the fertile phase can be expected to end on the sixth, or more safely on the seventh or eighth day thereafter. In this embodiment, the invention provides a method of monitoring fertility in an ongoing cycle, based only on data obtained from the determination of estradiol and / or its metabolite.

Another method to determine the end of the fertile period (albeit not exactly the day of ovulation) is to measure P3G hormone levels in the urine. P3G has a relatively low level in the urine until the luteal phase begins, when its level rises quite sharply. Therefore, if an elevated level of P3G is measured, it may notify the user that a luteal phase of the cycle has occurred, i.e., a terminal infertile period. Increased levels of P3G in the urine may be labeled based on data obtained during an ongoing and / or one of the preceding cycles. Increased levels of P3G may be

- 13 recorded, for example, when the level of detected P3G is greater than the sum of the four previously recorded P3G values in the same menstrual cycle, or greater than 3500 ng / ml, whichever is lower and previously reached. Once the elevated level is recorded once, the subject may be warned that it is infertile for the rest of the cycle.

If desired, detection of LH or P3G can be used as an activating agent to determine that the subject is not fertile until the end of the cycle, with one hormone acting to support another. However, it is preferred that the LH assay be used as a primary indicator of whether or not ovulation occurs, because the LH assay itself provides a more accurate determination of the exact day of ovulation than the use of P3G.

Methods for detecting the analyte in a body fluid, such as urinary hormone metabolites, suitable for the purpose of the method are well known to those skilled in the art. In a preferred embodiment, the analyte is detected by the assay methods and apparatus described in British Patent GB 2204398 and European Patent Application EP-A-383619, the contents of which are incorporated herein by reference.

Where the method of the invention relates to the measurement of the urine component, the measurement must be performed in a urine sample. A variety of immune assay techniques are available that allow measurement of urine components. Many solid-phase test devices, such as measuring rods and chromatographic strips, have been described in the literature and can be readily adapted for use in the determination of urinary analytes. The devices should at least be able to report relative levels of the analyte, eg E3G, in the threshold bars. Examples of a simple assay technique that can be readily adapted for use at home are given, for example, in EP 0225054, EP 0183442, EP 0186799, and GB 2204398, the disclosures of which are incorporated herein by reference. Disposable test strips, such as those described in GB 22004398, which only need to come into contact with the urine and which provide the test result in a semi-qualitative form may be used, eg by using test strip lines on the strip that are ascending positive at higher levels of the analyte in the urine. Multiple strips that correspond to different thresholds of the substances to be analyzed can be used rather than a single strip. Alternatively, a visually readable quantitative assay may be based on and visible, eg colored,

You don't have '3.3' inaps.

diffusion), using, for example, an enzyme-labeled assay.

In a more sophisticated embodiment of the invention, a recording device is provided which includes means for; reading the result of the determination in the urine, eg by measuring the absorbance of the test strip or the fluorescence of the test strip. This may provide a more accurate numerical evaluation of the level of the analyte and further increase the precision of the method.

In an embodiment of the invention, wherein two or more of the substances to be analyzed are simultaneously measured, such measurement may, if desired, be performed using a single body fluid testing device, eg a device comprising multiple test strips, or a single strip capable of independently detecting level of various analyzed substances.

The detailed electronic arrangement of the resorptive recording equipment, the storage and handling of analyte concentration data, as well as the assurance of preferred electronic features of the equipment disclosed herein and the prediction of future cycles based on these data can be easily ensured by those skilled in the electronics. such equipment must take into account and be warned of the fact that such equipment must serve the user. However, by way of example only, the basic functions that may be required with such a device are shown in Figure 3 of the accompanying drawings and are briefly described below.

BRIEF DESCRIPTION OF THE DRAWINGS

By way of example only, practical aspects of the invention are described below with reference

Figure 15 in the accompanying drawings illustrates an ovulation cycle monitoring device for use in accordance with the invention, together with an associated urine sample testing device.

Figure 2 shows the urine testing device in more detail.

Figure 3 shows in schematic form, the basic functions that may be required in an electronic monitor for use according to the invention.

Referring to Figure 1, the urine sample testing apparatus comprises a flat elongated housing 100 having positioning means represented by a ridge 101 on its lower surface 102. A sample absorbing member 103 protrudes from one end of the housing.

The monitor comprises a housing 110 having a recess 111 in the upper surface 112 to receive the housing 100 of the test device. The recess 111 includes a position groove 113 into which the positioning comb 101 of the housing of the test device can be positioned to correctly position the test device relative to the reading window 114 in the recess. The housing 110 includes means (not shown), such as a fluorescence or optical density reader, for measuring the result of the urine concentration determination of the analyte carried out using a test device according to a labeling system selected to represent the result of the assay.

The inclined front side 115 of the monitor housing includes a wide window 116 through which information can be transmitted to the user, e.g., via an LED display or other visual output. This information can be provided in various forms, such as calendar labeling and the need to perform urine tests, and to show the current stage of the ovulation cycle. The inclined front side 115 of the housing also includes a knob 117 which the user can press to indicate the start of the ovulation cycle and to

- 16 commencement of the monitoring data related to the cycle.

The data can be transmitted to the user, for example, via a liquid crystal display (LED display). If desired, the fertility stage information can be transmitted by simple visual representation, for example, by a combination of colors, such as a green aode 2 period for

Optionally, another signal, eg yellow, may be shown for any transitional period when conception is less likely but still possible. Especially if the device is primarily intended to facilitate contraception, it should be fail safe by showing a fertility signal.

The invention further provides a female ovulation cycle monitoring kit comprising a monitoring device as described above together with at least one test device that can be used to measure the level of one or more urine components. It is envisaged that the monitoring device will be of relatively durable nature and capable of being used for a significant number of cycles. Test devices for measuring urine components are preferably disposable and it is therefore expected that the user of the tracking device will need to supplement the testing device.

Generally, the monitor will be powered by batteries and includes an access point on the case side 118, such as a removable lid 119, allowing the batteries to be inserted and replaced.

In Figure 2, the test device is shown from the opposite side to Figure 1. The positioning comb 101 is now on the top surface 200. On the surface 200, now the top, is also the result window 201. The body of the test device may carry an immunochromatographic strip (not shown). containing all the necessary reagents to allow an immune assay to be performed to detect the presence and concentration of the analyte in the urine sample applied to the sample receiving member 103. The result of the assay can be achieved by immobilizing the labeled component, via a sandwich or competitive reaction in the presence of the analyte in the loaded urine sample, with the labeled reactant

- 17 concentrates in the zone exposed by the result window. When inverted and positioned in the monitor housing cutout 111, the result window is immediately adjacent to the monitor reading window 114 and the determination result can be determined. For example, if the label is a fluorescent reagent, the monitor reading means can detect and measure fluorescent radiation from the accumulated label in the strip detection zone to provide a numerically refined concentration of the analyte in the urine sample. This information can be processed by the monitor along with the calendar data resulting from the user's cycle start and the historical (previous) data that the monitor can store from previous cycles.

Figure 3 shows some of the elements that may be required in an electronic monitoring device. The features may be quite conventional, and those skilled in the art will appreciate that other combinations and arrangements may be used to achieve the present invention. For example, neural networks and so-called discrete file systems can be used instead of conventional chip-based microprocessors. As shown in Figure 3, the combination essentially comprises:

A readout unit 300 for obtaining data from a test device, such as a test rod, and the readout unit includes a lighting body 301 and a readout device 302 (represented herein by a photodiode). The readout unit is coupled to a conversion unit 303 to convert the optical signal into a form usable by the microprocessor 304. As an optional device, a calibration system 305 is provided to convert the signal obtained from the readout unit into data corresponding, for example, to an absolute concentration value. A time device, such as a clock 306., is required to control the measurement in the cycle. The microprocessor 304 processes, records and interprets the results according to the foregoing, especially recorded in the previous cycle. The area used by the user 307 will generally comprise at least means, such as a button, that the user may manipulate at the start of the cycle to start operation of the device as a whole. The 308 power supply should include

- 18 (historical) data if it becomes necessary to replace the batteries.

Aspects of the invention are exemplified in the following examples. Bleeding & monitoring the human ovulatory cycle.

Version:

Example 1

This example provides a suitable algorithm upon which the tracking method of the invention can be based. The kit, supplied to the user, includes a plurality of disposable urine test devices that are capable of determining E3G and LH in the urine in a form readable by the monitor as well. The monitor can accept any test equipment used and determine the urine concentration of each analyte. This information is stored by the monitor and compared with similar data obtained on the following days of the same cycle. The monitor has a menstrual button that the user must press at the start of the cycle, and a display panel (display unit) or the like to transmit cycle stage information and to notify the user that a measurement should be made.

a) Algorithm structure

The purpose is:

(i) determine the LH sudden rise position in a single cycle;

(ii) determine a significant increase in the E3G concentration in a single cycle relative to the E3G concentration on day 6 of the current cycle.

The number of tests available each routine month is limited to 8 and a testing strategy is adopted that will maximize the chances of achieving i) and ii).

b) Initial cycles

- 19 - Ensuring adequate initial inventory of data during the first cycle of monitor use requires 16 tests. This serves to provide the basic status data of the individual. The user presses the menstrual button on the monitor in the morning after menstruation begins. This day is recorded by the monitor as day i. Testing begins on day 8 and continues daily until day 23. This testing is aimed at maximizing the chance of observing a sudden increase in LH.

At the start of the second cycle and at the beginning of all subsequent cycles, the menstrual button is used as before. From the second cycle onwards, only 8 tests are used for each cycle. All 8 tests must be one lot and all must be performed. In all cycles from cycle 2 onwards, testing begins on day 6. For stage 2 a

In cycle 3, tests 2 to 8 are performed on consecutive days starting 4 days before the typical LH rise day. From cycle 4 onwards, considered the first routine cycle, tests 2 to 8 are performed subsequently from day 5 before the typical LH surge. A typical LH rise day is defined as the average LH rise day for the previous 6 months.

c) Beginning of the fertile phase

In cycle 1, the monitor indicates female fertility from day 6 onwards because no data was collected on cycle characteristics. In cycles 2 and 3, the monitor may use a typical LH surge location from the previous cycle (s) to determine the onset of the fertile phase. However, due to the limited amount of data available, during cycles 2 and 3, the monitor will still report female fertility on the day 6 or seven days before the typical LH rise date, whichever is later.

In the following routine tests, the onset of the fertile phase is determined by detecting a significant change in the E3G signal relative to day 6. When the ratio of the E3G signal on the current day (SJ to the signal on day 6 (S _s )) reaches a predetermined threshold as previously determined, the woman is considered fertile.

d) End of fertile phase

- 20 In the normal course, the end of the fertile phase is determined as the fourth in the morning after a sudden LH surge has occurred. In the absence of a measurable increase in LH during testing, the system designates the end of the fertile phase 6 days after the last test. The consideration for this calculation is as follows. The test mode is adjusted to cover a typical LH rise position plus one day. Published WHO (World Health Organization) studies • add differences between women and women in terms of LH rise position as 1.8 days. Adding 5 days to the stated fertile period after completion of testing admits the probability of a standard deviation 2 that a sudden increase in LH will occur within the specified fertile period.

In abnormal course (Cycle 1), where the monitor lacks typical LH surge location data, if this parameter has not been determined, it is designated the 28th day of the cycle as the end of the fertile period.

Example 2

This example uses representative E3G profiles of two women - one with low levels of E3G in the urine and the other with relatively high levels. The first two columns of each table show the 30 days of each cycle in their fertility data. The first phase is called infertile and consists of a portion of the follicular phase during which unprotected contact is not expected to result in conception, followed by a transitional phase during which there are changes leading to a fertile period and during which a positive signal is required, indicating the onset of the fertile phase. The fertile phase is the phase before and after ovulation, during which unprotected intercourse is most likely to lead to conception. Its duration before ovulation is fully determined by the effective lifetime of the sperm, which in turn is influenced by factors controlled by female hormones, particularly mucus. The fertile, luteal phase is the period after which the egg leaves the uterus and conception is no longer possible in the ongoing cycle.

E3G values are shown in the third column. They were obtained by immunoassay in morning urine samples taken daily. The immune assay was a conventional competitive assay using an enzyme labeled assay

-21 —antigen. Values are given in ng / ml.

Actual ovulation is taken 24 hours after a sudden increase in LH. These LH values were determined by conventional enzyme-labeled sandwich immune assays in the same samples, but the values are not included in the table as the main result is the date of ovulation.

The itmus of example 1 was applied in each cycle and the trigger point 13G was taken as:

LIL [day 6]> 2

- 22 JANUARY A.

CYCLE Al: initial cycle day test phase value stage current

E3G red ovulation o

4 »? 5 II 6 11 ♦ ** 7 lf * ♦ * 8 * II 1.9 9 * lf 3.1 ** # 10 * II 5.4 ** $ 11 * 11 2.1 *** 12 * II 5.3 * * * 13 * II 10.5 * ♦ * 14 * II 7.7 *** 15 Dec * prolific 5.2 * # * 16 * II 8.3 *** 17 * 11 6.8 ♦ ** 18 * II 4.3 *** 19 Dec * II 4.9 * * * 20 May * II 5.3 * * * 21 * post-fertile -n 22nd * II 4.9 23 * II 6.2

LHS + 1

25

II

II

II

II

II

II

II

The LH surge was on day 17, so repeat testing in the next cycle should begin on day 13.

- 23 -CXKL.US-A2:

day test phase value stage current

E3G red ”ovulation infertile

6 * If 3.5 7 If 8 It 9 It 10 It 11 It 12 It 13 * If 8.9 14 * prolific 14.6 15 Dec * If 12.6 16 * If 8.8 17 * II 15.8 18 * It 6.9 19 Dec * It 6.5 20 May post-fertile 21 »1 22nd II 23 If 24 II 25 If 26 It 25 If 27 Mar: It 28 It 29 It 30 II

*** * * * *** *** * * * * * * * * * * * Mc * *** LHS + 1 *** ** #

The average sudden increase of LH (LHS) in cycles A1 and A2 is day 16.5, therefore the repeat testing should start on day 12 of the next cycle.

- 24 CYCLE A3:

day test phase value cm

X - / - / XJ stage current

VWA * WUV sz barren

--I »t

J

6 7 * tt tt 1.6 8 II 9 tt *** 10 »» *** 11 II *** 12 * prolific 6.2 * * * 13 * tt 23.6 * * £ 14 * tt 21.3 * # * 15 Dec * tt 8.3 * ** 16 * tt 4,5 * * * 17 * tt 3.7 *** 18 * post-fertile 3.4 19 Dec tt 20 May II 21 tt 22nd tt 23 tt 24 tt 25 tt 26 tt 25 tt 27 Mar: tt 28 tt 29 tt 30 II

Mean LHS from cycles A1 through 13: day 15.7.

LHS + 1

Initial retest day for the first routine cycle: day 10.

- 25 CYCLE4: ------- Ό Ό 'J ι CL · 14 14 14 14 - Ο Ό L L LJ IJ ►- O' J '41 κ ^;

The first routine cycle

l test phase infertile 5 » II value E3G. stage red * II II II 1 » II 3.1 * II II 6.1 * prolific 16.7 * * # * II 10.8 *** * II 22.8 * * * * II 21.3 *** * II 9.4 * * * * II 12.2 *** post-fertile II II II II II II II II • t * II II II II II Days with current ovulation warning: 3 Average LHS from cycles A1 through A4: day 15.3.

The day of retesting for the next cycle of actual ovulation

LHS + 1 day 10.

- 26 CYCLE A5:

The second routine cycle

day test phase value E3G stage li in 'II oerve & e current ovulation - ---------.— --—............................ - ......-..... . ... 1 infertile 2 II II J 4 II 5 II 6 * II 4.8 7 II 8 II 9 II 10 * II 8.5 11 * II 7.3 12 * II 6.3 13 * II 7.0 14 ♦ prolific 11.8 * * * 15 Dec * II 19.3 * * * 16 * II 18.5 *** 17 II *** LHS + 18 II *** 19 Dec II *** 20 May post-fertile 21 II 22nd II 23 II 24 II 25 II 26 II 25 II 27 Mar: II 28 II 29 II 30 II Days with h warning of current ovulation: 3 Average LHS from cycles A1 to A5: day 15.4 ”. Day of retesting for next cycle; den 10

- 27 JANUARY Β

CYCLE Bl: Initial cycle

day test phase value E3G stage ff v » red 1 infertile HER O clay AND 11 5 11 6 »1 *** 7 tt *** 8 * It 25.1 *** 9 * It 10.1 *** 10 * 11 16.8 *** 11 * 11 28.2 *** 12 * it 24.6 * * * 13 * 11 28.7 * * * 14 ♦ 11 27.7 *** 15 Dec * 11 62.6 * * * 16 * 11 68.5 *** 17 * prolific 61.9 *** 18 * II 103.4 *** 19 Dec * It 85.4 # * * 20 May * It 45.4 *** 21 * II 14.9 * * * 22nd ♦ It 46.6 * * * 23 * post-fertile II 49.3 24 25 It 26 It 25 It 27 Mar: It 28 lf 29 lf 30 It

current ovulation

LHS + 1

The LH surge was on day 19, so repeat testing in the next cycle should begin on day 15.

- 28 CYCLE B2:

day test phase value stage current

E3G red ovulation

11 12

21 22

25 barren

1 «

II * »

II

II

II

II

II lf

II

II * fertile *

* »*

* »'*

* post-fertile

II

II

28.9

62.0

94.6

58.4

42.4

60.4 56.0 35.0 *** *** *** *** *** * * * * * * *** ***

LHS + 1

The average LHS in cycles BI and B2 is day 17.5, therefore retesting should start on day 13 of the next cycle.

- 29 CYCLE B3:

day test phase value stage current

E3G red ovulation infertile * ”17.2

10 II *** 11 II *** 12 II *** 13 * lf 23.9 *** 14 * prolific 63.8 *** 15 Dec * II 7? 1 *** 16 * lf 65.9 * * * 17 * II 41.2 *** 18 * II 7.6 *** 19 Dec * II *** 20 May * post-fertile 21 II 22nd II 23 II 24 II 25 lf 26 II 25 II 27 Mar: II 28 II 29 II 30 . II

LHS + 1

Mean LHS in cycles B1 through B3: day 17.

Initial retest day for the first routine cycle: day 12.

- 30 CYCLE B4: ______

The first routine cycle test phase value stage current E3G red ovulation

1 infertile 'tt j tt 4 II 5 lt 6 * lt 12.9 7 tt 8 tt 9 lt 10 II 11 lt 12 * lt 38.3 * * * 13 * prolific 70.6 *** 14 * lt 74.6 *** 15 Dec * II 70.6 ♦ ** 16 * 11 49.7 *** 17 * lt 23.5 *** 18 * lt 29.8 * ♦ * 19 Dec post-fertile 20 May II 21 lt 22nd II 23 th 24 tt 25 1 « 26 lt 25 II 27 Mar: lt 28 lt 29 lt lt

LHS + 1

Current ovulation alert days; 4

Average LHS of cycles B1 through B4; den 16,5.

Day of retesting for next cycle: Day 11

- 31 CYCLE B5:

The second routine cycle day test phase value stage current

E3G red ovulation infertile

6 * »1 7.2 7 II 8 II 9 II 10 II 11 * II 14.1 12 * II 17.4 13 * II 41.3 14 ♦ II 57.5 15 Dec * prolific 42.0 16 * II 55.4 17 * II 60.1 18 II 19 Dec II 20 May II 21 post-fertile 22nd tt 23 II 24 II 25 II 26 II 25 II 27 Mar: II 28 ^H 29 II 30 II

* * * * * * * * LHS + 1 * * * * * *

Days with current ovulation warning: 5

LHS determined on the last day of testing. Average LHS of cycles B1 through B5; day ”16.6.

Day of retesting for next cycle: Day 11

- 32 Example 3

This example illustrates a very simple but satisfactory system of axliiivCuCCpCC in CxOV3, Sjy vvx VajxCx exxxxCxxxC V in xxi 5 of the analyte E3G during the urine cycle.

The user is provided with a monthly dose of eight identical disposable test devices, each containing a test strip onto which a urine sample can be applied, the strip containing all the necessary reagents to allow a signal indicating the E3G concentration to be provided, for example by a competitive reaction. Such a reaction comprises a labeled specific binding reagent that binds to the detection zone of the strip in an amount that is directly or indirectly proportional to the concentration of E3G in the urine sample. Also provided is an optical electronic readout device that converts signal data from the used strip into numerical values and modifies this data to provide appropriate cycle stage information to the user.

Initial urine determinations are performed on day 6 of the ongoing cycle (day 1 is when menstruation is first observed) to ensure baseline E3G concentration in that cycle.

A second urine determination is performed on day 9 and each day thereafter until all tests have been performed or until an indication of an increased concentration of E3G indicating the occurrence of ovulation is provided. A sufficiently elevated E3G concentration is reported if the ratio of the reference concentration [r] to the test concentration [i] meets for the first time the following relation:

Clay

Μ * 2 in case of direct proportion between test signal and E3G concentration, or [i]> 2

- 33 in the case of indirect proportionality.

Unprotected contact is ruled out on a day when a sufficiently elevated E3G concentration is measured and for 12 immediately following days.

If a sufficiently elevated E3G concentration is not detected before all test facilities are exhausted, unprotected contact is excluded after 15 immediately λ -, -, Λ <:? n ie not li τι c ·. · ·>: ··. v *. «%:? 3« nr.9 ·> · »r · <· - r

- _and , - ·. · - .. · _£ . _f . _ "·. . · _....... ......

Conception cannot occur.

This example gives the user the advantage that only a few tests are required per month. Manufacturing simplicity is also ensured, since only one analyte (E3G) is determined.

If desired, the assay can be performed more complexly, by allowing ovulation to be detected by including LH concentration in the urine and collecting data from the previous cycle, so that the elimination time of contact can be further reduced without increasing the probability of conception, as described in detail above.

Claims (51)

__PATENT Claims ____ A method for monitoring the fertility stage of an individual female subject in a human body characterized in that it cross-links the analyte of the analyte, in particular estradiol or a metabolite thereof, in a body fluid, at least once during an interval comprising days 1 7 to 7 (inclusive) of the running cycle to determine the comparative value of the tester of the signal for the running cycle, and aforementioned testing is also performed later in the running cycle and the concentration or signal thus obtained is compared with the comparison value or signal. 2. The method of monitoring the fertility stage of an individual female subject in a mammal according to claim 1, wherein said later testing is performed after testing to determine said comparative concentration or signal value. The method of monitoring the fertility stage of an individual female subject in a mammal according to claim 1, characterized in that a maximum of 16 body fluid tests are performed in an ongoing cycle. The method of monitoring the fertility stage of an individual female subject in a mammal according to claim 1, wherein testing is performed for a maximum of 16 days in an ongoing cycle. A method for monitoring the fertility stage of an individual female subject in a mammal according to claim 1, comprising testing the concentration of the analyte, in particular estradiol or a metabolite thereof, in a body fluid and comparing the test result with a comparative value or signal to determine whether it is present. an elevated concentration that indicates an upcoming ovulation, wherein the reference value or signal in the ongoing ovulation cycle is determined by testing the concentration in body fluid in the same individual at least once during an interval including days 1 to 7 inclusive of the ongoing cycle - 35 __ 6. The method of monitoring the fertility stage of an individual female subject in a mammal according to claim 1, comprising testing the concentration of at least one analyte relevant to the ovulatory cycle stage during the preovulatory phase in a body fluid, wherein said analyte is tested for at least once during an interval that includes days 1 to 7 (inclusive) of the running cycle, counted from the onset of menstruation, to determine a comparative concentration or signal of the analyte in the running cycle, and then testing at least once before the day likely to occur during the cycle ovulation; the concentration values or the signals of the analyte obtained during said later testing are then compared to a comparative concentration value or a signal to determine whether there is a change in concentration indicating the occurring ovulation or has occurred since the previous test. 7. A method for monitoring the fertility stage of an individual female subject in a mammal according to claim 1, comprising testing the concentration of at least one analyte relevant to the ovulation cycle stage during the pre-ovulatory phase in a body fluid, wherein testing said analyte is performed. at least once during an interval comprising days 1 to 7 (inclusive) of the running cycle, counted from the onset of menstruation, to determine a comparative concentration or signal of said analyte in the running cycle, said testing is temporarily stopped and then tested at least once, preferably daily, during a period beginning on the fifth, but preferably at least six, ordinal day before the average ordinal day on which actual ovulation occurred in one or more of the previous ovulatory cycles of the same individual subject, the concentration levels of the analyte or the signals obtained during that period are compared with a comparative concentration value or a signal to determine whether there is a change in concentration indicating the occurring ovulation or has occurred since the previous test. Method according to any one of the preceding claims, characterized in that said comparative concentration value is determined from a single concentration - 36 test. Method according to any one of the preceding claims, characterized in that said comparative concentration value is determined from a test or tests performed during an interval comprising days 4 to 7 inclusive. ÁO. The method of claim 9. characterized in that said concentration reference value is determined from the test (s) performed on day 5 and / or day 6. The method of claim 8, wherein the single test is performed on day 6. The method of any one of the preceding claims, wherein said subject is a human. The method of any one of the preceding claims, wherein the body fluid is urine. The method of any one of the preceding claims, wherein the analyte is estradiol or a metabolite thereof, such as E3G. Method according to claim 14, characterized in that the significant difference between the reference value of the analyte concentration [r] and the value of the test [i], which indicates the upcoming ovulation, is taken as: Clay 1.5 <[r] <2.5 in the case of a direct proportion between the test signal and the analyte concentration, or as an inverse of the inverse proportion between the test signal and the analyte concentration. - 37 __ 16. The method of claim 15, wherein the analyte is E3G, and the significant difference in the concentration [i] of the E3G that indicates the upcoming ovulation is taken as: lil [r]> 2 in the absence of an even greater value between the E3GL concentration or the inverse value in the case of inverse proportion between the test signal and the E3G concentration. A method according to any one of the preceding claims, characterized in that the concentration of LH in the body fluid is determined to recognize the day of actual ovulation in an ongoing cycle. The method of any one of the preceding claims, wherein the average ovulation day is determined from data collected during at least three consecutive preceding cycles. A method according to any one of the preceding claims, characterized in that the average ovulation day is determined from data collected during at least five consecutive previous cycles. A method according to any one of the preceding claims, wherein the average day of ovulation is determined from data collected during at least the immediately preceding cycle. 21. The method of claim 20, wherein the average ovulation day is determined from data collected from a moving repetitive comparative basis that consists of a fixed number of consecutive cycles immediately preceding the current cycle. 22. The method of claim 21. This means that the moving repeating base consists of 3 to 12 immediately - 38 previous cycles. 23. The method of claim 21, wherein the moving repetitive base consists of 5 to 6 immediately preceding cycles. characterized in that the end of the fertile phase is determined by knowing the sudden rise of LH in the ongoing cycle. 25. The method of claim 24, wherein the end of the fertile phase is considered to have occurred on the fourth day following a sudden increase in LH. A method according to any one of the preceding claims, characterized in that the end of the fertile phase is determined by knowing the concentration of estradiol or its metabolite in the ongoing cycle. Method according to any one of the preceding claims, characterized in that the end of the fertile phase is determined by knowing the peak of the concentration of estradiol or its metabolite in an ongoing cycle, which peak is defined as the first opportunity in the cycle when it is noted that JiL [r]> 2.5, preferably> 3, in the case of a direct proportion between the test signal and the concentration of estradiol and / or its metabolite, or an inverse relationship in the case of an inverse proportion between the test signal and the concentration of estradiol and / or its metabolite. The method according to claim 27, characterized in that the end of the fertile phase is taken to occur on the eighth day following the peak of the estradiol concentration and / or its metabolite being recorded. Method according to any one of the preceding claims, characterized in that it is based solely on determinations of estradiol and / or its metabolite. A method according to any one of the preceding claims, characterized in that it does not use a basal body temperature measurement. A method according to any one of the preceding claims, using only the concentration of the analyte in the body fluid. 32. The method of claim 1, comprising: (a) providing the user with a plurality of disposable body fluid testing devices of at least 7, but not more than 16; and b) directing the user to the use of all said provided test devices during a single ovulation cycle, according to a predetermined test pattern, regardless of whether the determination of the upcoming ovulation was obtained before using all of the provided test devices. ’ 33. The method of claim 32, wherein the user is directed to perform one test on day 6 and to use all remaining test devices daily during the retest period. 34. A method for monitoring the fertility stage of an individual female subject in a mammal (generally a human) comprising testing the concentration of at least one analyte relevant to the ovulatory cycle stage during the pre-ovulatory phase in a body fluid wherein: (a) the user is provided with a plurality of disposable body fluid testing devices, preferably at least 7, but preferably not more than 12; and - 40 (b) the user is directed to the use of all of said provided test devices during a single ovulation cycle, according to a predetermined test pattern, regardless of whether the determination of the upcoming ovulation was obtained before using all of the provided test devices. Kit for use in the method of any preceding claim, comprising a plurality of disposable body fluid testing devices, together with means for reading and explaining the results of tests performed using said testing devices. A disposable pack of body fluid testing devices for use in a method according to any one of the preceding claims, together with an instruction for the user to use all of said included testing devices during one ovulation cycle. 37. The container of claim 36, comprising at most 12 disposable body fluid testing devices. 38. A container pack according to claim 36, comprising 7 to 10 disposable body fluid testing devices. 39. The method of claim 1 monitoring the fertility rate of an individual female person comprising testing the concentration of estradiol or a metabolite thereof in a body fluid and comparing the test result with a comparative value or signal to determine whether an elevated concentration is present to indicate an upcoming concentration. ovulation, wherein the reference value or signal in the ongoing ovulation cycle is determined by testing the body fluid concentration in the same individual at least once during an interval comprising days 4 to 7 inclusive, preferably during days 5 and / or 6 of the running cycle and testing is resumed on day 9 of a running cycle and then thereafter at least daily until at least a significant increase in concentration is noted and the stage of the running cycle is said to be fertile for a period beginning on day 41 recording a significantly increased concentration and comprising at least 12 immediately following days or until evidence of cycle termination is obtained, no matter which occurs first. 40. The method of claim 39, wherein, unless a significantly elevated concentration is observed on day 15 or earlier, the cycle is said to be fertile for an interval of at least 14, preferably 3 days immediately after day 15, or until there will be no evidence of cycle termination if earlier. 41. A method of contraception in humans comprising (a) testing the concentration of estradiol or its metabolite in the female urine at least once in an interval, including days 4 to 7 inclusive, and preferably on days 5 and / or 6 of an ongoing cycle to determine a comparative value or signal for the current cycle; b) retesting the urine concentration at least daily from day 9 of the ongoing cycle until day 15 (preferably day 14) of the ongoing cycle; and (c) Prevention of unprotected contact during a period of at least 12 days immediately following the date on which a significant increase in urine concentration was observed, or, if no significant increase in urine concentration was observed by day 15 (preferably on day 14), , lasting at least 14, preferably 15 days immediately after the day 15 (preferably day 14), in both cases the interval is optionally terminated earlier if evidence of cycle termination is obtained. 42. The method of claim 1, monitoring the stage of the human ovulation cycle, comprising using a plurality of disposable urine testing devices and an electronic subtractor and / or monitor, wherein: (A) the urinary comparison concentration or signal of estradiol or its metabolite, in particular E3G, is determined over days 1 to 7 of the running cycle, preferably by a single test; b) the succession of the tests, preferably daily, is performed to determine a pre-ovulatory increase in the concentration of estradiol and / or its metabolite in the urine relative to the observed concentration or signal reference; (c) the onset of the fertile phase of an ongoing cycle occurs when a pre-ovulatory rise is observed; and d) the end of the fertile phase of an ongoing cycle occurs more days, typically at least 12 days, after recording a pre-ovulatory rise, so that the method requires a maximum of 16, usually 7 to 12 tests in each ovulation cycle. 43. The method of claim 42, wherein determining the end of the fertile phase is made relative to the concentration of another analyte, preferably LH or P3G, also determined by disposable test devices. 44. The method of claim 1 monitoring the fertility rate of an individual female person comprising testing the concentration of the analyte, particularly estradiol or a metabolite thereof, in the urine, wherein the analyte exhibits a significant change in concentration prior to the fertile phase of the ovulation cycle, and in this method: (a) the concentration reference value or the signal of said analyte is determined from one or more tests carried out during an interval comprising days 1 to 7 inclusive of the running cycle; - 43 (b) since then, daily testing of the analyte is carried out to record the significant change in urine concentration and the beginning of the fertile phase is reported; (c) testing is carried out using disposable test devices and the user is equipped with no more than 16 such test devices for use in a single * ovulation cycle. Method according to claim 44, characterized in that the user is equipped with 7 to 16, preferably 7 to 12 and preferably 7 to 10 test devices for use in a single ovulation cycle. 46. The method of claim 44 or 45, wherein said analyte is estradiol or a metabolite thereof and said analyte is the only analyte tested to record the onset of the fertile phase. 47. The method of any one of claims 44 to 46, wherein said analyte is estrone-3-glucuronide (E3G). A method according to any one of claims 44 to 47, wherein the end of the fertile phase is reported to a predetermined number of days, preferably at least 12 days, after recording a significant change in urine concentration. Method according to any one of claims 44 to 47, characterized in that the concentration of luteinizing hormone (LH) in the urine is also measured. A method according to claim 49, characterized in that the end of the fertile phase is reported to a predetermined number of days, preferably at least 4 days, after recording a sudden increase in LH. - 44 Method according to any one of claims 44 to 47, characterized in that the concentration of pregnanediol-3-glucuronide (P3G) is also measured. 52. The method of claim 51, wherein the end of the fertile phase is reported upon recording. increased concentrations of P3G. The method of claim 1, essentially as described herein. 54. A method of monitoring the fertility stage of a human ovulatory cycle, characterized in that it uses disposable test devices and requires a maximum of 16 such devices per cycle, essentially as described herein.