Body temperature measurement

Abstract

The present disclosure relates to methods and systems for determining the fertility status of a female and / or the status of a biomarker in a mammal or human. A method includes determining a continuous series of temperature data points associated with body temperature for a plurality of first time intervals. The method also includes determining, for each of the plurality of first time intervals, a difference between a temperature maximum and a temperature minimum in the series of data points to obtain a plurality of temperature amplitudes. A series of temperature amplitudes is determined based on the plurality of temperature amplitudes, and it is determined whether a first portion of the series of temperature amplitudes has changed relative to a second portion of the series of temperature amplitudes, the change indicating a change in the biomarker status.

Description

Field of the Invention

[0001] The present disclosure relates to a method and system for monitoring a female's menstrual cycle. In particular, the present disclosure relates to a method and system for determining a female's hormone status and fertility status based on body temperature. Background Art

[0002] Fertility is one of the most important health care aspects in society. Fertility and fertility are related to several factors, such as psychological, environmental and chemical. The increasing knowledge about the impact of environmental factors and the risks associated with such factors has led to a growing need for methods that can assess population fertility without causing significant intrusion on the personal situation of the tester. There is a great need for a system of measurement methods for assessing a woman's menstrual cycle and fertility that does not intrude on her daily life.

[0003] Determining fertility for family planning or contraception is an important method in the female health care system and requires accurate determination of ovulation. The menstrual cycle is a complex interaction of many hormones and other body functions. So far, some indirect methods for determining a woman's ovulation are based on serum hormone levels or measurement of basal body temperature. Methods using serum hormone levels are reliable, but the laboratory assays required to use these urine measurements incur significant costs.

[0004] In addition, during the evaluation of the menstrual cycle, a temperature increase of about 0.5°C (+ / 0-1°C) after ovulation was recorded. This temperature increase is due to the circadian variation of the body's core temperature of about ±0.5°C. Conventional methods aim to identify and determine this variation in the body's core temperature. These conventional methods are based on an estimate of the basal temperature, i.e. an estimate of the lowest temperature of the day. Due to many other influences on body temperature, the basal temperature is mostly measured in the morning after waking up and involves the inconvenience of measuring the temperature immediately after waking up. The temperature measurement must then be repeated every day. This change in basal temperature is used as an indicator of ovulation. These methods are not very reliable.

[0005] There is a need to provide a more reliable method of determining a woman's menstrual cycle and to determine the actual fertility status of a woman or women. Summary of the invention

[0006] The present disclosure presents methods and systems for determining biomarker status in a mammal or human.

[0007] In one aspect, the method includes determining a continuous series of temperature data points associated with body temperature for a plurality of first time intervals. In this regard, the method also includes determining a series of representative temperature values ​​for a plurality of first time intervals and subtracting the series of representative temperature values ​​from the continuous series of temperature data points associated with body temperature to obtain a series of temperature fluctuations. The method also includes determining a difference between a temperature maximum and a temperature minimum in the series of temperature fluctuations for each of the plurality of first time intervals to obtain a plurality of temperature amplitudes. A series of temperature amplitudes is determined based on the plurality of temperature amplitudes, and determining whether a first portion of the series of temperature amplitudes has changed relative to a second portion of the series of temperature amplitudes, the change indicating a change in the state of the biomarker.

[0008] In another alternative or additional aspect, the present disclosure relates to a method for determining a progesterone response of a mammal or human, in particular a method for determining a progesterone response of a female. The method comprises the following steps: determining a continuous series of temperature data points associated with body temperature for a plurality of first time intervals; determining the difference between a temperature maximum and a temperature minimum in the series of data points for a plurality of first time intervals to obtain a plurality of temperature amplitudes. Determining a series of temperature amplitudes based on the plurality of temperature amplitudes, and determining whether a first portion of the series of temperature amplitudes changes relative to a second portion of the series of temperature amplitudes, the change indicating a change in the level of active progesterone in the mammal or human.

[0009] In yet another alternative or additional aspect, the present disclosure relates to a method for determining a progesterone response of a female. The method comprises the following steps: determining a continuous series of temperature data points associated with body temperature for a plurality of first time intervals; determining a difference between a temperature maximum and a temperature minimum in the series of data points for each of the plurality of first time intervals to obtain a plurality of temperature amplitudes; and determining a series of temperature amplitudes from the plurality of temperature amplitudes. A change in a first portion of the series of temperature amplitudes relative to a second portion of the series of temperature amplitudes indicates a change in the fertility status of the female.

[0010] In some examples, fertility status may relate to any of: menstrual cycle testing, CFG scoring, contraception and pregnancy, or any combination thereof.

[0011] In another aspect, the system includes a temperature measurement device for determining and recording a series of temperature data points associated with the female's body temperature and an analysis tool for analyzing the series of temperature data points, wherein the series of temperature data points are transmitted from the temperature measurement device to the analysis tool. The analysis tool performs at least one of the above method steps. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The present invention may be better understood upon reading the detailed description of examples of the present disclosure given in conjunction with the accompanying drawings, in which:

[0013] Figure 1 A pessary that may be used with the present disclosure is shown;

[0014] Figure 2a and Figure 2b Shows that it can be used Figure 1 Example of a temperature profile determined by an analytical system;

[0015] Figure 3 An example showing how to derive the base temperature from the temperature curve;

[0016] Figure 4a and Figure 4b shows how to determine the temperature amplitude from a set of temperature data points;

[0017] Figure 5a and Figure 5b It shows how to determine the temperature amplitude by correcting the absolute temperature value;

[0018] Figures 6a to 6e Different examples for different changes in hormone levels are shown;

[0019] Figure 7 Examples of temperature curves and temperature amplitudes indicating the onset of pregnancy are shown;

[0020] Figure 8 shows how different changes in hormone levels can be categorized;

[0021] Fig. 9 shows an example of how temperature amplitude is related to active progesterone; and

[0022] Fig.10 and Fig.11 Examples are shown of how temperature amplitude changes can be correlated with other parameters such as pH and nadir values. DETAILED DESCRIPTION

[0023] Examples of the present disclosure will now be described in more detail. It should be understood that the examples described and the examples shown in the figures are purely illustrative, and those skilled in the art will modify the examples as needed. It is not necessary to implement all the features shown in the examples, and those skilled in the art will combine the features shown or described in one figure with the examples shown in other figures or described elsewhere in the present disclosure.

[0024] The present disclosure relates in one example to methods and systems for determining biomarker status in a mammal or human. In one aspect, the biomarker is a progesterone response in a mammal or human, particularly a progesterone response in a woman. The progesterone response is associated with active progesterone, which is progesterone that causes a response in the body, such as whether the progesterone binds to a receptor and triggers other body responses. In contrast, free progesterone is the amount of progesterone available in the blood.

[0025] The method and system for performing the method include determining a continuous series of temperature data points associated with body temperature for a plurality of first time intervals.

[0026] In one example, the method includes determining the difference between the temperature maximum and the temperature minimum in the series of data points for a plurality of first time intervals to obtain a plurality of temperature amplitudes, and determining a change in the temperature amplitude, wherein the change in the temperature amplitude indicates a change in the state of the biomarker. The temperature amplitude may be determined for each of the plurality of time intervals. This may include removing some of the first time intervals if the data is incorrect. The term each of the first time intervals may be understood as the amplitude values ​​being determined or calculated for those of the plurality of time intervals where such determination is reasonable.

[0027] In another example, the method includes determining a series of representative temperature values ​​for a plurality of first time intervals, and subtracting the series of representative temperature values ​​from a continuous series of temperature data points associated with body temperature to obtain a series of temperature fluctuations. In this example, a difference between a temperature maximum value and a temperature minimum value is determined in the series of temperature fluctuations for the plurality of first time intervals to obtain a plurality of temperature amplitudes.

[0028] Determining the change in the temperature amplitude may include determining whether the first portion of the series of temperature amplitudes has changed relative to the second portion of the series of temperature amplitudes, and the change indicates a change in the biomarker state. If the first portion and the second portion are determined, it may be advantageous and increase reliability. An average value or mean may be determined for the first portion and the second portion, respectively. The first portion of the multiple temperature amplitudes may be a temperature amplitude determined in a subsequent first time interval. Similarly, the second portion of the multiple temperature amplitudes may be a temperature amplitude determined in a subsequent first time interval. The first portion and the second portion may include different numbers of temperature amplitudes and may involve different lengths of time. Measurements of temperature amplitudes with defects or erroneous values ​​may be filtered or otherwise excluded from the first portion or the second portion.

[0029] Determination of body temperature may include measuring the temperature and storing or recording the temperature or storing or recording data representative of or related to the temperature.

[0030] The body temperature may be the body core temperature, which is advantageously measured in a body cavity. A continuous series of temperature data points is related to the body core temperature. For example, a continuous series of temperature data points and the body core temperature measured in the vaginal passage of a woman is related to the body core temperature. A pessary with a temperature sensor may be used as an example. The body core temperature measured in a body cavity is more reliable than measuring on the skin. The temperature measurement on the skin is affected by external parameters, such as the position on the skin, the external temperature, external heat and light sources, and body reactions such as transpiration (non-explicit sweating), sweating or body movement. Skin temperature measurements usually only give an approximate measurement and are not very reliable.

[0031] Determine that continuous series of temperature data points are included in the continuous measurement of temperature data at intervals of every 15 minutes or shorter within at least 10 days. The series of temperature data points can be determined continuously, for example, in several days, a week or a whole menstrual cycle. Typical time intervals can be a measurement every 5 minutes, thereby generating about 288 temperature data points every day (within 24 hours). The time interval can be greater than or less than five minutes, for example, every minute or every 10 or 15 minutes, thereby generating more or less temperature data points every day. The temperature change in a shorter time interval will not give additional information, and the measurement in the time interval as described above is considered to produce a continuous temperature data curve. However, it is advantageous to continuously monitor temperature throughout the day and night. In the case of a female ovulation cycle, temperature can be measured in the whole menstrual cycle of women. A continuous temperature data curve can be evaluated from these temperature data points representing the actual body core temperature of women.

[0032] A continuous series of temperature data points can be determined for a plurality of first time intervals. The first time intervals can be directly one after another without any interruption, such as 24 hours a day, and one time interval can correspond to 24 hours or a day. The first time interval can be longer or shorter than a day. However, it has been found that daily measurement is useful for the daily life of the user. For example, the first time interval can be started by inserting a measuring device, and can be ended by removing the measuring device from the body for reading after about 24 hours a day. If it is explained herein that a value is determined for a first time interval or for each of the first time intervals, this can be understood as determining a value for the corresponding time interval of the first time interval. The term each can include that some of the time intervals may not produce a value and may be excluded from the series.

[0033] The difference between the temperature maximum and the temperature minimum may be referred to as the daily temperature amplitude. In other examples, the time interval may be interrupted, for example, by removing the measuring device from the body for reading. In some applications, only daytime or only nighttime periods may be used as the first time interval. However, continuous measurement without significant interruptions will provide more reliable data.

[0034] In one aspect, a series of representative temperature values ​​may be determined for a plurality of first time intervals. The series of representative values ​​may be a series of average temperature values, a minimum point value, or another value representing an absolute temperature, for example, in each of the first time intervals. The series of representative values ​​are subtracted from a continuous series of temperature data points associated with body temperature to obtain a series of temperature fluctuations. By subtracting the representative temperature values, the effects of temperature variations may be eliminated. It is advantageous to measure core body temperature in a body cavity to obtain more accurate temperature variations.

[0035] In the series of data points and / or the series of temperature fluctuations, for each of the plurality of first time intervals, the difference between the temperature maximum and the temperature minimum is determined to obtain a plurality of temperature amplitudes. The temperature amplitude is a relative value that is independent of the absolute temperature, and only the temperature change or difference within the first time interval is monitored. This indicates the temperature change within the first time interval, such as the temperature change within a day or 24 hours. If the series of temperature fluctuations is used to determine the series amplitude, the influence of temperature increase or body temperature decrease and the influence of human factors in some cases can be excluded.

[0036] A series of temperature amplitudes according to a plurality of temperature amplitudes. The method may include identifying a significant change in a representative temperature value and associating the significant change with a first portion of the series of temperature amplitudes and a second portion of the series of temperature amplitudes. One temperature amplitude value may be representative for each first time interval. If the first time interval is a day, the temperature amplitude may represent the amplitude or temperature change for that day and may be referred to as a daily temperature amplitude.

[0037] The change in temperature amplitude is then determined. A series or subset of temperature amplitudes can be determined based on multiple temperature amplitudes, and changes in temperature amplitude over time can be identified. For example, a change in a first portion of the series of temperature amplitudes relative to a second portion of the series of temperature amplitudes can indicate a change in biomarker state. The first portion and the second portion can be represented by a first mean or average amplitude of the temperature amplitude and a second mean or average temperature amplitude, respectively. The change between the first portion of the series of temperature amplitudes and the second portion of the series of temperature amplitudes can be at least one of: a change in the average amplitude of the temperature amplitudes, a change in the rate of change of the temperature amplitudes, an increase in the temperature amplitudes, or a decrease in the temperature amplitudes.

[0038] The hormone biomarker is progesterone in the example shown and is relevant to monitoring a woman's menstrual cycle. However, the present disclosure may also relate to the determination of other hormones or other biomarkers that can be determined by changes in temperature amplitude. The first average amplitude of the first portion may be greater than the second average amplitude of the second portion, thereby indicating a higher level of active progesterone in the second portion.

[0039] The female menstrual cycle is determined by a complex endocrine system. Current methods for measuring hormone status and / or changes in hormone levels are single-point measurements that only provide an endocrine point at the moment the measurement is made. These hormone levels undergo many changes, and therefore single-point observations are inadequate and imprecise. Detailed and personalized assessment of the female cycle is very limited.

[0040] The female cycle is a seismograph of a woman's health. Therefore, a single and continuous method is needed to scan women for accurate assessment of the following and more: fertility and infertility, hormone disorders and deficiencies, polycystic ovary syndrome (PCOS).

[0041] The present disclosure seeks to provide individualized assay information regarding the active progesterone hormone status of a woman's cycle to provide assays and predictions for the following, among others: fertility and infertility, hormone disorders and deficiencies, PCOS.

[0042] As an example, determining fertility for family planning or for contraception is an important approach to the female healthcare system and requires accurate determination of the current status of ovulation and / or menstrual cycle. The present disclosure seeks to provide assay information regarding menstrual cycle status and "fertility window" prognosis.

[0043] In addition to ovulation, a complex interaction of the endocrine system is required to establish pregnancy, in which hormones and changes in hormone levels at the right time play an important role.

[0044] The present disclosure relates in one example to a method and system for determining progesterone levels, in particular active progesterone levels, and female progesterone responses by measuring body core temperature. The method includes: determining a continuous series of temperature data points associated with body temperature for a plurality of first time intervals; determining the difference between a temperature maximum and a temperature minimum in the series of data points for each of the plurality of first time intervals to obtain a plurality of temperature amplitudes; and determining whether a first average temperature amplitude in a first subset or first portion of the plurality of temperature amplitudes is different relative to a second average temperature amplitude in a second subset or second portion of the plurality of temperature amplitudes, the difference indicating a change in progesterone response.

[0045] The inventors have found that temperature amplitude can be used as a measure of the progesterone response or active progesterone in the body. Active progesterone or progesterone response can be different from absolute progesterone levels, such as measured in the blood. When all progesterone receptors are activated and the progesterone response is saturated, the absolute progesterone level in the blood may also increase. The absolute progesterone level indicates how much progesterone is available in the body. The progesterone response is a measure of the progesterone that actually triggers a body response or is absorbed by the progesterone receptors.

[0046] Body core temperature can be measured by a temperature sensor placed in the vaginal passage of a woman. Body core temperature can also be measured in other body cavities and may not be limited to women. Body core temperature is the most reliable temperature measurement of a human or animal, far more accurate than temperature measurements taken elsewhere, such as the skin. Sensor patches or devices worn on the wrist tend to be affected by external or environmental conditions and are less reliable.

[0047] Examples of temperature sensors for measuring body core temperature that may be used with the present disclosure are described in Figure 1 The temperature sensor 10 is shown in a) to c) of and described in US2013 / 0237771 (EP 2567680), the contents of which are incorporated herein by reference. The temperature sensor 10 can be in the form of a pessary, or can be attached to a pessary 20 placed in the vaginal passage of a woman. The temperature sensor 10 can measure the actual body core temperature of the user within the vaginal passage. The temperature sensor is capable of measuring and recording a series of body core temperature data points of a near-monthly rhythm (30 days and above). The temperature sensor attached to the pessary provides high comfort to the user and provides high data reliability and is therefore beneficial to the method and system of the present disclosure. However, the method and system of the present disclosure can be used with other body temperature sensors that measure a continuous series of body core temperature data points inside the body or a series of temperature values ​​at other parts of the body, even if the temperature measurement at other parts may be less accurate.

[0048] It is advantageous to continuously monitor temperature throughout the day, night, and day, and if possible throughout the woman's menstrual cycle. A continuous temperature data curve can be evaluated from these temperature data points that represent the woman's actual body core temperature. Examples for continuous temperature data curves are shown in Figure 2a and 2b , where 288 temperature data points per day are measured and recorded continuously every 5 minutes during the menstrual cycle (approximately 30 days or more).

[0049] For example, conventional methods measure temperature data only during limited time intervals, such as after waking up or during the nighttime sleep stage. The temperature sensor is removed in the morning for reading. These methods attempt to estimate the basal temperature based on the lowest temperature measured during the sleep stage. These methods aim to determine the basal temperature, which is often not clearly defined. This method is not very reliable. In addition, these methods are also affected by the user's behavior and condition. Not every night and sleep stage is the same, and changes in lifestyle, the amount and time of sleep may have a significant impact on the measured values. These conventional methods usually do not measure during the day or ignore any measurements taken during the day, because daytime activities usually increase body temperature and are therefore useless for determining basal temperature.

[0050] The basal temperature can also be determined based on a continuous series of data points, such as in the present disclosure. Figure 3 As shown. For each day in the menstrual cycle, the lowest data point is determined, i.e., the minimum value in the series of data points is determined. An increase or decrease in these basal temperature values ​​can be determined. These basal temperature changes are well-known and widely used indicators related to ovulation. The natural variation of basal temperature limits the reliability of this method. However, basal temperature can be used as an additional indicator in combination with other indicators and features in the series of data points as described below.

[0051] The inventors have found that the temperature curve contains additional information in addition to the base temperature and that specific features in the temperature data curve can be analyzed. An example of feature analysis in a series of temperature data points is described in WO 2015 / 044398 A1, the contents of which are incorporated herein by reference.

[0052] The present disclosure proposes to use a continuous series of temperature data points of the body core temperature measured in the vaginal passage of a woman, which are continuously determined and recorded rhythmically over multiple days, weeks or nearly months to determine a temperature profile of the body core temperature over a long period of time. Depending on the application, the sensor can remain in the vagina throughout the menstrual cycle, and the recorded data can be read out at the end of the menstrual cycle. Alternatively, the recorded temperature data can be read out from time to time, such as once a week, once a day, or at other time intervals. The measurement and reading of the actual temperature data can determine the status of the menstrual cycle in "real time".

[0053] These recorded temperature curves are analyzed and / or evaluated. According to one aspect of the present disclosure, a continuous series of temperature data points is analyzed for temperature amplitude. The temperature amplitude is the temperature difference between the maximum temperature value and the minimum temperature value within a predetermined time interval. The predetermined time interval can generally be one day or 24 hours, and the corresponding temperature amplitude can be referred to as the daily temperature amplitude. The (daily) temperature amplitude is independent of the absolute temperature value and is therefore independent of the effects that affect body temperature and basal temperature. Figure 4a It shows how to determine the temperature amplitude from a set of temperature data points.

[0054] Determining and recording a continuous series of temperature data points associated with body temperature for a plurality of first time intervals may include: determining a representative temperature value based on a raw data set associated with the temperature measured by a temperature sensor. The representative temperature value may be obtained by filtering and / or fitting the temperature raw data. For example, filtering may include at least one of: determining a mean, a median from a group or a subset of temperature values. Filtering may also include a low-pass filter or a moving average filter. Fitting the temperature raw data may include at least one of: smoothing the generated temperature curve; and approximating the temperature raw data, for example, by a cosine or sine function. If necessary, the cosine or sine function may have an additional correction factor.

[0055] The maximum temperature value and the minimum temperature value can be determined directly from the temperature data point group. A filter can be applied to filter out and / or delete unrealistic and defective data points or data values ​​from the temperature data point group. It is also possible to use more than one temperature data point but to use a series of temperature data points to determine a representative maximum temperature value and a representative minimum temperature value. Common methods for data processing can be applied if they are considered applicable by those skilled in the art.

[0056] The temperature maximum and temperature minimum may be determined based on the representative temperature value and may be the representative temperature maximum and the representative temperature minimum. For simplicity, the terms temperature maximum and temperature minimum are also used herein for the representative temperature maximum and the representative temperature minimum, respectively.

[0057] The inventors have found that the daily temperature amplitude and the change of the daily temperature amplitude can be used as an indicator of the active progesterone level, especially in women, but more generally in mammals. The inventors have found that the temperature amplitude is a measure of the body's response or reaction to the presence of progesterone. The body response may be related to the presence of free progesterone in the blood in some cases, but may be unrelated to it in other cases. Only part of the free progesterone can bind to the progesterone receptor, and the progesterone receptor may be saturated, so that the additional free progesterone cannot bind to the receptor or cannot trigger a response. In other cases, the triggering signal may be interrupted or interfered at a certain point in the signal cascade. In these cases, the free progesterone in the blood may still be high, but the body will not respond to progesterone or only have a reduced response. Therefore, the temperature amplitude is a biomarker for active progesterone levels or progesterone responses, and the change of the temperature amplitude indicates the change of active progesterone. Generally, the reduction of the temperature amplitude indicates an increase in the active progesterone level, that is, the progesterone response increases, and the increase of the temperature amplitude indicates a decrease in the active progesterone level, that is, a decrease in the progesterone response.

[0058] Further evaluation of the temperature data may be advantageous. The calculation of the temperature amplitude may be affected by changes in body temperature, ie by increases or decreases in body temperature. Figure 5a and Figure 5b An example of how a more accurate amplitude can be obtained is shown. This is particularly useful for accurate and / or real-time measurement of progesterone levels. Figure 5a A series of temperature data from a female cycle is shown. From these data a smoothed average or mean is calculated, such as Figure 5a This may correspond to the average body temperature. The average body temperature can be subtracted from the series of temperature data to produce a series of daily temperature changes or daily temperature fluctuations, such as Figure 5b As shown. Now, a representative maximum temperature and a representative minimum temperature can be determined based on the daily temperature variation, thereby determining the daily temperature amplitude and the daily temperature amplitude variation. The advantage of using daily temperature variation instead of directly using temperature data is that changes in absolute temperature caused by health status or other influences can be excluded. The inventors have found that using the body core temperature data measured in the body cavity to produce more accurate daily temperature variations, thereby producing more reliable temperature amplitudes and amplitude variations.

[0059] The menstrual cycle can be categorized based on temperature and the low temperature phase based on progesterone levels, e.g. Figures 6a to 6e , Figure 7 ,and Figure 8 The method is called Cyclofertilography by the applicant. TM or CFG score TM The fertility score is used to classify menstrual cycles into different fertility levels. The score distinguishes six levels based on the presence and length of the luteal phase. The presence and length of the luteal phase are determined by measuring progesterone levels, which can be derived from the temperature amplitude described in this article.

[0060] CFG score A: If the temperature rise and / or the progesterone level rise is determined by a decrease in the temperature amplitude, and if the temperature amplitude remains low for more than 20 days, the cycle is classified as an extended low temperature phase, which is an indicator of the onset of pregnancy. The temperature amplitude may or may not remain high during the onset of pregnancy ( Figure 6a , Figure 7 ).like Figure 7 As shown in the figure above, during the initial period of pregnancy, the temperature level slowly decreases, while the temperature amplitude shown in the figure below remains stable at a low level, indicating that the active progesterone level remains high. Figure 6a, the temperature level remains high, while the temperature amplitude remains at a lower level. This clearly shows that the determination of the temperature amplitude can give additional information. Monitoring the reduced amplitude can help monitor the pregnancy status. This helps to monitor any abnormal events in the pregnancy during the entire pregnancy process. An increase in the daily amplitude and / or a strong change in the daily temperature may indicate a problem in the pregnancy that requires medical attention.

[0061] CFG Rating: B Figure 6b An example of a temperature data curve (upper graph) and corresponding temperature amplitude (lower graph) for a fertile menstrual cycle with a long low temperature phase and a good probability of starting a pregnancy is shown. A temperature rise is determined and lasts for about 16 to 19 days, with the temperature rising for about 3-5 days and falling from days 16-19. If this pattern occurs frequently in a patient, an interfering early pregnancy or ovarian cyst should be ruled out by advanced testing.

[0062] CFG score C: Figure 6c An example of a temperature data curve (top graph) and corresponding temperature amplitude (bottom graph) for a "normal" or average female menstrual cycle with a luteal phase is shown. The temperature increase lasts for 11 to 15 days, while the temperature amplitude decreases over the same period. This indicates an "ideal" or "normal" luteal phase. The temperature amplitude was determined to decrease significantly within approximately 11 to 15 days, which also indicates a "normal" fertile menstrual cycle.

[0063] CFG score: D Figure 6d An example of a temperature data curve (upper figure) and corresponding temperature amplitude (lower figure) for a female menstrual cycle with a shorter luteal phase is shown, which may be due to limited active progesterone. The temperature increase lasts for 8 to 10 days. Further medical examination may be required. If progesterone is given within the correct time window, progesterone treatment may increase fertility in this case. The application provides a method for determining the correct time window for progesterone treatment to limit the total amount of hormone in treatment.

[0064] CFG Score E: Figure 6e An example of a temperature data curve (upper figure) and corresponding temperature amplitude (lower figure) for a monophasic female menstrual cycle in which ovulation did not occur is shown. No temperature change could be detected, nor could a significant change in the temperature amplitude be determined. The menstrual cycle was monophasic, and there was no interruption in homogeneity, and an increase in temperature and / or an increase in progesterone levels were determined. No ovulation occurred during this cycle.

[0065] If it is determined that the temperature rises and / or the progesterone level rises, and in the CFG score E, the rise continues for less than 6 to 7 days, this may indicate an example of a temperature data curve (upper figure) and a corresponding temperature amplitude (lower figure) for a female menstrual cycle indicating luteinized unruptured follicle syndrome (LUF syndrome). The temperature may only rise slightly and the temperature rise may be less than the temperature rise in a normal cycle. In these 6-7 days, the temperature amplitude (lower figure) only shows a slight reduction. Compared with a normal "fertile" cycle, and compared with a short luteal phase (CFG score 3), the reduction time is shorter and the difference in amplitude is smaller. This may indicate the presence of so-called LUF syndrome (luteinized unruptured follicle syndrome). Pregnancy in this case may be difficult, and more detailed testing and treatment may be required.

[0066] A break in homogeneity can be defined as a break of at least 0.2 degrees Celsius in the measured temperature curve. If the temperature break is positive, i.e., it involves a temperature rise, and if the second cycle phase lasts for at least a few days, the cycle can be considered biphasic. An example for a biphasic cycle is Figures 6b to 6c The cycle shown in .

[0067] Monitoring the level of active progesterone may help improve hormone therapy, especially progesterone therapy. The time interval and amount of progesterone prescribed to the user can be determined based on the actual active progesterone level measured as described above. The total amount of additional progesterone can be limited and adjusted according to individual needs.

[0068] Progesterone is usually measured from a blood sample to indicate the absolute progesterone level in the body. It is an indicator of the free progesterone available in the body. However, this absolute progesterone is not necessarily active in the body. The inventors have found that the reduction in body temperature amplitude is related to the amount of active progesterone, that is, progesterone that is attached to the progesterone receptor and triggers a body response and is within the other range of reduced temperature amplitude. In other words, the body temperature amplitude is an indicator for the body's progesterone response. The active progesterone level may be different from the absolute progesterone level. For example, the absolute progesterone level continues to increase during pregnancy, while the progesterone response and active progesterone level are saturated. This is indicated by a continuously lower temperature amplitude. Fig. 9 Comparison of temperature change, progesterone response and free progesterone in blood is shown.

[0069] In some cases, the absolute progesterone level may be high enough to allow and / or ensure pregnancy, but the body's absorption of progesterone may be too low, resulting in no progesterone response or a lower progesterone response, as evidenced by a lower amplitude or no decrease. The present disclosure may also be used to test and assess the function of the endocrine system by monitoring the response of the temperature amplitude and monitoring this progesterone response by active progesterone to increase absolute progesterone. Absolute progesterone can be altered by natural processes or by medication.

[0070] The temperature data points of the time series can be read and evaluated at any time during the menstrual cycle. For example, the temperature data points can be read or transmitted to a reader or analysis device once every 24 hours or twice a day. The temperature curve then corresponds to the current menstrual cycle of the woman until the last temperature measurement before the reading, i.e. until the last temperature measurement before the pessary was removed from the vagina. Therefore, the temperature data points of the time series are not in this case a complete menstrual cycle, but only the first part. The current state can be determined in real time during the menstrual cycle.

[0071] The female cycle is determined by a complex endocrine system. Additional parameters can help improve the determination of the state of the endocrine system and the female cycle. In some examples of the present disclosure, progesterone measurements can be supplemented by additional parameters. For example, absolute temperature values ​​or other parameters such as the pH of cervical mucus can be considered. pH information can be obtained by a measuring device, and the pH sensor can be integrated into a temperature measuring device that can be placed in the vagina. For some applications, manual pH measurements at predetermined time intervals using conventional pH test strips may be sufficient. For example, it may be sufficient to perform a pH measurement once a day. The measurement sequence can also be changed during the cycle and / or during treatment. Measuring the pH of cervical mucus may provide additional information about the pre-ovulation process.

[0072] Fig.10 An example of how changes in temperature amplitude are related to the pH of cervical mucus is shown. Representative maximum and minimum temperature values ​​are determined from a set of consecutive temperature data points (top graph), and the daily temperature amplitude is determined (middle graph) as described with respect to Figure 4a , Figure 4b and Figure 5a and Figure 5b Additional daily measurements of ht pH, such as once a day with pH test strips, indicate an increase in pH (lower graph) or a more alkaline cervical mucus. The increase in pH is associated with a decrease in temperature amplitude (middle graph), which may indicate and / or confirm ovulation and / or progesterone delivery.

[0073] Fig.11 Another example is referred to, in which the nadir value is considered as an additional parameter. The nadir value corresponds to the lowest temperature value measured during a specific period of time. The nadir value can be a representative temperature minimum during a 24-hour or daily time interval. In one aspect, the nadir value can vary during a woman's cycle, for example, Figure 3In the luteal phase after ovulation, the lowest point value may increase by 0.3°C to 0.4°C. The experimental results shown in Table 1 show that the lowest point value increases by an average of 0.36°C between the follicular phase and the luteal phase. The increase in temperature can be related to the change in the daily temperature amplitude. With the change in daily amplitude, the representative temperature maximum or peak shows a less significant increase, depending on the progesterone level.

[0074]

[0075] Table 1

[0076] The inventors have also discovered that the lowest point value also shifts at the time point in a day when the lowest point value occurs.

[0077] In this regard, the present disclosure relates to a method for determining a female's fertility status, the method comprising: determining a continuous series of temperature data points associated with body temperature for a plurality of first time intervals; determining a temperature minimum time in the series of data points for each of the plurality of first time intervals; and determining a change in the temperature minimum time, wherein the change in the temperature minimum time indicates a change in the female's fertility status.

[0078] The temperature minimum time is the time point at which a representative temperature minimum or minimum value occurs for each first time interval. The first time interval is usually a day or 24-hour interval, and the temperature minimum time can be the time point at which a representative temperature minimum or minimum value occurs in a day. In this regard, the temperature minimum time can be referred to as the daily temperature minimum time or minimum time. The change or offset of the evaluation time.

[0079] The absolute minimum temperature or nadir value is not necessarily determined but may be used as an additional or supplementary parameter. For example, the minimum temperature value may change at a different time or at a different rate than the shift or change in the temperature minimum time. The time point in a day at which a representative minimum temperature or nadir is found is referred to as the nadir time.

[0080] The inventors discovered a shift in the nadir time in the biphasic cycle, while the nadir time remained within a time window within the follicular phase. Fig.11 The temperature curves of multiple biphasic cycles are shown plotted on top of each other. In this example, 20 temperature curves of biphasic cycles are used for simplicity, but more curves can be used to obtain sufficient statistics. A significant change in the nadir time can be seen between the follicular phase and the luteal phase. The offset in the nadir time can be at least 0.5 hours. Fig.11In the example shown in Table 1, the average time shift of the nadir time is 0.67 hours. This time shift is observed in biphasic cycles and can be used as an indicator of biphasic cycles in which ovulation occurs. This shift in the nadir time can be correlated with changes in the daily temperature amplitude and can be used as a supplement or additional information for progesterone levels.

[0081] The temperature measurement and evaluation methods and systems can be used and applied as explained above with respect to the change in temperature amplitude, with the difference that the nadir time is evaluated instead of the temperature amplitude. The temperature amplitude change can be associated or otherwise combined with information derived from the change in the nadir time.

[0082] The above disclosure has been given with respect to determining the biomarker, the hormone progesterone, and the fertility status of human females. However, the method and system are equally applicable to any female mammal for which continuous temperature measurements may be made. The present disclosure and in particular the measurement of temperature amplitude may also be related to other physical parameters of men and women or mammals if not related to fertility or pregnancy.

Claims

1. A method for determining the status of a biomarker in a human or mammal, the method comprising: determining a continuous series of temperature data points associated with body temperature for a plurality of first time intervals, the body temperature being a body core temperature, the body core temperature being measured in a body cavity, the determining the continuous series of temperature data points comprising continuously measuring temperature data at intervals of 15 minutes or less for at least 10 days; determining a series of representative temperature values ​​for the plurality of first time intervals, the series of representative temperature values ​​being at least one of a series of average temperature values, a series of lowest point values, and a value representing an absolute temperature, and subtracting the series of representative temperature values ​​from the continuous series of temperature data points associated with the body core temperature to obtain a series of temperature fluctuations; For the plurality of first time intervals, determining a difference between a temperature maximum value and a temperature minimum value in the series of temperature fluctuations to obtain a plurality of temperature amplitudes; determining a series of temperature amplitudes based on the plurality of temperature amplitudes; as well as Determining whether a first portion of the series of temperature amplitudes changes relative to a second portion of the series of temperature amplitudes, a change in the first portion relative to the second portion indicating a change in the state of the biomarker, wherein the first portion and the second portion include different numbers of temperature amplitudes and involve different lengths of time.

2. The method according to claim 1, wherein: A change in the first portion of the series of temperature amplitudes that decreases in amplitude relative to the second portion of the series of temperature amplitudes indicates a higher level of the biomarker.

3. The method according to claim 1 or 2, wherein: The biomarker is the progesterone response in humans or mammals.

4. The method of claim 1 or 2, further comprising determining a rate of change of the temperature amplitude.

5. The method according to claim 1 or 2, wherein: The change between the first portion of the series of temperature amplitudes and the second portion of the series of temperature amplitudes is at least one of: a change in an average amplitude of the temperature amplitudes, a change in a rate of change of the temperature amplitudes, an increase in the temperature amplitudes, or a decrease in the temperature amplitudes.

6. The method according to claim 3, wherein: A change in the first portion of the series of temperature amplitudes that decreases in amplitude relative to the second portion of the series of temperature amplitudes indicates a higher level of progesterone as a biomarker.

7. The method of claim 6, further comprising determining a time length of the second portion and characterizing the female cycle based on the time length of the second portion.

8. The method according to claim 7, wherein: A first portion of the series of temperature amplitudes changes in magnitude with respect to a second portion of the series of temperature amplitudes that decreases in magnitude, and wherein the second portion lasts for at least 17 days, indicating the onset of pregnancy.

9. The method of claim 1 or 2, further comprising determining the duration of the significant change by determining the number of first time intervals during which the series of representative temperature values ​​change.

10. The method according to claim 1 or 2, further comprising: Determining a series of pH values; identifying a change in the pH values; and correlating a change between a first portion of the series of temperature amplitudes and a second portion of the series of temperature amplitudes to the change in the pH values.

11. A method for determining a progesterone response in a mammal or human, the method comprising: determining a continuous series of temperature data points associated with body temperature for a plurality of first time intervals, the body temperature being a body core temperature, the body core temperature being measured in a body cavity, the determining the continuous series of temperature data points comprising continuously measuring temperature data at intervals of 15 minutes or less for at least 10 days; determining, for the plurality of first time intervals, a difference between a temperature maximum and a temperature minimum in the continuous series of temperature data points to obtain a plurality of temperature amplitudes; determining a series of temperature amplitudes based on the plurality of temperature amplitudes; as well as Determining whether a first portion of the series of temperature amplitudes changes relative to a second portion of the series of temperature amplitudes, a change in the first portion relative to the second portion indicating a change in active progesterone levels in the mammal or human, wherein the first portion and the second portion include different numbers of temperature amplitudes and involve different lengths of time.

12. The method of claim 11 further comprising determining a rate of change of the temperature amplitude.

13. The method according to claim 11 or 12, wherein: The change between the first portion of the series of temperature amplitudes and the second portion of the series of temperature amplitudes is at least one of: a change in the average amplitude of the temperature amplitudes, a change in the rate of change of the temperature amplitudes, an increase in the temperature amplitudes, or a decrease in the temperature amplitudes.

14. The method according to claim 11 or 12, wherein: A first portion of the series of temperature amplitudes that varies by a smaller amplitude relative to a second portion of the series of temperature amplitudes indicates a higher level of active progesterone.

15. The method of claim 14, further comprising determining a time length of the second portion and characterizing the female cycle based on the time length of the second portion.

16. The method according to claim 15, wherein: The first portion of the series of temperature amplitudes varies by a smaller amplitude relative to the second portion of the series of temperature amplitudes, and wherein the second portion lasts for at least 17 days, indicating the onset of pregnancy.

17. The method according to claim 11 or 12, further comprising: determining a representative temperature value for each of the first time intervals; and identifying significant changes in the representative temperature value; And the significant change is associated with a first portion of the series of temperature amplitudes and a second portion of the series of temperature amplitudes.

18. The method according to claim 17, wherein: The representative temperature value is at least one of an average temperature value or a lowest point value.

19. The method of claim 17, further determining the duration of the significant change by determining the number of first time intervals during which the representative temperature value changes.

20. The method according to claim 11 or 12, further comprising: Determining a series of pH values; identifying a change in the pH values; and correlating a change between a first portion of the series of temperature amplitudes and a second portion of the series of temperature amplitudes to the change in the pH values.

21. A system for determining the status of a biomarker in a human or mammal, the system comprising: a temperature measurement device for determining and recording a series of temperature data points associated with the female's body temperature, the body temperature being a body core temperature, the body core temperature being measured in a body cavity; an analysis tool for analyzing the series of temperature data points, wherein the series of temperature data points are transmitted from the temperature measurement device to the analysis tool; the analysis tool performing the following steps: determining a continuous series of temperature data points associated with the body core temperature for a plurality of first time intervals, wherein determining the continuous series of temperature data points comprises continuously measuring temperature data at intervals of 15 minutes or less for at least 10 days; determining a series of representative temperature values ​​for the plurality of first time intervals, the series of representative temperature values ​​being at least one of a series of average temperature values, a series of lowest point values, and a value representing an absolute temperature, and subtracting the series of representative temperature values ​​from the continuous series of temperature data points associated with the body core temperature to obtain a series of temperature fluctuations; For the plurality of first time intervals, determining a difference between a temperature maximum value and a temperature minimum value in the series of temperature fluctuations to obtain a plurality of temperature amplitudes; determining a series of temperature amplitudes based on the plurality of temperature amplitudes; and Determining whether a first portion of the series of temperature amplitudes changes relative to a second portion of the series of temperature amplitudes, a change in the first portion relative to the second portion indicating a change in the state of the biomarker, wherein the first portion and the second portion include different numbers of temperature amplitudes and involve different lengths of time.

22. A system for determining a progesterone response in a human or mammal, the system comprising: a temperature measurement device for determining and recording a series of temperature data points associated with the female's body temperature, the body temperature being a body core temperature, the body core temperature being measured in a body cavity; An analysis tool for analyzing the series of temperature data points, wherein the series of temperature data points are transmitted from the temperature measurement device to the analysis tool; the analysis tool performs the following steps: determining and recording a continuous series of temperature data points associated with the body core temperature for a plurality of first time intervals, wherein determining the continuous series of temperature data points comprises continuously measuring temperature data at intervals of 15 minutes or less for at least 10 days; determining, for each of one of the plurality of first time intervals, a difference between a temperature maximum and a temperature minimum in the continuous series of temperature data points to obtain a plurality of temperature amplitudes; determining a series of temperature amplitudes based on the plurality of temperature amplitudes; and Determining whether a first portion of the series of temperature amplitudes changes relative to a second portion of the series of temperature amplitudes, a change in the first portion relative to the second portion indicating a change in the level of active progesterone in the mammal or human, wherein the first portion and the second portion include different numbers of temperature amplitudes and involve different lengths of time.

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