System and method for predicting the dosage of exogenous follicle-stimulating hormone drugs during the COS cycle

Abstract

A system for predicting the dosage of exogenous FSH administered to a subject during a COS cycle, the system comprising: a data collection module for obtaining the age, basal AMH, basal FSH or ΔINHB, and basal AFC data of the subject; a first calculation is performed on the obtained data to calculate the predicted NRO of the subject; a second calculation is performed on the obtained data to calculate the ratio of the predicted NRO of the subject to the dosage of the exogenous FSH drug administered to the subject; and an exogenous FSH drug dosage calculation module for calculating the dosage of the exogenous FSH drug to be administered based on the predicted NRO calculated in the first calculation and this ratio. This system first calculates the predicted NRO, then calculates the predicted ovarian sensitivity, that is, the ratio of the predicted NRO to the dosage of the exogenous FSH drug, to obtain the dosage of the exogenous FSH drug to be administered. When the only unknown variable among the predicted ovarian sensitivity result variables is the dosage of the exogenous FSH drug, the dosage of the exogenous FSH drug can be predicted.

Description

Detailed Description of the Invention

[0001] [Technical Field] The present application relates to the field of medical technology, and in particular, to a system and method for obtaining an initial dose and an adjusted dose of an exogenous FSH agent to be administered to a subject by calculating a predicted ovarian sensitivity in a controlled ovarian stimulation cycle, that is, a ratio of a predicted number of retrieved oocytes to the dose of an exogenous follicle-stimulating hormone (FSH) agent. [Background Art]

[0002] In the case of women undergoing controlled ovarian stimulation (COS) and in vitro fertilization / intracytoplasmic sperm injection (IVF / ICSI) cycles, the number of retrieved oocytes, that is, the number of oocytes obtained after COS treatment (The number of retrieved oocytes, NRO), is considered a strong surrogate prognostic marker for pregnancy success. An optimal NRO helps improve the live-birth-rate (LBR).

[0003] Infertility is defined as the failure to conceive after 12 months of unprotected regular sexual intercourse. In China, the infertility rate among women of childbearing age is as high as 12 - 15%. Assisted reproductive technology (ART) is the most common and effective method used in the treatment of infertility. On the other hand, controlled ovarian stimulation (COS), in vitro fertilization (IVF), and embryo transfer (ET) are the most common and effective types of ART. Personalized COS is a milestone in the history of ART. Selecting an appropriate dose of exogenous follicle-stimulating hormone (FSH) is important for COS. There are two important time points in personalized COS. One is when the initial dose is selected at the start of a new treatment cycle, and the other is when dose adjustment is performed within a given COS cycle.

[0004] The selection of the initial dose for ovulation induction treatment is very important. So far, clinicians often rely on personal experience to estimate the predicted number of eggs retrieved by combining the size and number of follicles under ultrasonic examination during treatment with the growth changes of LH (luteinizing hormone), estradiol (E2), and progesterone (P), and adjust the dosage of ovulation induction agents. However, internationally, the dosage adjustment of exogenous FSH drugs during ovulation induction has mainly relied on subjective experience and there is no unified standard. Our research team has previously developed a system and method for predicting ovarian responsiveness to ovulation induction treatment using basic ovarian reserve indicators (indicators before ovulation induction treatment). The outcome variable of this system is the probability of poor ovarian response. People with similar probabilities of poor response are classified according to the population and given a recommended dosage. Although this recommended dosage is somewhat advanced, there is no dosage in the outcome variable. Its essence is the combination of the prediction of a low response probability and clinical experience, which is a commonly used method worldwide. However, it clearly involves human experiential judgment and is not intelligent enough, so further improvement is needed.

[0005] Furthermore, some researchers have used models to predict the number of eggs retrieved (NRO) and combined the predicted NRO with clinical hypotheses to recommend a specific starting dose of exogenous FSH for patients with similar ovarian responses. The main outcome variable of these models is NRO. La Marca et al. proposed a new idea of using the ratio of the actual NRO to the actual initial dose as the outcome variable to predict the starting dose of exogenous FSH drugs. For the first time, they included a dosage variable in the outcome variable, that is, instead of making a judgment based on experience, they incorporated the dosage into the model. They used three basic indicators, age, FSH, and anti-Müllerian hormone (AMH), to predict ovarian sensitivity, that is, the value obtained by dividing the actual NRO by the actual initial dose of exogenous FSH, and the R of the model 2It was 0.3. However, the ratio of the result variable, that is, the actual NRO to the initial dose of exogenous FSH, was unknown before ovarian stimulation for both, and it was necessary to assume before the final calculation of the dose. They assumed that the NRO of all individuals was 9 and calculated the initial dose of exogenous FSH. This study has great innovative value in predicting the starting dose of exogenous FSH compared with previous models, but fixing the NRO at 9 lacks individual guidance and does not suit the actual situation of most patients. [Disclosure of the Invention]

[0006] Selecting an appropriate dose of exogenous follicle-stimulating hormone (FSH) agent is the key to a controlled ovarian stimulation (COS) cycle. The standard fixed dose of exogenous FSH is not suitable for all women because ovarian reserve and ovarian response are different. Based on individual ovarian reserve and ovarian drug response to exogenous FSH, determining the optimal starting dose and adjusted dose of exogenous FSH agent has been the goal of many physicians. So far, no simple and applicable online tool has been developed. Therefore, the present application provides a system and method for predicting the initial dose and adjusted dose of exogenous FSH agent administered to a subject during a controlled ovarian stimulation cycle based on individualized ovarian reserve and response to exogenous FSH agent, and can realize the prediction of the initial dose and adjusted dose based on basic indicators. The R of the prediction model of the present application 2 is greater than 0.9 and much higher than existing technical models.

[0007] From the above, the present application relates to the following content.

[0008] 1. A system for predicting the dose of exogenous follicle-stimulating hormone (FSH) agent administered to a subject during a controlled ovarian stimulation cycle, a data collection module for obtaining data on the age of the subject, the level of basal anti-Müllerian hormone (AMH), the level of basal follicle-stimulating hormone (FSH), or the dynamic change (ΔINHB) of inhibin B level, and the number of basal antral follicles (AFC); Perform a first calculation on the above data obtained by the data collection module to calculate the predicted number of retrieved oocytes (predicted NRO) of the subject in the ovulation induction cycle; perform a second calculation on the above data obtained by the data collection module to calculate the ratio of the predicted number of retrieved oocytes (predicted NRO) of the subject in the ovulation induction cycle to the dose of exogenous FSH drug, that is, the predicted ovarian sensitivity; based on the predicted number of retrieved oocytes (predicted NRO) calculated in the first calculation and the ratio value obtained in the second calculation, an exogenous follicle-stimulating hormone (FSH) drug dose calculation module for calculating the dose of exogenous FSH drug to be administered to the subject and A system comprising. 2. The subject is a subject receiving standard ovulation induction treatment, and the number of retrieved oocytes (NRO) of the subject is obtained after the subject has received ovulation induction treatment, after the diameters of 1 to 2 dominant follicles reach 18 mm or more during the ovarian stimulation process and then hCG injection is performed to induce follicle maturation, and it is the number of mature oocytes with a diameter of 10 mm or more, preferably 15 mm or more. The system according to item 1. 3. In the data collection module, the obtained basal anti-Müllerian hormone (AMH) level refers to the concentration of anti-Müllerian hormone in the venous blood of the subject at any time point during the menstrual period before ovulation induction treatment. The system according to item 1 or 2. 4. In the data collection module, the obtained basal follicle-stimulating hormone (FSH) level refers to the concentration of follicle-stimulating hormone (FSH) in the venous blood of a female subject on the 2nd to 4th days of menstruation before ovulation induction treatment. The system according to any one of items 1 to 3. 5. In the data collection module, the obtained basal antral follicle count (AFC) refers to the number of all follicles with a diameter of 2 to 10 mm visible by transvaginal B-ultrasound examination in both ovaries of a female subject on the 2nd day of menstruation. The system according to any one of items 1 to 4. 6. In the data collection module, the obtained dynamic change in inhibin B level (ΔINHB) refers to the dynamic change in inhibin B level (ΔINHB) at the initial stage of ovulation induction treatment, preferably the difference between the serum inhibin B concentration on the 6th day of menstruation and the inhibin B concentration in venous blood on the 2nd day of menstruation in the ovulation induction treatment cycle of female subjects receiving GnRH antagonist regimen. The system according to any one of items 1 to 5. 7. The data collection module is used to obtain data on the age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level, and basal antral follicle count (AFC) of the subject. The exogenous follicle-stimulating hormone (FSH) drug dosage calculation module performs a first calculation on the above data obtained by the data collection module to calculate the predicted number of oocytes retrieved (predicted NRO) of the subject in the ovulation induction cycle; performs a second calculation on the above data obtained by the data collection module to calculate the ratio of the predicted number of oocytes retrieved (predicted NRO) of the subject in the ovulation induction cycle to the initial dosage of the exogenous FSH drug, that is, the predicted ovarian sensitivity; and is used to calculate the initial dosage of the exogenous FSH drug to be administered to the subject based on the predicted number of oocytes retrieved (predicted NRO) calculated in the first calculation and the ratio value obtained in the second calculation. The system according to any one of items 1 to 6. 8. In the exogenous FSH drug dosage calculation module, formula 1 for calculating the predicted number of oocytes retrieved (predicted NRO) of the subject fitted based on data on the age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level, basal antral follicle count (AFC), and actual number of oocytes retrieved of patients who received ovulation induction treatment with a standard GnRH antagonist regimen is pre-stored in an existing database. The system according to item 7. 9. In the exogenous FSH drug dosage calculation module, Formula 1 is a calculation formula obtained by fitting, using the negative binomial distribution of the result variable, the data of the age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level, basal antral follicle count (AFC), and actual number of retrieved oocytes (result variable) of patients who received ovulation induction treatment with a standard GnRH antagonist regimen from an existing database. Formula 1 can calculate the predicted number of retrieved oocytes (predicted NRO) of the subject using the age data of the subject, the basal anti-Müllerian hormone (AMH) level data of the subject, the basal follicle-stimulating hormone (FSH) level data of the subject, and the basal antral follicle count (AFC) data of the subject obtained by the data collection module. The system according to item 8. 10. Formula 1 is Predicted NRO = EXP(a + b * age + c * basal FSH + d * LN[basal AMH] + f * LN[basal AFC]), where a is an arbitrary value selected from 1.5576128 to 2.6037078, preferably 2.0806603. b is an arbitrary value selected from -0.019097 to 0.0044064, preferably -0.007345. c is an arbitrary value selected from -0.045234 to -0.004054, preferably -0.024644. d is an arbitrary value selected from 0.348168 to 0.4948875, preferably 0.4215277. f is an arbitrary value selected from 0.0415663 to 0.2566199, preferably 0.1490931. The system according to item 9. 11. In the exogenous FSH drug dosage calculation module, among existing databases, based on the age of patients who received ovulation induction treatment with a standard GnRH antagonist regimen, the basal anti-Müllerian hormone (AMH) level, the basal follicle-stimulating hormone (FSH) level, the basal antral follicle count (AFC) data, and the data of the ratio of the predicted number of oocytes retrieved (predicted NRO) calculated by Formula 1 to the average daily dosage of the exogenous FSH drug used by the patient, that is, the predicted ovarian sensitivity of the subject fitted based on these data, specifically, Formula 2 for calculating the ratio value of the predicted number of oocytes retrieved (predicted NRO) to the initial dosage of the exogenous FSH drug is pre-stored. The average daily dosage of the exogenous FSH drug used by the patient refers to the ratio value of the total dosage of the exogenous FSH drug used by the patient during the past ovulation induction treatment period with a standard GnRH antagonist regimen to the number of days of use of the exogenous FSH drug. The system according to item 10. 12. In the exogenous FSH drug dosage calculation module, Formula 2 can use the age data of the subject obtained by the data collection module, the basal anti-Müllerian hormone (AMH) level data of the subject, the basal follicle-stimulating hormone (FSH) level data of the subject, and the basal antral follicle count (AFC) data of the subject to calculate the predicted ovarian sensitivity of the subject, that is, the ratio value of the predicted number of oocytes retrieved (predicted NRO) to the initial dosage of the exogenous FSH drug of the subject. The system according to item 11. 13. Formula 2 is The predicted ovarian sensitivity of the subject, that is, predicted NRO / calculated by Formula 1 / initial dosage of exogenous FSH drug = EXP(g + h * age + i * basal FSH + j * LN[basal AMH] + k * basal AFC), where g is an arbitrary value selected from -3.167587 to -2.751518, preferably -2.959552. h is an arbitrary value selected from -0.025951 to -0.016355, preferably -0.021153. i is an arbitrary value selected from -0.048143 to -0.025727, preferably -0.036935. j is an arbitrary value selected from 0.5174476 to 0.6075545, preferably 0.5625011, k is an arbitrary value selected from 0.0241595 to 0.0365579, preferably 0.0303587, The system according to item 11 or 12. 14. Based on the predicted number of retrieved eggs (predicted NRO) calculated in the first calculation and the ratio value calculated in the second calculation, using Equation 3, calculate the initial dose of exogenous FSH drug to be administered to the subject. Equation 3 is Initial dose of exogenous FSH drug = Round(Predicted NRO calculated by Equation 1 / Predicted ovarian sensitivity calculated by Equation 2, 0) The system according to item 13. 15. The data collection module is used to obtain data on the age of the subject, basal anti-Müllerian hormone (AMH) level, basal antral follicle count (AFC), and dynamic change in inhibin B level (ΔINHB), The exogenous follicle-stimulating hormone (FSH) drug dose calculation module performs a first calculation on the above data obtained by the data collection module to calculate the predicted number of retrieved eggs (predicted NRO) of the subject in the ovulation induction cycle; performs a second calculation on the above data obtained by the data collection module to calculate the ratio of the predicted number of retrieved eggs (predicted NRO) of the subject in the ovulation induction cycle to the adjusted dose of exogenous FSH drug, that is, the predicted ovarian sensitivity; based on the predicted number of retrieved eggs (predicted NRO) calculated in the first calculation and the ratio value obtained in the second calculation, it is used to calculate the adjusted dose of exogenous FSH drug to be administered to the subject. The system according to any one of items 1 to 6. 16. In the exogenous FSH drug dosage calculation module, that is, based on the early dynamic change indicators and basic indicators of ovulation induction treatment, in the existing database, according to the age of patients who received ovulation induction treatment with a standard GnRH antagonist regimen, the basic anti-Müllerian hormone (AMH) level, the basic antral follicle count (AFC), the dynamic change of inhibin B level (ΔINHB), and the actual number of oocytes retrieved, formula 4 for calculating the predicted number of oocytes retrieved (predicted NRO) of the subjects fitted based on the data is pre-stored. The system according to item 15. 17. In the exogenous FSH drug dosage calculation module, formula 4 is a calculation formula 4 that fits the data of the age of patients who received ovulation induction treatment with a standard GnRH antagonist regimen, the basic anti-Müllerian hormone (AMH) level, the basic antral follicle count (AFC) data, the dynamic change of inhibin B level (ΔINHB), and the actual number of oocytes retrieved (result variable) in the existing database using the negative binomial distribution of the result variable. Formula 4 can calculate the predicted number of oocytes retrieved (predicted NRO) of the subject using the age data of the subject, the basic anti-Müllerian hormone (AMH) level data of the subject, the basic antral follicle count (AFC) data of the subject, and the dynamic change of inhibin B level (ΔINHB) data of the subject obtained by the data collection module. The system according to item 16. 18. Formula 4 is Predicted NRO = EXP(w + m * age * + n * LN[basic AMH] + o * LN[ΔINHB] + p * LN[basic AFC]), where w is an arbitrary value selected from -0.447201 to 0.9161863, preferably 0.2344927. m is an arbitrary value selected from -0.017165 to 0.0039328, preferably -0.006616. n is an arbitrary value selected from 0.1318094 to 0.3113979, preferably 0.2216036. o is an arbitrary value selected from 0.1901643 to 0.3850919, preferably 0.2876281, p is an arbitrary value selected from 0.0541966 to 0.2338079, preferably 0.1440023, The system according to item 17. 19. In the exogenous FSH drug dosage calculation module, among the existing databases, the age, basal anti-Müllerian hormone (AMH) level, basal antral follicle count (AFC), dynamic change of inhibin B level (ΔINHB), and the ratio of the predicted number of oocytes retrieved (predicted NRO) calculated by formula 4 to the average daily dosage of the exogenous FSH drug used by the patient are based on the data of the predicted ovarian sensitivity of the subject fitted according to the data of the predicted ovarian sensitivity of the subject, that is, the ratio value of the predicted number of oocytes retrieved (predicted NRO) to the adjusted dosage of the exogenous FSH drug is pre-stored with formula 5 for calculation, The average daily dosage of the exogenous FSH drug used by the patient refers to the ratio value of the total dosage of the exogenous FSH drug used by the patient during the past ovulation induction treatment period according to the standard GnRH antagonist regimen to the number of days of use of the exogenous FSH drug. The system according to item 18. 20. In the exogenous FSH drug dosage calculation module, formula 5 can calculate the predicted ovarian sensitivity of the subject, that is, the ratio value of the predicted number of oocytes retrieved (predicted NRO) to the adjusted dosage of the exogenous FSH drug of the subject, using the age data of the subject obtained by the data collection module, the basal anti-Müllerian hormone (AMH) level data of the subject, the basal antral follicle count (AFC) data of the subject, and the dynamic change of inhibin B level (ΔINHB) data of the subject. The system according to item 19. 21. Formula 5 is The predicted ovarian sensitivity of the subject, that is, predicted NRO / calculated by formula 4 / adjusted dosage of exogenous FSH drug = EXP(q + r * age * + s * LN[basal AMH] + t * basal AFC + u * LN[ΔINHB]), Wherein, q is an arbitrary value selected from -5.63461 to -5.108612, preferably -5.371611, r is an arbitrary value selected from -0.0264 to -0.015183, preferably -0.020792, s is an arbitrary value selected from 0.2696292 to 0.3684551, preferably 0.3190421. t is an arbitrary value selected from 0.0273504 to 0.0399372, preferably 0.0336438, u is an arbitrary value selected from 0.3327566 to 0.3940448, preferably 0.3634007, The system according to item 19 or 20. 22. Based on the predicted number of retrieved eggs (predicted NRO) calculated in the first calculation and the ratio value calculated in the second calculation, using Equation 6, calculate the adjusted dose of exogenous FSH drug to be administered to the subject, and Equation 6 is Adjusted dose of exogenous FSH drug = Round(predicted NRO calculated by Equation 4 / predicted ovarian sensitivity calculated by Equation 5, 0) The system according to item 21. 23. A method for predicting the dose of exogenous FSH drug to be administered to a subject during a controlled ovarian stimulation cycle, A data collection step of obtaining data on the subject's age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level or dynamic change in inhibin B level (ΔINHB), and basal antral follicle count (AFC), Perform a first calculation on the data obtained in the data collection step to calculate the predicted number of retrieved oocytes (predicted NRO) of the subject in the ovulation induction cycle; perform a second calculation on the data obtained by the data collection module to calculate the ratio of the predicted number of retrieved oocytes (predicted NRO) of the subject in the ovulation induction cycle to the exogenous FSH drug dosage, that is, the predicted ovarian sensitivity; based on the predicted number of retrieved oocytes (predicted NRO) calculated in the first calculation and the ratio value obtained in the second calculation, calculate the exogenous FSH drug dosage to be administered to the subject, an exogenous FSH drug dosage calculation step A method comprising. 24. The subject is a subject receiving standard ovulation induction treatment, and the number of retrieved oocytes (NRO) of the subject is the number of mature oocytes with a diameter of 10 mm or more, preferably 15 mm or more, obtained after the subject has received ovulation induction treatment and after hCG injection is performed to induce follicle maturation after the diameters of 1 to 2 dominant follicles have reached 18 mm or more during the ovarian stimulation process. The method according to item 23. 25. In the data collection step, the obtained basal anti-Müllerian hormone (AMH) level refers to the concentration of anti-Müllerian hormone in the venous blood of the subject at any time point during the menstrual period before ovulation induction treatment. The method according to item 23 or 24. 26. In the data collection step, the obtained basal follicle-stimulating hormone (FSH) level refers to the concentration of follicle-stimulating hormone (FSH) in the venous blood of a female subject on the 2nd to 4th days of menstruation before ovulation induction treatment. The method according to any one of items 23 to 25. 27. In the data collection step, the obtained basal antral follicle count (AFC) refers to the number of all follicles with a diameter of 2 to 10 mm in both ovaries of a female subject on the 2nd day of menstruation that can be seen by transvaginal B-ultrasound examination. The method according to any one of items 23 to 26. 28. In the data collection step, the obtained dynamic change in inhibin B level (ΔINHB) refers to the dynamic change in inhibin B level (ΔINHB) at the initial stage of ovulation induction treatment, preferably the difference between the serum inhibin B concentration on the 6th day of menstruation and the inhibin B concentration in venous blood on the 2nd day of menstruation in the ovulation induction treatment cycle of female subjects receiving a GnRH antagonist regimen. The method according to any one of items 23 to 27. 29. In the data collection step, data on the age of the subject, the level of basal anti-Müllerian hormone (AMH), the dynamic change in inhibin B level (ΔINHB), and the number of basal antral follicles (AFC) are obtained. In the exogenous follicle-stimulating hormone (FSH) drug dosage calculation step, a first calculation is performed on the above data obtained by the data collection module to calculate the predicted number of oocytes retrieved (predicted NRO) of the subject in the ovulation induction cycle; a second calculation is performed on the above data obtained by the data collection module to calculate the ratio of the predicted number of oocytes retrieved (predicted NRO) of the subject in the ovulation induction cycle to the adjusted dosage of the exogenous FSH drug, that is, the predicted ovarian sensitivity; based on the predicted number of oocytes retrieved (predicted NRO) calculated in the first calculation and the ratio value obtained in the second calculation, the adjusted dosage of the exogenous FSH drug to be administered to the subject is calculated. The method according to any one of items 23 to 28. 30. In the exogenous FSH drug dosage calculation step, in an existing database, formula 1 for calculating the predicted number of oocytes retrieved (predicted NRO) of a subject fitted based on data on the age, basal anti-Müllerian hormone (AMH) level, dynamic change in inhibin B level (ΔINHB), number of basal antral follicles (AFC), and actual number of oocytes retrieved of patients who received ovulation induction treatment with a standard GnRH antagonist regimen is pre-stored. The method according to item 29. 31. In the step of calculating the dosage of the exogenous FSH agent, Formula 1 is a calculation formula obtained by fitting, using the negative binomial distribution of the result variable, the data of the age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level, basal antral follicle count (AFC), and actual number of oocytes retrieved (result variable) of patients who received ovulation induction treatment with a standard GnRH antagonist regimen from an existing database. Formula 1 can calculate the predicted number of oocytes retrieved (predicted NRO) of the subject using the subject's age data, subject's basal anti-Müllerian hormone (AMH) level data, subject's basal follicle-stimulating hormone (FSH) level data, and subject's basal antral follicle count (AFC) data obtained in the data collection step. The method according to item 30. 32. Formula 1 is Predicted NRO = EXP(a + b * age + c * basal FSH + d * LN[basal AMH] + f * LN[basal AFC]), wherein a is an arbitrary value selected from 1.5576128 to 2.6037078, preferably 2.0806603; b is an arbitrary value selected from -0.019097 to 0.0044064, preferably -0.007345; c is an arbitrary value selected from -0.045234 to -0.004054, preferably -0.024644; d is an arbitrary value selected from 0.348168 to 0.4948875, preferably 0.4215277; f is an arbitrary value selected from 0.0415663 to 0.2566199, preferably 0.1490931. The method according to item 31. 33. In the step of calculating the dosage of the exogenous FSH agent, among the existing databases, the age of patients who received ovulation induction treatment with a standard GnRH antagonist regimen, the level of basic anti-Müllerian hormone (AMH), the level of basic follicle-stimulating hormone (FSH), the data of the number of basic antral follicles (AFC), and the ratio of the predicted number of oocytes retrieved (predicted NRO) calculated by Formula 1 to the average daily dosage of the exogenous FSH agent used by the patient. Based on this data, the predicted ovarian sensitivity of the subject fitted, that is, Formula 2 for calculating the ratio value of the predicted number of oocytes retrieved (predicted NRO) to the initial dosage of the exogenous FSH agent is pre-stored. The average daily dosage of the exogenous FSH agent used by the patient refers to the ratio value of the total dosage of the exogenous FSH agent used by the patient during the past ovulation induction treatment period with a standard GnRH antagonist regimen to the number of days of use of the exogenous FSH agent. The method according to item 32. 34. In the step of calculating the dosage of the exogenous FSH agent, Formula 2 can use the age data of the subject obtained by the data collection module, the basic anti-Müllerian hormone (AMH) level data of the subject, the basic follicle-stimulating hormone (FSH) level data of the subject, and the basic antral follicle count (AFC) data of the subject to calculate the predicted ovarian sensitivity of the subject, that is, the ratio value of the predicted number of oocytes retrieved (predicted NRO) to the initial dosage of the exogenous FSH agent of the subject. The method according to item 33. 35. Formula 2 is The predicted ovarian sensitivity of the subject, that is, predicted NRO / calculated by Formula 1 / initial dosage of the exogenous FSH agent = EXP(g + h * age * + i * basic FSH + j * LN[basic AMH] + k * basic AFC), In the formula, g is an arbitrary value selected from -3.167587 to -2.751518, preferably -2.959552. h is an arbitrary value selected from -0.025951 to -0.016355, preferably -0.021153. i is an arbitrary value selected from -0.048143 to -0.025727, preferably -0.036935. j is an arbitrary value selected from 0.5174476 to 0.6075545, preferably 0.5625011, k is an arbitrary value selected from 0.0241595 to 0.0365579, preferably 0.0303587, The method according to item 33 or 34. 36. Based on the predicted number of retrieved eggs (predicted NRO) calculated in the first calculation and the ratio value calculated in the second calculation, using Equation 3, calculate the initial dose of exogenous FSH drug to be administered to the subject. Equation 3 is Initial dose of exogenous FSH drug = Rounding (predicted NROs calculated by Equation 1 / predicted ovarian sensitivity calculated by Equation 2, 0) The method according to item 35. 37. In the data collection step, obtain data on the age of the subject, basal anti-Müllerian hormone (AMH) level, basal antral follicle count (AFC), and dynamic change in inhibin B level (ΔINHB). In the exogenous FSH drug dose calculation step, perform a first calculation on the above data obtained by the data collection module to calculate the predicted number of retrieved eggs (predicted NRO) of the subject in the ovulation induction cycle; perform a second calculation on the above data obtained by the data collection module to calculate the ratio of the predicted number of retrieved eggs (predicted NRO) of the subject in the ovulation induction cycle to the adjusted dose of exogenous FSH drug, that is, the predicted ovarian sensitivity; based on the predicted number of retrieved eggs (predicted NRO) calculated in the first calculation and the ratio value obtained in the second calculation, calculate the adjusted dose of exogenous FSH drug to be administered to the subject. The method according to any one of items 23 to 28. 38. In the exogenous FSH drug dose calculation step, in the existing database, Equation 4 for calculating the predicted number of retrieved eggs (predicted NRO) of the subject fitted based on the data of the age, basal anti-Müllerian hormone (AMH) level, basal antral follicle count (AFC), dynamic change in inhibin B level (ΔINHB), and actual number of retrieved eggs of patients who received ovulation induction treatment with a standard GnRH antagonist regimen is pre-stored. The method according to item 37. 39. In the exogenous FSH dosage calculation step, formula 4 is a calculation formula 4 obtained by fitting, in an existing database, data on the age, basal anti-Müllerian hormone (AMH) level, basal antral follicle count (AFC) data, dynamic change in inhibin B level (ΔINHB), and actual number of oocytes retrieved (result variable) of patients who received ovulation induction treatment with a standard GnRH antagonist regimen, using the negative binomial distribution of the result variable. Formula 4 can calculate the predicted number of oocytes retrieved (predicted NRO) of the subject using the subject's age data, subject's basal anti-Müllerian hormone (AMH) level data, subject's basal antral follicle count (AFC) data, and subject's dynamic change in inhibin B level (ΔINHB) data obtained by the data collection module. The method according to item 38. 40. Formula 4 is Predicted NRO = EXP(w + m * age + n * LN[basal AMH] + o * LN[ΔINHB] + p * LN[basal AFC]), where w is an arbitrary value selected from -0.447201 to 0.9161863, preferably 0.2344927. m is an arbitrary value selected from -0.017165 to 0.0039328, preferably -0.006616. n is an arbitrary value selected from 0.1318094 to 0.3113979, preferably 0.2216036. o is an arbitrary value selected from 0.1901643 to 0.3850919, preferably 0.2876281. p is an arbitrary value selected from 0.0541966 to 0.2338079, preferably 0.1440023. The method according to item 39. 41. In the exogenous FSH drug dosage calculation step, in the existing database, based on the data of the ratio of the age, basal anti-Müllerian hormone (AMH) level, basal antral follicle count (AFC), dynamic change of inhibin B level (ΔINHB), and predicted number of retrieved oocytes (predicted NRO) calculated by Equation 4 to the average daily dosage of the exogenous FSH drug used by the patient among patients who received ovulation induction treatment with a standard GnRH antagonist regimen, that is, a formula 5 for calculating the ratio value of the predicted oocyte sensitivity of the subject, i.e., the predicted number of retrieved oocytes (predicted NRO) to the adjusted dosage of the exogenous FSH drug, is pre-stored. The average daily dosage of the exogenous FSH drug used by the patient refers to the ratio value of the total dosage of the exogenous FSH drug used by the patient during the past ovulation induction treatment period with a standard GnRH antagonist regimen to the number of days of use of the exogenous FSH drug. The method according to item 40. 42. In the exogenous FSH drug dosage calculation step, in Formula 5, the predicted oocyte sensitivity of the subject, that is, the ratio value of the predicted number of retrieved oocytes (predicted NRO) to the adjusted dosage of the exogenous FSH drug of the subject, can be calculated using the age data of the subject, the basal anti-Müllerian hormone (AMH) level data of the subject, the basal antral follicle count (AFC) data of the subject, and the dynamic change of inhibin B level (ΔINHB) data of the subject obtained by the data collection module. The method according to item 41. 43. Formula 5 is The predicted oocyte sensitivity of the subject, that is, predicted NRO / calculated by Equation 4 / adjusted dosage of exogenous FSH drug = EXP(q + r * age + s * LN[basal AMH] + t * basal AFC + u * LN[ΔINHB]), where q is an arbitrary value selected from -5.63461 to -5.108612, preferably -5.371611. r is an arbitrary value selected from -0.0264 to -0.015183, preferably -0.020792. s is an arbitrary value selected from 0.2696292 to 0.3684551, preferably 0.3190421. t is an arbitrary value selected from 0.0273504 to 0.0399372, preferably 0.0336438, u is an arbitrary value selected from 0.3327566 to 0.3940448, preferably 0.3634007, The method according to item 41 or 42. 44. Based on the number of oocytes retrieved (predicted NRO) calculated in the first calculation and the ratio value calculated in the second calculation, using Equation 6, calculate the adjusted dose of exogenous FSH drug to be administered to the subject, and Equation 6 is Adjusted dose of exogenous FSH drug = Rounding (predicted NROs calculated by Equation 4 / predicted ovarian sensitivity calculated by Equation 5, 0) The method according to item 43. [Advantages of the Invention]

[0009] The system or method of the present application first establishes a model for predicting the number of mature oocytes that a subject will obtain during an ovulation induction cycle based on several basic indicators, and then establishes a model for predicting ovarian sensitivity. As a result, the only unknown variable in the result variable of ovarian sensitivity is the dose of the exogenous FSH drug. In this case, the dose is predictable, and the R of this model 2 is greater than 0.9, which means that the algorithm of the present application can explain more than 90% of ovarian sensitivity. As far as is known, this is the best model for predicting ovarian sensitivity in the world. The use of this algorithm may change the clinical routine of COS in the near future, thereby helping to improve pregnancy outcomes, reduce the incidence of OHSS, reduce costs during the COS period, significantly improve the treatment effect of ART, especially improve the uniformity of treatment by ART physicians, and accelerate the learning curve of physicians. The method or system of the present application can predict the initial dose and adjusted dose based on basic indicators. The method or system according to the present application can be used to guide the initial dose and adjusted dose of exogenous FSH used by an individual during ovulation induction.

Brief Description of the Drawings

[0010] Various other advantages and merits of the present application will become apparent to those skilled in the art upon reading the following detailed description of the preferred embodiments. The drawings of the specification are for the sole purpose of illustrating the preferred embodiments and are not to be construed as limiting the present application. Obviously, the drawings described below are only some embodiments of the present application, and those skilled in the art can obtain other drawings based on these drawings without creative efforts. Also, throughout all the drawings, the same parts are denoted by the same reference numerals.

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Mode for Carrying Out the Invention

[0011] [Details of the Invention] For specific embodiments of the present application, the following will be described in more detail with reference to the accompanying drawings. Although specific embodiments of the present application are shown in the drawings, it should be understood that the present application can be embodied in various forms and should not be limited to the embodiments described herein. Rather, these embodiments are provided to provide a complete understanding of the present application and to fully convey the scope of the present application to those skilled in the art.

[0012] Since the terms "comprising" or "including" referred to throughout the specification and claims are open terms, they should be construed as "including but not limited to". The following description is a preferred embodiment for carrying out the present application, but these descriptions are for the purpose of the general principles of the specification and do not limit the scope of the present application. The protection scope of the present application shall be determined by the appended claims.

[0013] Type of variable: In statistics, the type of variable can be classified into two types: quantitative variables and qualitative variables (also called categorical variables).

[0014] Quantitative variables are variables used to describe the quantity or number of things and can be classified into continuous and discrete types. A continuous variable refers to a variable that can take any value within a certain interval, and its value is continuous and can include decimals. For example, blood pressure values, blood glucose levels, height, weight, chest circumference in human measurements, etc. are continuous variables, and their values can only be obtained by measurement or metering methods. A discrete variable is a variable whose value can only be in natural numbers or integer units. For example, pain scores, the number of metastatic lesions, the number of eggs retrieved, etc. can only be positive numbers without decimals, and the values of such variables are usually obtained by counting methods.

[0015] The type of a variable is not static and can be converted between different types of variables according to the needs of the research purpose. For example, the amount of hemoglobin (g / L) is originally a numerical variable. When hemoglobin is classified into two categories: normal and low, the data can be analyzed according to binary classification. However, if it is divided into five levels: severe anemia, moderate anemia, mild anemia, normal, and increased hemoglobin, the data can be analyzed according to the levels. Categorical data can sometimes be quantified. For example, when a patient's nausea reaction can be expressed as 0, 1, 2, or 3, the data (quantitative data) can be analyzed as a numerical variable.

[0016] The outcome variable is also called the resultant variable, abbreviated as outcome, and refers to the result event expected to occur during the follow-up observation, that is, the event that the researcher wants to track and observe.

[0017] The explanatory variable refers to the factor or condition that changes the outcome variable through the active operation of the researcher. Therefore, the explanatory variable is regarded as the cause of the outcome variable.

[0018] The Poisson distribution is a discrete probability distribution commonly seen in statistics and probability. The Poisson distribution is suitable for describing the number of random events occurring within a unit of time (or space). For example, the number of diseases appearing in a certain space-time, the number of recurrences of a certain disease, the number of metastatic sites of a certain tumor focus, the number of vomiting episodes of a certain patient, etc. can be cited.

[0019] The negative binomial distribution is a discrete probability distribution in statistics. Those that satisfy the following conditions are called negative binomial distributions. The experiment includes a series of independent experiments, each experiment has two results: success and failure, the probability of success is constant, the experiment continues until r successes occur, and r is a positive integer. The negative binomial distribution is similar to the Poisson distribution and can also be used to describe the relative frequency of rare events in a certain unit of time and space. The difference from the Poisson distribution is that the Poisson distribution can only be used to describe independent events, while the negative binomial distribution is often used to explain clustered events such as the distribution of snails in the soil and the distribution of a certain infectious disease. Usually, when it is found that the mean value of the count data is larger than the variance, the Poisson distribution often does not have a good fitting effect, and the negative binomial distribution can be considered.

[0020] The normal distribution is a probability distribution in statistics and is the distribution of a continuous random variable with two parameters μ and σ2. The first parameter μ is the mean value of the random variable following the normal distribution, and the second parameter σ2 is the variance of this random variable. Therefore, the normal distribution is recorded as N(μ,σ2). The probability rule of the random variable following the normal distribution is that the probability of taking a value close to μ is high, and the probability of taking a value far from μ is small. The smaller the value, the more concentrated the distribution is around μ, and the larger the value, the more dispersed the distribution is. The characteristics of the probability density function of the normal distribution are symmetric with respect to μ, taking the maximum value at μ, having a value of 0 at positive (negative) infinity, and having inflection points at μ±. The shape is high in the center and low on both sides, and as an image, it is a bell-shaped curve above the x-axis. When μ = 0 and σ2 = 1, it is called the standard normal distribution and is recorded as N(0,1).

[0021] In this specification, anti-Müllerian hormone (AMH) is a hormone secreted by the granulosa cells of small ovarian follicles. Female babies start producing AMH during the fetal period, and the more small follicles there are in the ovaries, the higher the AMH concentration. Conversely, as follicles are gradually consumed due to aging and various factors, the AMH concentration gradually decreases, and the AMH concentration tends to reach 0 as menopause approaches.

[0022] In this specification, follicle-stimulating hormone (FSH) refers to a hormone secreted by the basophilic cells of the anterior pituitary gland. Its component is a glycoprotein, and its main function is to promote the maturation of follicles. FSH promotes the proliferation and differentiation of follicular granulosa cells and promotes the growth of the entire ovary. Its effect on the seminiferous tubules of the testis can promote spermatogenesis. FSH is secreted in pulses in the human body and varies according to the menstrual cycle in women. Measuring FSH in serum is extremely important for diagnosing and treating infertility, such as understanding the endocrine function of the pituitary gland, indirectly grasping the functional state of the ovaries, evaluating ovarian reserve and ovarian responsiveness, and determining the dosage of ovulation induction agents.

[0023] Recently, serum inhibin B levels have been considered as a marker for follicular development. Inhibin B is involved in follicle selection during the normal menstrual cycle through endocrine and paracrine effects, and promotes follicular growth. One of the functions of inhibin B is to down-regulate FSH secretion in the mid-follicular phase of the natural menstrual cycle. It also exerts a paracrine effect, stimulating theca cells to produce androgen and LH. The secretion of inhibin B reaches its peak in the initial stage of the follicle, and the follicle diameter is 10 - 12 mm. Inhibin B on the 5th day (early follicular phase) has been shown to be an excellent marker for poor ovarian response and live birth compared to the basal marker. Inhibin B is mainly produced by FSH-sensitive follicles, and exogenous FSH administration increases inhibin B in growing follicles. Consistent with this, the inventor of the present application discovered that the dynamic change of inhibin B (ΔINHB), that is, the difference in inhibin B concentration between the 6th and 2nd days of the menstrual cycle during ovulation induction, is the best marker for predicting the adjusted dose of FSH drugs.

[0024] Luteinizing hormone (LH) is a glycoprotein gonadotropin secreted by adenohypophysis cells, which can promote the conversion of cholesterol to sex hormones in gonadal cells. In women, in combination with follicle-stimulating hormone (FSH), it promotes follicle maturation, estrogen secretion, ovulation, corpus luteum formation and maintenance, and progesterone and estrogen secretion. In men, luteinizing hormone promotes the synthesis and release of testosterone from testicular Leydig cells. The LH level refers to the LH concentration in a venous serum sample collected from female subjects on the 2nd to 4th days after menstruation.

[0025] The basal E2 level refers to the level of estradiol, a steroid estrogen. There are two types, α-type and β-type, and the α-type has strong physiological effects. Due to its strong sex hormone action, it or its ester is considered to be the most important sex hormone actually secreted from the ovary. The basal estradiol level detected in this application is the estradiol concentration in a venous serum sample from female subjects on the 2nd to 4th days of menstruation.

[0026] BMI is an important criterion commonly used internationally to determine human obesity and health status, and is mainly used in statistical analysis. Obesity cannot be judged by the absolute value of body weight, and body weight is naturally related to height. Therefore, BMI obtains a relatively objective parameter through two values of human body weight and height, and uses the range of this parameter to evaluate the physical quality. BMI = body weight / square of height (international unit kg / m 2 ).

[0027] In this specification, the antral follicle count (AFC) refers to the number of all visible follicles with a diameter of 2-10 mm in both ovaries on the 2nd to 4th day of menstruation. The AFC can measure and count follicles by ultrasound.

[0028] Ovarian sensitivity is the ratio of the number of mature oocytes (NRO) obtained to the dose of exogenous FSH drug.

[0029] In order to solve the problem of the lack of individual guidance when predicting the dosage of exogenous FSH drugs in the prior art, the present application provides a system for predicting the dosage of exogenous follicle-stimulating hormone (FSH) drugs used during a controlled ovarian stimulation cycle when a subject undergoes ovulation induction treatment with a standard GnRH antagonist regimen. This system includes a data collection module for obtaining data on the subject's age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level or dynamic change in inhibin B level (ΔINHB), and basal antral follicle count (AFC), and a first calculation is performed on the above data obtained by the data collection module to calculate the predicted number of oocytes retrieved (predicted NRO) of the subject in the ovulation induction cycle; a second calculation is performed on the above data obtained by the data collection module to calculate the ratio of the predicted number of oocytes retrieved (predicted NRO) of the subject in the ovulation induction cycle to the dosage of exogenous FSH drug administered to the subject in the ovulation induction cycle, that is, the predicted ovarian sensitivity; and an exogenous follicle-stimulating hormone (FSH) drug dosage calculation module for calculating the dosage of exogenous FSH drug to be administered to the subject based on the predicted number of oocytes retrieved (predicted NRO) calculated in the first calculation and the ratio value.

[0030] The system of the present application first establishes a model for predicting the number of mature oocytes obtained by a subject during an ovulation induction cycle based on several basic indicators, and then establishes a model for predicting ovarian sensitivity. As a result, the only unknown variable in the result variable of ovarian sensitivity is the dosage of exogenous FSH drug. Thus, the dosage of exogenous FSH drug is predictable, and the model R 2 is greater than 0.9 and is much superior to the model of Lar Marca et al., and is an optimized version of the existing technical model. The system of the present application is expected to help improve pregnancy outcomes, reduce the incidence of OHSS, and reduce costs during the COS period, and significantly improve the treatment effect of ART.

[0031] The subjects described in this application are subjects who receive ovulation induction treatment with a standard GnRH antagonist regimen. The number of retrieved oocytes (NRO) of the subjects is the number of mature oocytes with a diameter of 10 mm or more, preferably 15 mm or more, obtained after the subjects receive ovulation induction treatment and after hCG injection is performed to induce follicle maturation after the diameters of 1 to 2 dominant follicles reach 18 mm or more during the ovarian stimulation process.

[0032] Among them, in a specific embodiment, the standard GnRH antagonist ovarian stimulation protocol described in this application is carried out as follows: Exogenous FSH (human recombinant FSH, abbreviated as human rFSH) (for example, Gonal-F alfa [Merck Serono, Germany], Puregon beta [MSD, USA], Urofollitropin [Livzon Pharmaceutical Group Inc., China], or Menotrophins [Livzon Pharmaceutical] Group Inc., China]) is administered starting from the second day of the menstrual cycle. The starting dose of human rFSH is selected based on age, basal AMH level, basal FSH level, basal AFC level, and BMI, etc. The rFSH dose is further adjusted based on the size and number of growing follicles observed by ultrasound and the monitoring of serum E2 levels during the ovarian stimulation period. When the diameter of the developing follicles reaches 10 - 12 mm, treatment with a GnRH antagonist is initiated. When it is observed by ultrasound that at least two dominant follicles exceed a diameter of 18 mm, hCG (chorionic gonadotropin alfa, Merck Serono) is injected at a dose of 5000 - 10000 IU to induce the final maturation of the oocytes. The recovery of oocytes is performed 36 - 38 hours after hCG administration. One to two embryos are transferred or the embryos are cryopreserved. Next, the subjects are provided with luteal phase progesterone support (progesterone vaginal gel, Merck Serono).

[0033] In certain embodiments of the present application, the subject of the system and method according to the present application is a subject who has received ovulation induction treatment with the above standard GnRH antagonist regimen.

[0034] Those skilled in the art know that there are many factors that generally affect the number of oocytes collected from a subject, such as the BMI index, infertility duration, number of previous in vitro fertilization / intracytoplasmic sperm injection-embryo transfer (IVF / ICSI-ET) attempts, serum basal E2 level, FSH level and LH level, serum AMH level, left and right ovarian AFC, the first, second, third, fourth, and fifth causes of infertility, traditional or mild ovarian stimulation cycles, ovarian stimulation type / COS regimen, starting dose and total dose of rFSH, rFSH treatment duration (days), name of rFSH, endometrial thickness on the day of human chorionic gonadotropin (hCG) induction, etc. In the present application, after the inventors of the present application screened various indicators, they finally confirmed four important parameters: the age of the subject, the basal anti-Müllerian hormone (AMH) level, the basal follicle-stimulating hormone (FSH) level, and the basal antral follicle count (AFC), and calculated the NRO of the subject.

[0035] In this specification, there is no limitation on the data collection module as long as it can be used to obtain data on the age of the subject, the dynamic change (ΔINHB) in the level of basic anti-Müllerian hormone (AMH), the level of basic follicle-stimulating hormone (FSH), or inhibin B level, and the level of basic antral follicle count (AFC). Specifically, the basic anti-Müllerian hormone (AMH) level obtained by the data collection module refers to the concentration of anti-Müllerian hormone in the venous blood of a female subject at any point during the menstrual period; the basic follicle-stimulating hormone (FSH) level obtained by the data collection module refers to the follicle-stimulating hormone concentration in the venous blood of a female subject on the second day of menstruation; the basic antral follicle count (AFC) obtained by the data collection module refers to the number of all follicles with a diameter of 2-10 mm in both ovaries of a female subject on the second day of menstruation that can be seen by transvaginal B-ultrasound examination; the dynamic change (ΔINHB) in the inhibin B level obtained by the data collection module refers to the dynamic change (ΔINHB) in the inhibin B level at the initial stage of ovulation induction treatment, preferably the difference between the serum inhibin B concentration on the sixth day of menstruation and the inhibin B concentration in the venous blood on the second day of menstruation in the ovulation induction treatment cycle of a female subject receiving a GnRH antagonist regimen. By a subject who needs to predict the number of oocytes obtained during ovarian stimulation, the number of eggs retrieved can be predicted based on the system of the present application using the data within the above-mentioned predetermined period.

[0036] In this specification, using the exogenous follicle-stimulating hormone dosage calculation module, the first calculation and the second calculation are performed on the above data obtained by the data collection module, thereby calculating the ratio between the predicted number of eggs retrieved (predicted NRO) of the subject obtained in the ovulation induction cycle and the dosage of the exogenous FSH drug administered to the subject in the ovulation induction cycle. The system of the present application can predict the recommended initial dosage and adjusted dosage of the exogenous FSH drug administered to the subject during the controlled ovarian stimulation cycle.

[0037] In the above system, the brand of the exogenous follicle-stimulating hormone agent is not limited. For example, Gonal-F, Puregon, urofolitropin for injection, HMG, etc. may be mentioned, and the brand of FSH does not affect the accuracy of predicting the initial dose and adjusted dose by the system.

[0038] In a specific embodiment, the system of the present application is a system for predicting the initial dose of an exogenous follicle-stimulating hormone (FSH) agent administered to a subject during a controlled ovarian stimulation cycle, wherein the data collection module is used to obtain data on the subject's age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level, and basal antral follicle count (AFC). The exogenous FSH agent dose calculation module performs a first calculation on the above data obtained by the data collection module to calculate the predicted number of oocytes retrieved (predicted NRO) of the subject in the ovulation induction cycle; performs a second calculation on the above data obtained by the data collection module to calculate the ratio of the predicted number of oocytes retrieved (predicted NRO) of the subject in the ovulation induction cycle to the initial dose of the exogenous FSH agent, that is, the predicted ovarian sensitivity; and is used to calculate the initial dose of the exogenous FSH agent to be administered to the subject based on the predicted number of oocytes retrieved (predicted NRO) calculated in the first calculation and the ratio value obtained in the second calculation.

[0039] First, it should be understood that in this module, in the existing database, there are pre-stored data on the age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level, basal antral follicle count (AFC), and the number of actually detected and collected oocytes (actual number of oocytes retrieved) of patients who received ovulation induction treatment with a standard GnRH antagonist regimen, as well as a formula 1 for calculating the predicted number of oocytes retrieved (predicted NRO) of the subject fitted based on the pre-stored patient data and the negative binomial distribution. Using the pre-stored formula 1, calculations can be performed for any subject to predict the number of mature oocytes retrieved (NRO) from that subject, that is, the predicted number of oocytes retrieved (predicted NRO) can be obtained.

[0040] Furthermore, it should be understood that this module pre-stores data in an existing database on the age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level, basal antral follicle count (AFC), and the ratio of the predicted number of retrieved oocytes (predicted NRO) calculated by Formula 1 to the average daily dose of exogenous FSH drug used by the patient among patients who received ovulation induction treatment with a standard GnRH antagonist regimen, as well as the predicted ovarian sensitivity of the subjects fitted based on these data, that is, Formula 2 for calculating the ratio value of the predicted number of retrieved oocytes (predicted NRO) of the subject to the initial dose of exogenous FSH drug of the subject. Calculations can be performed for any subject using the pre-stored Formula 2.

[0041] In the present application, the average daily dose of the exogenous follicle-stimulating hormone drug used by the patient refers to the ratio value of the total dose of the exogenous FSH drug used by the patient during the period of receiving ovulation induction treatment with a standard GnRH antagonist regimen to the number of days of use of the exogenous FSH drug.

[0042] Specifically, this pre-stored Formula 1 is fitted based on data of the age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level, basal antral follicle count (AFC), and the actually detected number of collected oocytes among patients who received ovulation induction treatment with a standard GnRH antagonist regimen in an existing database. This pre-stored Formula 2 is fitted based on data of the age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level, basal antral follicle count (AFC), and the ratio of the predicted number of retrieved oocytes (predicted NRO) calculated by Formula 1 to the average daily dose of exogenous FSH drug used by the patient among patients who received ovulation induction treatment with a standard GnRH antagonist regimen pre-stored in an existing database.

[0043] When calculating, this pre-stored formula 1 is a formula for calculating the predicted number of retrieved oocytes (predicted NRO) of the subject using the age data of the subject, the basic anti-Müllerian hormone (AMH) level data of the subject, the basic follicle-stimulating hormone (FSH) level data of the subject, and the basic antral follicle count (AFC) data of the subject obtained by the data collection module. This pre-stored formula 2 is a formula for calculating the ratio of the predicted number of retrieved oocytes (predicted NRO) of the subject to the initial dose of exogenous FSH drug administered to the subject using the age data of the subject, the basic anti-Müllerian hormone (AMH) level data of the subject, the basic follicle-stimulating hormone (FSH) level data of the subject, and the basic antral follicle count (AFC) data obtained by the data collection module.

[0044] Furthermore, the inventor of the present application constructed a specific formula 1 for predicting NRO. Predicted NRO = EXP(a + b * age + c * basic FSH + d * LN[basic AMH] + f * LN[basic AFC]); Furthermore, in the formula 1, a is an arbitrary value selected from 1.5576128 to 2.6037078, preferably 2.0806603, b is an arbitrary value selected from -0.019097 to 0.0044064, preferably -0.007345, c is an arbitrary value selected from -0.045234 to -0.004054, preferably -0.024644, d is an arbitrary value selected from 0.348168 to 0.4948875, preferably 0.4215277, f is an arbitrary value selected from 0.0415663 to 0.2566199, preferably 0.1490931.

[0045] Based on formula 1, the inventor of the present application constructed a formula 2 for predicting the initial dose of exogenous FSH drug. The predicted ovarian sensitivity of the subject, that is, the initial dose of the predicted NRO / exogenous FSH agent calculated by the above formula 1 = EXP(g + h * age + i * basal FSH + j * LN[basal AMH] + k * basal AFC); Furthermore, in the above formula 2, g is an arbitrary value selected from -3.167587 to -2.751518, preferably -2.959552, h is an arbitrary value selected from -0.025951 to -0.016355, preferably -0.021153, i is an arbitrary value selected from -0.048143 to -0.025727, preferably -0.036935, j is an arbitrary value selected from 0.5174476 to 0.6075545, preferably 0.5625011, k is an arbitrary value selected from 0.0241595 to 0.0365579, preferably 0.0303587.

[0046] In the above system, when the predicted NRO calculated by formula 1 is divided by the ratio value calculated by formula 2, the initial dose of the exogenous FSH agent administered to the subject can be calculated.

[0047] In the above system, the initial dose of the exogenous FSH agent administered to the subject can be calculated by formula 3. Formula 3 is Initial dose of exogenous FSH agent = Round (predicted NROs calculated by formula 1 / predicted ovarian sensitivity calculated by formula 2, 0).

[0048] In a specific embodiment, the system of the present application is a system for predicting an adjusted dose of exogenous FSH agent administered to a subject during a controlled ovarian stimulation cycle, where the data collection module is used to obtain data on the subject's age, basal anti-Müllerian hormone (AMH) level, basal antral follicle count (AFC), and dynamic change in inhibin B level (ΔINHB), and the exogenous FSH agent dose calculation module performs a first calculation on the above data obtained by the data collection module to calculate the predicted number of retrieved oocytes (predicted NRO) of the subject in the ovulation induction cycle; performs a second calculation on the above data obtained by the data collection module to calculate the ratio of the predicted number of retrieved oocytes (predicted NRO) of the subject in the ovulation induction cycle to the adjusted dose of the exogenous FSH agent, i.e., the predicted ovarian sensitivity; and is used to calculate the adjusted dose of the exogenous FSH agent to be administered to the subject based on the predicted number of retrieved oocytes (predicted NRO) calculated in the first calculation and the ratio value obtained in the second calculation.

[0049] First, it should be understood that in this module, among the existing databases, there are stored in advance data on the age, basal anti-Müllerian hormone (AMH) level, dynamic change in inhibin B level (ΔINHB), basal antral follicle count (AFC), and actual number of retrieved oocytes of patients who received ovulation induction treatment with a standard GnRH antagonist regimen, as well as formula 4 for calculating the predicted number of retrieved oocytes (predicted NRO) of the subject, which is fitted based on the pre-stored patient data and the negative binomial distribution. Using the pre-stored formula 4, calculations can be performed for any subject to obtain the predicted number of retrieved oocytes (predicted NRO).

[0050] Furthermore, it should be understood that this module pre-stores data on the age, basal anti-Müllerian hormone (AMH) level, dynamic change in inhibin B level (ΔINHB), basal antral follicle count (AFC), and the ratio of the predicted number of retrieved oocytes (predicted NRO) calculated by Equation 4 to the average daily dose of exogenous FSH agent used by the patient among patients who received ovulation induction treatment with a standard GnRH antagonist regimen in an existing database, as well as Equation 5 for calculating the predicted ovarian sensitivity of a subject, that is, the ratio value of the predicted number of retrieved oocytes (predicted NRO) of the subject to the adjusted dose of exogenous FSH agent of the subject, which is fitted based on these data. Calculations can be performed for any subject using the pre-stored Equation 5.

[0051] In this application, the average daily dose of the exogenous follicle-stimulating hormone agent used by the patient refers to the ratio value of the total dose of the exogenous FSH agent used by the patient during the period of receiving ovulation induction treatment with a standard GnRH antagonist regimen to the number of days of use of the exogenous FSH agent.

[0052] Specifically, this pre-stored Equation 4 is fitted based on the age, basal anti-Müllerian hormone (AMH) level, dynamic change in inhibin B level (ΔINHB), basal antral follicle count (AFC) data, and actual number of retrieved oocytes data of patients who received ovulation induction treatment with a standard GnRH antagonist regimen in an existing database. This pre-stored Equation 5 is fitted based on the age, basal anti-Müllerian hormone (AMH) level, dynamic change in inhibin B level (ΔINHB), basal antral follicle count (AFC), and the ratio data of the predicted number of retrieved oocytes (predicted NRO) calculated by Equation 4 to the average daily dose of the exogenous FSH agent used by the patient among patients who received ovulation induction treatment with a standard GnRH antagonist regimen pre-stored in an existing database.

[0053] When calculating, this pre-stored formula 4 is a formula for calculating the predicted number of retrieved oocytes (predicted NRO) of the subject using the age data of the subject acquired by the data collection module, the basic anti-Müllerian hormone (AMH) level data of the subject, the dynamic change (ΔINHB) data of the inhibin B level of the subject, and the basic antral follicle count (AFC) data of the subject. This pre-stored formula 5 is a formula for calculating the ratio of the predicted number of retrieved oocytes (predicted NRO) of the subject to the adjusted dose of exogenous FSH drug administered to the subject using the age data of the subject acquired by the data collection module, the basic anti-Müllerian hormone (AMH) level data of the subject, the dynamic change (ΔINHB) data of the inhibin B level of the subject, and the basic antral follicle count (AFC) data of the subject.

[0054] Furthermore, the inventors of the present application constructed a specific formula 4 for predicting NRO. Predicted NRO = EXP(w + m * age * + n * LN[basic AMH] + o * LN[ΔINHB] + p * LN[basic AFC]); Furthermore, in the formula 4, w is an arbitrary value selected from -0.447201 to 0.9161863, preferably 0.2344927, m is an arbitrary value selected from -0.017165 to 0.0039328, preferably -0.006616, n is an arbitrary value selected from 0.1318094 to 0.3113979, preferably 0.2216036, o is an arbitrary value selected from 0.1901643 to 0.3850919, preferably 0.2876281, p is an arbitrary value selected from 0.0541966 to 0.2338079, preferably 0.1440023.

[0055] The inventors of the present application constructed a formula 5 for predicting the adjusted dose of exogenous FSH drug based on formula 4. The predicted ovarian sensitivity of the subject, that is, the adjusted dose of the predicted NRO / exogenous FSH agent calculated by the above formula 4 = EXP(q + r * age + s * LN[basal AMH] + t * basal AFC + u * LN[ΔINHB]); Furthermore, in the above formula 5, q is an arbitrary value selected from -5.63461 to -5.108612, preferably -5.371611, r is an arbitrary value selected from -0.0264 to -0.015183, preferably -0.020792, s is an arbitrary value selected from 0.2696292 to 0.3684551, preferably 0.3190421. t is an arbitrary value selected from 0.0273504 to 0.0399372, preferably 0.0336438, u is an arbitrary value selected from 0.3327566 to 0.3940448, preferably 0.3634007.

[0056] In the above system, when the predicted NRO calculated by formula 4 is divided by the ratio value calculated by formula 5, the adjusted dose of the exogenous FSH agent administered to the subject can be calculated.

[0057] In the above system, the adjusted dose of the exogenous FSH agent administered to the subject can be calculated by formula 6. Formula 6 is Adjusted dose of exogenous FSH agent = Round(The predicted NROs calculated by formula 4 / The predicted ovarian sensitivity calculated by formula 5, 0).

[0058] In order to solve the problem that there is a lack of individual guidance when predicting the dose of the exogenous FSH agent in the prior art, the present application also provides a method for predicting the dose of the exogenous follicle-stimulating hormone agent administered to a subject during a controlled ovarian stimulation cycle. This method includes A data collection step of obtaining data on the age of the subject, the basal anti-Müllerian hormone (AMH) level, the dynamic change (ΔINHB) of the basal follicle-stimulating hormone (FSH) level or inhibin B level, and the basal antral follicle count (AFC), Performing a first calculation on the above data obtained in the data collection step to calculate the predicted number of retrieved oocytes (predicted NRO) of the subject in the ovulation induction cycle; performing a second calculation on the above data obtained by the data collection module to calculate the ratio of the predicted number of retrieved oocytes (predicted NRO) of the subject in the ovulation induction cycle to the initial dose of exogenous FSH agent administered to the subject in the ovulation induction cycle, that is, the predicted ovarian sensitivity; and calculating the dose of exogenous follicle-stimulating hormone for calculating the dose of exogenous FSH agent to be administered to the subject based on the predicted number of retrieved oocytes (predicted NRO) calculated in the first calculation and the ratio.

[0059] In the above method, the subject is a subject undergoing ovulation induction treatment with a standard GnRH antagonist regimen, and the number of mature oocytes of the subject is the number of mature oocytes with a diameter of 10 mm or more, preferably 15 mm or more, obtained after the subject has received ovulation induction treatment, after hCG injection is performed to induce follicle maturation after the diameters of 1 to 2 dominant follicles reach 18 mm or more during the ovarian stimulation process.

[0060] In the above method, in the data collection step, the obtained basal anti-Müllerian hormone (AMH) level refers to the concentration of anti-Müllerian hormone in the venous blood of the subject at any time during the menstrual period before ovulation induction treatment.

[0061] In the above method, in the data collection step, the obtained basal follicle-stimulating hormone (FSH) level refers to the concentration of follicle-stimulating hormone (FSH) in the venous blood of a female subject on the second day of menstruation before ovulation induction treatment.

[0062] In the above method, in the data collection step, the obtained basal antral follicle count (AFC) refers to the number of all follicles with a diameter of 2 to 10 mm visible by transvaginal B-ultrasound examination in both ovaries of a female subject on the second day of menstruation.

[0063] In the above method, in the data collection step, the obtained dynamic change in inhibin B level (ΔINHB) refers to the dynamic change in inhibin B level (ΔINHB) at the initial stage of ovulation induction treatment, preferably the difference between the serum inhibin B concentration on the 6th day of menstruation and the inhibin B concentration in venous blood on the 2nd day of menstruation in the ovulation induction treatment cycle of female subjects receiving a GnRH antagonist regimen.

[0064] In the above method, the brand of the exogenous follicle-stimulating hormone agent is not limited. For example, Gonal-F, Puregon, urofolitropin for injection, HMG, etc. can be mentioned, and the brand of FSH does not affect the accuracy of predicting the initial dose and adjusted dose by the method.

[0065] In a specific embodiment, the method of the present application is a system for predicting the initial dose of an exogenous follicle-stimulating hormone (FSH) agent administered to a subject during a controlled ovarian stimulation cycle. Here, in the above method, in the data collection step, data on the age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level, and basal antral follicle count (AFC) of the subject are obtained. In the exogenous FSH agent dosage calculation step, a first calculation is performed on the above data obtained by the data collection module to calculate the predicted number of oocytes retrieved (predicted NRO) of the subject in the ovulation induction cycle; a second calculation is performed on the above data obtained by the data collection module to calculate the ratio of the predicted number of oocytes retrieved (predicted NRO) of the subject in the ovulation induction cycle to the initial dose of the exogenous FSH agent, that is, the predicted ovarian sensitivity; based on the predicted number of oocytes retrieved (predicted NRO) calculated in the first calculation and the ratio value obtained in the second calculation, the initial dose of the exogenous FSH agent to be administered to the subject is calculated.

[0066] First, it should be understood that in the above method, in the exogenous FSH drug dosage calculation step, in the existing database, there are data on the age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level, basal antral follicle count (AFC), and the number of actually detected and collected oocytes (actual oocyte retrieval number) of patients who received ovulation induction treatment with a standard GnRH antagonist regimen, as well as formula 1 for calculating the predicted oocyte retrieval number (predicted NRO) of the subject, which is fitted based on the pre-stored patient data and the negative binomial distribution, is pre-stored. Using the pre-stored formula 1, calculations can be performed for any subject to predict the number of mature oocytes retrieved (NRO) from that subject, that is, the predicted oocyte retrieval number (predicted NRO) can be obtained.

[0067] Furthermore, it should be understood that in the above method, in the exogenous FSH drug dosage calculation step, in the existing database, there are data on the age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level, basal antral follicle count (AFC) data of patients who received ovulation induction treatment with a standard GnRH antagonist regimen, and the ratio data of the predicted oocyte retrieval number (predicted NRO) calculated by formula 1 to the average daily dose of the exogenous FSH drug used by the patient, as well as formula 2 for calculating the predicted ovarian sensitivity of the subject, that is, the ratio of the predicted oocyte retrieval number (predicted NRO) of the subject to the initial dose of the exogenous FSH drug of the subject, which is fitted based on these data, is pre-stored. Using the pre-stored formula 2, calculations can be performed for any subject.

[0068] In this application, the average daily dose of the exogenous follicle-stimulating hormone drug used by the patient refers to the ratio of the total dose of the exogenous FSH drug used by the patient during the period of receiving ovulation induction treatment with a standard GnRH antagonist regimen to the number of days of use of the exogenous FSH drug.

[0069] Specifically, this pre-stored formula 1 is fitted based on the age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level, basal antral follicle count (AFC) data, and the data of the actually detected number of collected oocytes of patients who received ovulation induction treatment with a standard GnRH antagonist regimen in an existing database. This pre-stored formula 2 is based on the pre-stored data of the age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level, basal antral follicle count (AFC), and the ratio data of the predicted number of oocytes retrieved (predicted NRO) calculated by formula 1 and the average daily dose of exogenous FSH drug used by the patient among patients who received ovulation induction treatment with a standard GnRH antagonist regimen in an existing database.

[0070] When calculating, this pre-stored formula 1 is a formula for calculating the predicted number of oocytes retrieved (predicted NRO) of the subject using the age data of the subject obtained in the data collection step, the basal anti-Müllerian hormone (AMH) level data of the subject, the basal follicle-stimulating hormone (FSH) level data of the subject, and the basal antral follicle count (AFC) data of the subject. This pre-stored formula 2 is a formula for calculating the ratio of the predicted number of oocytes retrieved (predicted NRO) of the subject to the initial dose of exogenous FSH drug administered to the subject using the age data of the subject obtained in the data collection step, the basal anti-Müllerian hormone (AMH) level data of the subject, the basal follicle-stimulating hormone (FSH) level data of the subject, and the basal antral follicle count (AFC) data of the subject.

[0071] In the above method, formula 1 is as follows. Predicted NRO = EXP(a + b * age + c * basal FSH + d * LN[basal AMH] + f * LN[basal AFC]); Furthermore, in formula 1, a is an arbitrary value selected from 1.5576128 to 2.6037078, preferably 2.0806603, b is an arbitrary value selected from -0.019097 to 0.0044064, preferably -0.007345, c is an arbitrary value selected from -0.045234 to -0.004054, preferably -0.024644, d is an arbitrary value selected from 0.348168 to 0.4948875, preferably 0.4215277, f is an arbitrary value selected from 0.0415663 to 0.2566199, preferably 0.1490931.

[0072] In the above method, Formula 2 is as follows. The predicted ovarian sensitivity of the subject, that is, the initial dose of the predicted NRO / exogenous FSH agent calculated by Formula 1 = EXP(g + h * age + i * basal FSH + j * LN[basal AMH] + k * basal AFC); Furthermore, in Formula 2, g is an arbitrary value selected from -3.167587 to -2.751518, preferably -2.959552, h is an arbitrary value selected from -0.025951 to -0.016355, preferably -0.021153, i is an arbitrary value selected from -0.048143 to -0.025727, preferably -0.036935, j is an arbitrary value selected from 0.5174476 to 0.6075545, preferably 0.5625011, k is an arbitrary value selected from 0.0241595 to 0.0365579, preferably 0.0303587.

[0073] In the above method, when the predicted NRO calculated by Formula 1 is divided by the ratio value calculated by Formula 2, the initial dose of the exogenous FSH agent administered to the subject can be calculated.

[0074] In the above method, the initial dose of the exogenous FSH agent administered to the subject can be calculated by Formula 3. Formula 3 is The initial dose of exogenous FSH agent = round (predicted NROs calculated by formula 1 / predicted ovarian sensitivity calculated by formula 2, 0).

[0075] In a specific embodiment, the method of the present application is a method for predicting an adjusted dose of an exogenous FSH agent administered to a subject during a controlled ovarian stimulation cycle. Here, in the data collection step, data on the age of the subject, basal anti-Müllerian hormone (AMH) level, basal antral follicle count (AFC), and dynamic change in inhibin B level (ΔINHB) are obtained. In the exogenous FSH agent dose calculation step, a first calculation is performed on the above data obtained by the data collection module to calculate the predicted number of retrieved oocytes (predicted NRO) of the subject in the ovulation induction cycle; a second calculation is performed on the above data obtained by the data collection module to calculate the ratio of the predicted number of retrieved oocytes (predicted NRO) of the subject in the ovulation induction cycle to the adjusted dose of the exogenous FSH agent, that is, the predicted ovarian sensitivity; based on the predicted number of retrieved oocytes (predicted NRO) calculated in the first calculation and the ratio obtained in the second calculation, the adjusted dose of the exogenous FSH agent to be administered to the subject is calculated.

[0076] First, it should be understood that in the existing database, there are pre-stored data on the age, basal anti-Müllerian hormone (AMH) level, dynamic change in inhibin B level (ΔINHB), basal antral follicle count (AFC), and actual number of retrieved oocytes of patients who received ovulation induction treatment with a standard GnRH antagonist regimen, as well as formula 4 for calculating the predicted number of retrieved oocytes (predicted NRO) of the subject fitted based on the pre-stored patient data and negative binomial distribution. Using the pre-stored formula 4, calculations can be performed for any subject to obtain the predicted number of retrieved oocytes (predicted NRO).

[0077] Furthermore, it should be understood that the above method pre-stores data in an existing database on the age of patients who received ovulation induction treatment with a standard GnRH antagonist regimen, the levels of basal anti-Müllerian hormone (AMH), the dynamic change in inhibin B level (ΔINHB), the number of basal antral follicles (AFC), and the ratio of the predicted number of retrieved oocytes (predicted NRO) calculated by Equation 4 to the average daily dose of exogenous FSH drug used by the patient, as well as the predicted ovarian sensitivity of the subjects fitted based on these data, that is, Equation 5 for calculating the ratio of the predicted number of retrieved oocytes (predicted NRO) of the subject to the adjusted dose of exogenous FSH drug of the subject. Calculations can be performed for any subject using the pre-stored Equation 5.

[0078] In this application, the average daily dose of the exogenous follicle-stimulating hormone drug used by the patient refers to the ratio of the total dose of the exogenous FSH drug used by the patient during the period of receiving ovulation induction treatment with a standard GnRH antagonist regimen to the number of days of use of the exogenous FSH drug.

[0079] Specifically, this pre-stored Equation 4 is fitted based on the age, basal anti-Müllerian hormone (AMH) level, dynamic change in inhibin B level (ΔINHB), number of basal antral follicles (AFC) data, and actual number of retrieved oocytes data of patients who received ovulation induction treatment with a standard GnRH antagonist regimen in the existing database. This pre-stored Equation 5 is fitted based on the age, basal anti-Müllerian hormone (AMH) level, dynamic change in inhibin B level (ΔINHB), number of basal antral follicles (AFC), and the ratio of the predicted number of retrieved oocytes (predicted NRO) calculated by Equation 4 to the average daily dose of exogenous FSH drug used by the patient in the pre-stored existing database of patients who received ovulation induction treatment with a standard GnRH antagonist regimen.

[0080] When calculating, this pre - saved formula 4 is a formula for calculating the predicted number of retrieved oocytes (predicted NRO) of the subject using the age data of the subject acquired by the data collection module, the basic anti - Müllerian hormone (AMH) level data of the subject, the dynamic change (ΔINHB) data of the inhibin B level of the subject, and the basic antral follicle count (AFC) data of the subject. This pre - saved formula 5 is a formula for calculating the ratio value of the predicted number of retrieved oocytes (predicted NRO) of the subject to the adjusted dosage of exogenous FSH agent administered to the subject using the age data of the subject acquired by the data collection module, the basic anti - Müllerian hormone (AMH) level data of the subject, the dynamic change (ΔINHB) data of the inhibin B level of the subject, and the basic antral follicle count (AFC) data of the subject.

[0081] In the above method, formula 4 is: predicted NRO = EXP(w + m * age + n * LN[basic AMH]+o * LN[ΔINHB]+p * LN[basic AFC]). Furthermore, in the above formula 4, w is an arbitrary value selected from - 0.447201 to 0.9161863, preferably 0.2344927; m is an arbitrary value selected from - 0.017165 to 0.0039328, preferably - 0.006616; n is an arbitrary value selected from 0.1318094 to 0.3113979, preferably 0.2216036; o is an arbitrary value selected from 0.1901643 to 0.3850919, preferably 0.2876281; p is an arbitrary value selected from 0.0541966 to 0.2338079, preferably 0.1440023.

[0082] In the above method, the formula 5 is as follows. The predicted ovarian sensitivity of the subject, that is, predicted NRO calculated by formula 4 / adjusted dosage of exogenous FSH agent = EXP(q + r * age + s * LN[basic AMH]+t * basic AFC+u * LN[ΔINHB]); Furthermore, in Formula 5, q is any value selected from -5.63461 to -5.108612, preferably -5.371611, r is any value selected from -0.0264 to -0.015183, preferably -0.020792, s is any value selected from 0.2696292 to 0.3684551, preferably 0.3190421. t is any value selected from 0.0273504 to 0.0399372, preferably 0.0336438, u is any value selected from 0.3327566 to 0.3940448, preferably 0.3634007.

[0083] In the above method, when the predicted NRO calculated by Formula 4 is divided by the ratio value calculated by Formula 5, the adjusted dosage of the exogenous FSH agent administered to the subject can be calculated.

[0084] In the above method, the adjusted dosage of the exogenous FSH agent administered to the subject can be calculated by Formula 6. Formula 6 is Adjusted dosage of exogenous FSH agent = Round (predicted NROs calculated by Formula 4 / predicted ovarian sensitivity calculated by Formula 5, 0).

[0085] The initial dosage and adjusted dosage of exogenous FSH predicted by the system or method of the present application are highly individualized, and it is impossible for current exogenous FSH products to achieve such accuracy. Therefore, the physician in ART should select a dosage close to the recommended dosage accordingly. For example, if the predicted starting dosage is 70 IU, 75 IU may be an alternative.

Example

[0086] Subjects for model construction Data were collected from 669 patients who received treatment at the Third Hospital of Peking University from April 2020 to September 2020, and data from 60 patients with incomplete records such as AFC, infertility causes, or dosages were further excluded, and a preliminary model was constructed. For the patients used in the preliminary model construction, the basic and clinical characteristics of the patients were collected, including surname, medical record number, serial number, age, BMI index, infertility duration, number of previous in vitro fertilization / intracytoplasmic sperm injection-embryo transfer (IVF / ICSI-ET) attempts, serum basal E2 level, FSH level and LH level, serum AMH level, left and right ovarian AFC, first, second, third, fourth, and fifth causes of infertility, traditional or mild ovarian stimulation cycles, ovarian stimulation type / COS regimen, starting dose and total dose of rFSH, rFSH treatment duration (days), name of rFSH, endometrial thickness on the day of human chorionic gonadotropin (hCG) induction, oocyte retrieval day and NRO.

[0087] 2 COS treatment The standard GnRH antagonist ovarian stimulation protocol was performed as follows. Human rFSH (e.g., Gonal-F alfa [Merck Serono, Germany], Puregon beta [MSD, USA], Urofollitropin [Livzon Pharmaceutical Group Inc., China], or Menotrophins [Livzon Pharmaceutical Group Inc., China]) was administered starting from day 2 of the menstrual cycle. The starting dose of human rFSH was selected based on factors such as age, AMH level, basal FSH level, AFC level, BMI, and the results of previous ovarian stimulation. On day 6 of the menstrual cycle, the rFSH dose was further adjusted based on the size and number of growing follicles observed by ultrasound and the serum E 2 level monitored during ovarian stimulation. When the diameter of the growing follicles reached 10-12 mm, treatment with GnRH antagonist was initiated. When at least two dominant follicles were observed by ultrasound to exceed 18 mm in diameter, hCG (chorionic gonadotropin alpha, Merck Serono) was injected at a dose of 5000 - 10000 IU to induce final oocyte maturation. For those at high risk of ovarian hyperstimulation syndrome, it was induced by using GnRH antagonist alone or in combination with 2000 IU of hCG. Oocyte retrieval was performed 36 - 38 hours after hCG administration. One or two embryos were transferred or the embryos were cryopreserved. Next, luteal phase progesterone support (progesterone vaginal gel, Merck Serono) was provided to the patient or subject.

[0088] 3 Measurement of indicators for model construction On the second day of the menstrual cycle, follicles with a diameter of 2 - 10 mm in both ovaries were measured by transvaginal ultrasound scan, and AFC was calculated. Venous blood samples were collected from the subjects using blood coagulation tubes on the second day of menstruation. Among these, the measurements on the second day included AMH, inhibin B concentration, FSH, LH, E2, testosterone (T), progesterone (P), and androstenedione (A4). The measurements on the sixth day included AMH, inhibin B concentration, LH, E2, testosterone (T), progesterone (P), and androstenedione (A4). Among these, serum FSH, LH, E2, P, T, and A4 were measured using the Siemens Immulite 2000 immunoassay system (Siemens Healthcare Diagnostics, Shanghai, China). The measurements of FSH, LH, E2, and progesterone were performed using the Siemens Immulite 2000 immunoassay system (Siemens Healthcare Diagnostics, Shanghai, PR China). The three-level quality control for FSH, LH, and E2 was provided by Bio-RAD Laboratories (Lyphochek Immunoassay Plus Control, Trilevel, catalog number 370, lot number 40390). Serum AMH concentration and inhibin B concentration were measured using an ultrasensitive ELISA (Ansh Laboratories, Webster, TX, USA) kit and the quality control attached to the kit. For AMH, inhibin B, FSH, and LH, the tertiary or secondary control by coefficient of variation measurement was less than 5% respectively. For E2, T, and A4, the tertiary or secondary control by coefficient of variation measurement was less than 10% respectively. The measurement results are shown in Table 1.

[0089]

Table 1

[0090] At the same time, the average daily dose of exogenous FSH used (the ratio of the total dose of exogenous FSH drug used to the number of days of use of exogenous FSH drug), the main causes of infertility, the brand of exogenous FSH drug used, and the results of various ovarian stimulations are shown in Tables 2 - 4 below.

[0091]

Table 2

[0092]

Table 3

[0093]

Table 4

[0094] 4 Construction of a System Model for Predicting the Initial Dosage When predicting the initial dosage of exogenous FSH agents administered to a subject during a controlled ovarian stimulation cycle, this application constructed two models, one before and one after. First, Model 1 was constructed to predict the NRO obtained by the subject during the ovulation induction cycle, and then Model 2 was constructed based on the NRO predicted by Model 1. Model 2 is a model used to obtain the ratio value between the predicted number of retrieved oocytes (predicted NRO) of the subject in the ovulation induction cycle and the initial dosage of the exogenous FSH agent administered to the subject in the ovulation induction cycle, that is, a model used to predict the ovarian sensitivity of the subject. The initial variables included in Model 1 and Model 2 are the same, both being age, BMI, cause of infertility, basal FSH, AFC, AMH on Day 2 and Day 6, inhibin B, LH, E2, P, testosterone, and androstenedione levels.

[0095] 4.1 Model 1 In Model 1, based on the data of the 609 patients above, the distribution of the number of retrieved oocytes was first determined. Since the number of retrieved oocytes is count data, usually, a Poisson distribution or a negative binomial distribution can be considered, but in this example, the number of retrieved oocytes of the 609 patients is more consistent with the negative binomial distribution. In this example, negative binomial regression was selected to construct statistical model 1. For the selection of prediction indicators, the pruning forward method and 30% hold-back validation were used, and the software JMP Pro v.16 was used to establish the prediction model. The dataset consisting of the above 609 patients was randomly divided into two parts, one part was used as the training set (426 data, 70%), and the other part was used as the validation set (183 data, 30%). First, the model was constructed using the training set, and the effect of the model was verified using the validation set. The selection of the prediction model was mainly based on the negative log-likelihood value of the validation set. The lower the negative log-likelihood value of the validation set, the better the model. When including four variables, the scaled -Log L(β) no longer decreased. Therefore, the four variables of ln[basal AMH], ln[basal AFC], age, and basal FSH were finally incorporated into the model according to their importance. The parameter estimation results of each variable in this prediction model at this time are shown in Table 5. Table 5 also shows the 95% confidence intervals of each parameter.

[0096]

Table 5

[0097] Based on the above - mentioned method, in this example, the following Equation 1 was confirmed. NRO = EXP(a + b * age + c * basal FSH + d * LN[basal AMH]+f * LN[basal AFC]); In the formula, NRO represents the number of mature oocytes, age represents the age of the subject, basal FSH represents the basal follicle - stimulating hormone level of the subject before ovulation induction treatment, basal AMH represents the basal anti - Müllerian hormone level of the subject before ovulation induction treatment, and basal AFC represents the number of all visible follicles with a diameter of 2 - 10 mm in both ovaries on the second day of menstruation. In a specific embodiment, AMH refers to the concentration of anti - Müllerian hormone in the venous blood of the subject at any time point during the menstrual period before ovulation induction treatment. FSH refers to the follicle - stimulating hormone concentration in the venous blood of a female subject on the second day of menstruation before ovulation induction treatment. AFC refers to the number of all visible follicles with a diameter of 2 - 10 mm in both ovaries of a female subject on the second day of menstruation before ovulation induction treatment. In the above Equation 1, a is an arbitrary value selected from 1.5576128 - 2.6037078, and a is preferably 2.0806603. b is an arbitrary value selected from - 0.019097 - 0.0044064, and b is preferably - 0.007345. c is an arbitrary value selected from - 0.045234 - - 0.004054, and c is preferably - 0.024644. d is an arbitrary value selected from 0.348168 to 0.4948875, and d is preferably 0.4215277. f is an arbitrary value selected from 0.0415663 to 0.2566199, and f is preferably 0.1490931. Table 6 shows the prediction effect of Model 1 constructed using the above method for the training set and the validation set. It can be seen that Model 1 constructed above achieved good prediction results in both the training set and the validation set, and the prediction data has a high consistency with the actual detection number.

[0098]

Table 6

[0099] 4.2 Model 2 In Model 2, based on the data of the above 609 patients, the result variable is ovarian sensitivity, that is, the ratio of the number of eggs retrieved (NOR) predicted by Model 1 to the starting dose of exogenous FSH. Based on Model 1, the predicted NRO was calculated using four basic predictors: basal AMH, basal AFC, basal FSH, and age. The main effects (contributions) were 90.2%, 3.6%, 1.2%, and 0.3% respectively.

[0100] 4.2.1 Normality test of the result variable First, a normality test was performed on the result variable, that is, the ratio of the predicted NRO to exogenous FSH using the basic predictors. The results showed a skewed distribution (Shapiro-Wilk test, W = 0.8691) (Figure 1A), and logarithmic transformation was considered to approximate a log-normal distribution. After logarithmic transformation, it approached a normal distribution (Shapiro-Wilk test, W = 0.9907) (Figure 1B), so the logarithmic transformation of the result variable was used as the dependent variable in subsequent analyses.

[0101] 4.2.2 Investigation of the linear relationship between the main variables The linear relationships between each independent variable and the dependent variable were investigated individually. Except for AMH, most variables had a linear relationship. AMH showed a non-linear relationship with the results (Figure 1C). When AMH was logarithmically transformed, the R 2 before transformation was 0.6574, and the R 2 after transformation was 0.8643. The goodness of fit after logarithmic transformation was significantly improved compared to before transformation. Therefore, in subsequent analyses, AMH was analyzed in logarithmic form, and the other independent variables were not transformed.

[0102] 4.2.3 Screening of Predictors Using Lasso Regression All predictors were screened using lasso regression. First, the data were randomly divided into a training set and a validation set at a ratio of 0.7:0.3. The optimal subset method was used for variable selection. The variable screening process is shown in Figures 2A and 2B. When four variables were included, the scale - LogL(β) value of the validation set stopped decreasing. The R 2 of this model was 0.911 and 0.923 for the training set and the validation set, respectively. The RMSE of the training set and the validation set were 0.237 and 0.224, respectively. Finally, four variables, namely logarithmically transformed basal AMH, AFC, basal FSH, and age, were incorporated into the model that predicts the starting dose of exogenous FSH, that is, Model 2. The contributions of the four predictors were evaluated through main effects and total effects respectively, and the results are shown in Figure 2C. Among them, AMH contributed the most. The parameter estimation results of each variable in the prediction model at this time are shown in Table 7. Table 7 also shows the 95% confidence intervals of each parameter.

[0103]

Table 7

[0104] Based on the above method, in this example, the following formula 2 was confirmed. Initial dose of NRO / exogenous follicle-stimulating hormone calculated by Equation 1 = EXP(g + h * age + i * basal FSH + j * LN[basal AMH] + k * basal AFC) In the formula, NRO represents the number of mature oocytes, age represents the age of the subject, AFC represents the number of all visible follicles with diameters of 2 to 10 mm in both ovaries of the subject on the second day of menstruation, basal AMH represents the basal anti-Müllerian hormone level of the subject before ovulation induction treatment, and basal FSH represents the basal follicle-stimulating hormone level of the subject before ovulation induction treatment. In a specific embodiment, AMH refers to the concentration of anti-Müllerian hormone in the venous blood of the subject at any time during the menstrual period before ovulation induction treatment. AFC refers to the number of all visible follicles with diameters of 2 to 10 mm in both ovaries of a female subject on the second day of menstruation before ovulation induction treatment. FSH refers to the follicle-stimulating hormone concentration in the venous blood of a female subject on the second day of menstruation before ovulation induction treatment. In the above Equation 2, g is an arbitrary value selected from -3.167587 to -2.751518, preferably -2.959552, h is an arbitrary value selected from -0.025951 to -0.016355, preferably -0.021153, i is an arbitrary value selected from -0.048143 to -0.025727, preferably -0.036935, j is an arbitrary value selected from 0.5174476 to 0.6075545, preferably 0.5625011, k is an arbitrary value selected from 0.0241595 to 0.0365579, preferably 0.0303587. Finally, Equation 3 was used to calculate the initial dose of exogenous FSH agent administered to the subject. Equation 3 is Initial dose of exogenous FSH agent = Rounding( Predicted NROs calculated by Equation 1 / Predicted ovarian sensitivity calculated by Equation 2, 0). The effects of Model 2 constructed using the above method on the training set and the validation set in predicting the starting dose of exogenous FSH are shown in Table 8 and the scatter plot. The scatter plot shows the relationship between the predicted outcome variable and the actual outcome variable. If the prediction results perfectly match the actual results, the scatter points should be completely distributed on the diagonal line. As shown in Figures 2D and 2E, the points are evenly distributed on both sides of the diagonal line, indicating good prediction performance. Residual plots are also used to estimate the effect, and the ideal approximation (fitting) should be evenly distributed on the diagonal line. As shown in Figures 2F and 2G, the points are also evenly distributed on both sides of the diagonal line of the residual plot and are normally distributed, and the prediction deviation is very small. All these results indicate that Model 2 has excellent prediction performance.

[0105]

Table 8

[0106] 5 Construction of the Model of the System for Predicting the Adjusted Dose When predicting the adjusted dose of exogenous FSH agent administered to a subject during a controlled ovarian stimulation cycle, this application constructed two models before and after. First, Model 3 was constructed to predict the NRO obtained by the subject during the ovulation induction cycle, and then Model 4 was constructed based on the NRO predicted by Model 3. Model 4 is a model used to obtain the ratio value of the predicted number of oocytes retrieved (predicted NRO) of the subject in the ovulation induction cycle and the adjusted dose of the exogenous FSH agent administered to the subject in the ovulation induction cycle, that is, a model used to predict the ovarian sensitivity of the subject. The initial variables included in Model 3 and Model 4 are also the same, namely age, BMI, cause of infertility, basal FSH, AFC, AMH on day 2 and day 6, inhibin B, LH, E2, P, testosterone, and androstenedione levels.

[0107] 5.1 Model 3 In Model 3, based on the data of the above 609 patients, the distribution of the number of retrieved oocytes was first determined. Since the number of retrieved oocytes is count data, usually, a Poisson distribution or a negative binomial distribution can be considered. However, in this example, the number of oocytes retrieved from 609 patients is more consistent with a negative binomial distribution. In this example, negative binomial regression was selected to construct Statistical Model 3. For the selection of prediction indicators, the pruning forward method and 30% hold-back validation were used. The software JMP Pro v.16 was used to establish a prediction model. The dataset consisting of the above 609 patients was randomly divided into two parts. One part was used as a training set (426 data, 70%), and the other part was used as a validation set (183 data, 30%). First, the model was constructed using the training set, and the effect of the model was verified using the validation set. The selection of the prediction model was mainly based on the negative log-likelihood value of the validation set. The lower the negative log-likelihood value of the validation set, the better the model indicates. When including four variables, the scaled -Log L(β) no longer decreased. Therefore, the four variables of ln[ΔINHB], ln[baseline AMH], AFC, and age were finally incorporated into the model according to their importance. The parameter estimation results of each variable in this prediction model at this time are shown in Table 9. Table 9 also shows the 95% confidence intervals of each parameter.

[0108]

Table 9

[0109] Based on the above method, in this example, the following Equation 4 was confirmed. Predicted NRO = Predicted NRO = EXP(w + m * age + n * LN[baseline AMH] + o * LN[ΔINHB] + p * LN[baseline AFC]); In the formula, NRO represents the number of mature oocytes, age represents the age of the subject, ΔINHB represents the dynamic change in the inhibin B level of the subject at the beginning of ovulation induction treatment, basal AMH represents the basal anti-Müllerian hormone level of the subject before ovulation induction treatment, and basal AFC represents the number of all visible follicles with a diameter of 2-10 mm in both ovaries on the second day of menstruation. In a specific embodiment, AMH refers to the concentration of anti-Müllerian hormone in the venous blood of the subject at any point during the menstrual period before ovulation induction treatment. ΔINHB refers to the difference between the serum inhibin B concentration on the sixth day of the menstrual cycle of a female subject receiving a GnRH antagonist regimen and the inhibin B concentration in the venous blood of the female subject on the second day of menstruation. AFC refers to the number of all visible follicles with a diameter of 2-10 mm in both ovaries of a female subject on the second day of menstruation before ovulation induction treatment. In the above formula 4, w is an arbitrary value selected from -0.447201 to 0.9161863, preferably 0.2344927, m is an arbitrary value selected from -0.017165 to 0.0039328, preferably -0.006616, n is an arbitrary value selected from 0.1318094 to 0.3113979, preferably 0.2216036, o is an arbitrary value selected from 0.1901643 to 0.3850919, preferably 0.2876281, p is an arbitrary value selected from 0.0541966 to 0.2338079, preferably 0.1440023. Table 10 shows the prediction effect of Model 3 constructed using the above method for the training set and the validation set. It can be seen that Model 3 constructed above achieves good prediction results in both the training set and the validation set, and the prediction data has a high consistency with the actual detection number.

[0110]

Table 10

[0111] 5.2 Model 4 In Model 4, based on the data of the above 609 patients, the outcome variable is ovarian sensitivity, that is, the ratio of the number of retrieved oocytes (NOR) predicted by Model 1 to the starting dose of exogenous FSH. Based on Model 3, the predicted NRO was calculated using four basic predictors: the dynamic change in inhibin B level (subtracting Day 2 from Day 6), basal AMH, basal AFC, and age. The main effects (contributions) were 48.9%, 30.0%, 12.7%, and 2.0% respectively, and the total effects (contributions) were 50.8%, 31.8%, 14.5%, and 3.2% respectively.

[0112] 5.2.1 Normality test of the outcome variable First, a normality test was performed on the outcome variable, that is, the ratio of the predicted NRO to exogenous FSH using the basic predictors. The results showed a skewed distribution (Shapiro-Wilk test, W = 0.8522), and logarithmic transformation was considered to approximate a log-normal distribution. After logarithmic transformation, it approached a normal distribution (Shapiro-Wilk test, W = 0.9916), so the logarithmic transformation of the outcome variable was used as the dependent variable in subsequent analyses.

[0113] 5.2.2 Investigation of the linear relationship between the main variables The linear relationship between each independent variable and the dependent variable was investigated individually. Most variables had a linear relationship, but AMH, inhibin B level, and the dynamic change in inhibin B level showed an obvious non-linear relationship with the results. When these three variables were logarithmically transformed, the goodness of fit after transformation was significantly improved compared to before transformation. In the case of AMH, the R 2 before transformation was 0.5829, and the R 2 after transformation was 0.7904. In the case of the inhibin B level, the R 2 before transformation was 0.2255, and the R 2 after transformation was 0.2608. In the case of the dynamic change in inhibin B level, the R 2 before transformation was 0.5613, and the R 2It was 0.7247. Therefore, in subsequent analyses, AMH, inhibin B levels, and the dynamic changes in inhibin B levels were analyzed in logarithmic form, while the other independent variables were not transformed.

[0114] 5.2.3 Screening of Predictors Using Lasso Regression All predictors were screened using lasso regression. First, the data were randomly divided into a training set and a validation set at a ratio of 0.7:0.3. The optimal subset method was used for variable selection. The variable screening process is shown in Figures 3A and 3B. When four variables were included, the scale - LogL(β) value of the validation set no longer decreased. The R 2 of this model was 0.922 and 0.909 for the training set and the validation set, respectively. The RMSE of the training set and the validation set were 0.236 and 0.231, respectively. Finally, four variables, namely logarithmically transformed basal AMH, logarithmically transformed ΔINHB, AFC, and age, were incorporated into the model for predicting the adjusted dose of exogenous FSH, that is, Model 4. The contributions of the four predictors were evaluated through main effects and overall effects respectively, and the results are shown in Figure 3C. Among them, ΔINHB contributed the most. The parameter estimation results of each variable in the prediction model at this time are shown in Table 11. Table 11 also shows the 95% confidence intervals of each parameter.

[0115]

Table 11

[0116] Based on the above method, in this example, the following Equation 5 was confirmed. NRO / adjusted dose of exogenous follicle - stimulating hormone calculated by Equation 5 = EXP(q + r * age + s * LN[basal AMH] + t * basal AFC + u * LN[ΔINHB]); In the formula, NRO represents the number of mature oocytes, age represents the age of the subject, AFC represents the number of all visible follicles with a diameter of 2 to 10 mm in both ovaries of the subject on the second day of menstruation, basal AMH represents the basal anti-Müllerian hormone level of the subject before ovulation induction treatment, and ΔINHB represents the dynamic change in the inhibin B level of the subject at the initial stage of ovulation induction treatment. In a specific embodiment, AMH refers to the concentration of anti-Müllerian hormone in the venous blood of the subject at any time point during the menstrual period before ovulation induction treatment. AFC refers to the number of all visible follicles with a diameter of 2 to 10 mm in both ovaries of a female subject on the second day of menstruation before ovulation induction treatment. ΔINHB refers to the difference between the serum inhibin B concentration on the sixth day of menstruation during ovulation induction treatment of a female subject receiving a GnRH antagonist regimen and the inhibin B concentration in the venous blood of the female subject on the second day of menstruation. In the above formula 5, q is an arbitrary value selected from -5.63461 to -5.108612, preferably -5.371611, r is an arbitrary value selected from -0.0264 to -0.015183, preferably -0.020792, s is an arbitrary value selected from 0.2696292 to 0.3684551, preferably 0.3190421. t is an arbitrary value selected from 0.0273504 to 0.0399372, preferably 0.0336438, u is an arbitrary value selected from 0.3327566 to 0.3940448, preferably 0.3634007. Table 12 and the scatter plot show the effect of Model 4, constructed using the above method for the training set and the validation set, in predicting the adjusted dose of exogenous FSH. The scatter plot shows the relationship between the predicted outcome variable and the actual outcome variable. If the prediction exactly matches the actual result, the scatter points should be perfectly distributed on the diagonal. As shown in FIGS. 3D and 3E, the scatter points are evenly distributed on both sides of the diagonal, indicating good prediction performance. The residual plot is also used to estimate the effect, and the ideal approximation should be evenly distributed on the diagonal. As shown in FIGS. 3F and 3G, the scatter points are also evenly distributed on both sides of the diagonal of the residual plot and are normally distributed, and the deviation of the prediction is very small. All these results indicate that Model 4 has excellent prediction performance.

[0117]

Table 12

[0118] As described above, the embodiments of the present application have been described in combination with the accompanying drawings. However, the present application is not limited to the specific embodiments and application fields described above. The above specific embodiments are not restrictive and are merely illustrative and instructive. Under the teachings of this specification, those skilled in the art can also create many forms without departing from the protection scope of the claims of the present application, and all of them are included in the protection scope of the present application.

Claims

1. A system for predicting the dosage of exogenous follicle-stimulating hormone (FSH) agent administered to a subject during a controlled ovarian stimulation cycle, comprising: a data collection module for obtaining data on the subject's age, basal anti-Müllerian hormone (AMH) level, dynamic change in basal follicle-stimulating hormone (FSH) level or inhibin B level (ΔINHB), and basal antral follicle count (AFC); an exogenous follicle-stimulating hormone (FSH) agent dosage calculation module that performs a first calculation on the data obtained by the data collection module to calculate the predicted number of retrieved oocytes (predicted NRO) of the subject in the ovulation induction cycle; performs a second calculation on the data obtained by the data collection module to calculate the ratio of the predicted number of retrieved oocytes (predicted NRO) of the subject in the ovulation induction cycle to the dosage of exogenous FSH agent, i.e., the predicted ovarian sensitivity; and calculates the dosage of exogenous FSH agent to be administered to the subject based on the predicted number of retrieved oocytes (predicted NRO) calculated in the first calculation and the ratio obtained in the second calculation A system comprising the above.

2. The subject is a subject undergoing standard ovulation induction treatment, and the number of retrieved oocytes (NRO) of the subject is the number of mature oocytes with a diameter of 10 mm or more, preferably 15 mm or more, obtained after the subject has received ovulation induction treatment and after hCG injection has been performed to induce follicle maturation after the diameter of 1-2 dominant follicles has reached 18 mm or more during the ovarian stimulation process. The system according to claim 1.

3. In the data collection module, the obtained basal anti-Müllerian hormone (AMH) level is the concentration of anti-Müllerian hormone in the subject's venous blood at any point during the menstrual period before ovulation induction treatment. The system according to claim 1 or 2.

4. In the data collection module, the obtained basal follicle-stimulating hormone (FSH) level is the concentration of follicle-stimulating hormone (FSH) in the venous blood of a female subject on the 2nd to 4th day of menstruation before ovulation induction treatment. The system according to any one of claims 1 to 3.

5. In the data collection module, the obtained basal antral follicle count (AFC) is the number of all follicles with a diameter of 2-10 mm visible by transvaginal B-ultrasound examination in both ovaries of a female subject on the 2nd day of menstruation. The system according to any one of claims 1 to 4.

6. In the data collection module, the obtained dynamic change in inhibin B level (ΔINHB) refers to the dynamic change in inhibin B level (ΔINHB) at the initial stage of ovulation induction treatment, preferably the difference between the serum inhibin B concentration on the 6th day of menstruation and the inhibin B concentration in venous blood on the 2nd day of menstruation in the ovulation induction treatment cycle of female subjects receiving a GnRH antagonist regimen. The system according to any one of claims 1 to 5. Claim 7 The data collection module is used to obtain the age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level, and basal antral follicle count (AFC) data of the subject. The exogenous follicle-stimulating hormone (FSH) drug dosage calculation module performs a first calculation on the above data obtained by the data collection module to calculate the predicted number of retrieved oocytes (predicted NRO) of the subject in the ovulation induction cycle; a second calculation is performed on the above data obtained by the data collection module to calculate the ratio of the predicted number of retrieved oocytes (predicted NRO) of the subject in the ovulation induction cycle to the initial dosage of the exogenous FSH drug, that is, the predicted ovarian sensitivity; it is used to calculate the initial dosage of the exogenous FSH drug to be administered to the subject based on the predicted number of retrieved oocytes (predicted NRO) calculated in the first calculation and the ratio obtained in the second calculation. The system according to any one of claims 1 to 6. Claim 8 In the exogenous FSH drug dosage calculation module, formula 1 for calculating the predicted number of retrieved oocytes (predicted NRO) of the subject fitted based on the age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level, basal antral follicle count (AFC), and actual number of retrieved oocytes data of patients who have received ovulation induction treatment with a standard GnRH antagonist regimen is pre-stored in an existing database. The system according to claim 7. Claim 9 In the exogenous FSH drug dosage calculation module, Formula 1 is a calculation formula obtained by fitting, using the negative binomial distribution of the result variable, the data of the age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level, basal antral follicle count (AFC) data, and the actual number of retrieved oocytes (result variable) of patients who received ovulation induction treatment with a standard GnRH antagonist regimen in an existing database. Formula 1 can calculate the predicted number of retrieved oocytes (predicted NRO) of the subject using the age data of the subject, the basal anti-Müllerian hormone (AMH) level data of the subject, the basal follicle-stimulating hormone (FSH) level data of the subject, and the basal antral follicle count (AFC) data of the subject obtained by the data collection module. The system according to claim 8.

10. Formula 1 is predicted NRO = EXP(a + b * age * + c * basal FSH + d * LN[basal AMH] + f * LN[basal AFC]), wherein a is an arbitrary value selected from 1.5576128 to 2.6037078, preferably 2.0806603; b is an arbitrary value selected from -0.019097 to 0.0044064, preferably -0.007345; c is an arbitrary value selected from -0.045234 to -0.004054, preferably -0.024644; d is an arbitrary value selected from 0.348168 to 0.4948875, preferably 0.4215277; f is an arbitrary value selected from 0.0415663 to 0.2566199, preferably 0.1490931. The system according to claim 9.

11. In the exogenous FSH drug dosage calculation module, there is pre-stored a formula 2 for calculating the predicted ovarian sensitivity of the subject, that is, the ratio of the predicted number of retrieved oocytes (predicted NRO) to the initial dosage of the exogenous FSH drug, based on the data of the age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level, basal antral follicle count (AFC) data of patients who received ovulation induction treatment with a standard GnRH antagonist regimen in an existing database, and the ratio data of the predicted number of retrieved oocytes (predicted NRO) calculated by Formula 1 and the average daily dosage of the exogenous FSH drug used by the patient. The average daily dose of the exogenous FSH drug used by the patient is the ratio of the total dose of the exogenous FSH drug used by the patient during the past ovulation induction treatment period according to the standard GnRH antagonist regimen to the number of days of use of the exogenous FSH drug. The system according to claim 10.

12. In the exogenous FSH drug dose calculation module, the formula 2 can use the age data of the subject, the basic anti-Müllerian hormone (AMH) level data of the subject, the basic follicle-stimulating hormone (FSH) level data of the subject, and the basic antral follicle count (AFC) data of the subject obtained by the data collection module to calculate the predicted ovarian sensitivity of the subject, that is, the ratio of the predicted number of oocytes retrieved (predicted NRO) to the initial dose of the exogenous FSH drug of the subject. The system according to claim 11.

13. The formula 2 is The predicted ovarian sensitivity of the subject, that is, predicted NRO / calculated initial dose of exogenous FSH drug in formula 1 = EXP(g + h*age* + i*basic FSH + j*LN[basic AMH] + k*basic AFC), where g is any value selected from -3.167587 to -2.751518, preferably -2.959552, h is any value selected from -0.025951 to -0.016355, preferably -0.021153, i is any value selected from -0.048143 to -0.025727, preferably -0.036935, j is any value selected from 0.5174476 to 0.6075545, preferably 0.5625011, k is any value selected from 0.0241595 to 0.0365579, preferably 0.0303587. The system according to claim 11 or 12.

14. Based on the predicted number of oocytes retrieved (predicted NRO) calculated in the first calculation and the ratio calculated in the second calculation, use formula 3 to calculate the initial dose of the exogenous FSH drug to be administered to the subject. Formula 3 is Initial dose of exogenous FSH drug = round (predicted NROs calculated in formula 1 / predicted ovarian sensitivity calculated in formula 2, 0) The system according to claim 13.

15. The data collection module is used to obtain data on the age of the subject, the level of basal anti-Müllerian hormone (AMH), the number of basal antral follicles (AFC), and the dynamic change in inhibin B level (ΔINHB). The exogenous follicle-stimulating hormone (FSH) drug dosage calculation module performs a first calculation on the above data obtained by the data collection module to calculate the predicted number of oocytes retrieved (predicted NRO) of the subject in the ovulation induction cycle; performs a second calculation on the above data obtained by the data collection module to calculate the ratio of the predicted number of oocytes retrieved (predicted NRO) of the subject in the ovulation induction cycle to the adjusted dosage of the exogenous FSH drug, that is, the predicted ovarian sensitivity; and is used to calculate the adjusted dosage of the exogenous FSH drug to be administered to the subject based on the predicted number of oocytes retrieved (predicted NRO) calculated in the first calculation and the ratio value obtained in the second calculation. The system according to any one of claims 1 to 6.

16. In the exogenous FSH drug dosage calculation module, that is, based on the early dynamic change index and the basal index of ovulation induction treatment, in the existing database, the age of patients who received ovulation induction treatment with a standard GnRH antagonist regimen, the level of basal anti-Müllerian hormone (AMH), the number of basal antral follicles (AFC), the dynamic change in inhibin B level (ΔINHB), and the formula 4 for calculating the predicted number of oocytes retrieved (predicted NRO) of the subject fitted based on the data of the actual number of oocytes retrieved are pre-stored. The system according to claim 15.

17. In the exogenous FSH drug dosage calculation module, the formula 4 is a calculation formula 4 obtained by fitting the data of the age of patients who received ovulation induction treatment with a standard GnRH antagonist regimen, the level of basal anti-Müllerian hormone (AMH), the number of basal antral follicles (AFC) data, the dynamic change in inhibin B level (ΔINHB), and the actual number of oocytes retrieved (result variable) in the existing database using the negative binomial distribution of the result variable. The formula 4 can calculate the predicted number of retrieved oocytes (predicted NRO) of the subject using the age data of the subject, the basic anti-Müllerian hormone (AMH) level data of the subject, the basic antral follicle count (AFC) data of the subject, and the dynamic change (ΔINHB) data of the inhibin B level of the subject obtained by the data collection module. The system according to claim 16. **Claim 18** The formula 4 is predicted NRO = EXP(w + m * age * + n * LN[basic AMH] + o * LN[ΔINHB] + p * LN[basic AFC]), wherein w is an arbitrary value selected from -0.447201 to 0.9161863, preferably 0.2344927; m is an arbitrary value selected from -0.017165 to 0.0039328, preferably -0.006616; n is an arbitrary value selected from 0.1318094 to 0.3113979, preferably 0.2216036; o is an arbitrary value selected from 0.1901643 to 0.3850919, preferably 0.2876281; p is an arbitrary value selected from 0.0541966 to 0.2338079, preferably 0.1440023. The system according to claim 17. **Claim 19** In the exogenous FSH drug dosage calculation module, in an existing database, based on the age, basic anti-Müllerian hormone (AMH) level, basic antral follicle count (AFC), dynamic change of inhibin B level (ΔINHB), and the ratio of the predicted number of retrieved oocytes (predicted NRO) calculated by formula 4 to the average daily dosage of the exogenous FSH drug used by the patient of patients who received ovulation induction treatment with a standard GnRH antagonist regimen, the predicted ovarian sensitivity of the subject, that is, formula 5 for calculating the ratio of the predicted number of retrieved oocytes (predicted NRO) to the adjusted dosage of the exogenous FSH drug is pre-stored. The average daily dosage of the exogenous FSH drug used by the patient is the ratio of the total dosage of the exogenous FSH drug used by the patient during the past ovulation induction treatment period with a standard GnRH antagonist regimen to the number of days of use of the exogenous FSH drug. The system according to claim 18. **Claim 20** In the exogenous FSH drug dosage calculation module, Equation 5 can use the age data of the subject acquired by the data collection module, the basic anti-Müllerian hormone (AMH) level data of the subject, the basic antral follicle count (AFC) data of the subject, and the dynamic change (ΔINHB) data of the inhibin B level of the subject to calculate the predicted ovarian sensitivity of the subject, that is, the ratio of the predicted number of oocytes retrieved (predicted NRO) to the adjusted dosage of the exogenous FSH drug for the subject. The system according to claim 19.

21. Equation 5 is The predicted ovarian sensitivity of the subject, that is, predicted NRO / calculated adjusted dosage of exogenous FSH drug = EXP(q + r*age* + s*LN[basic AMH] + t*basic AFC + u*LN[ΔINHB]) calculated by Equation 4, where q is any value selected from -5.63461 to -5.108612, preferably -5.371611, r is any value selected from -0.0264 to -0.015183, preferably -0.020792, s is any value selected from 0.2696292 to 0.3684551, preferably 0.3190421. t is any value selected from 0.0273504 to 0.0399372, preferably 0.0336438, u is any value selected from 0.3327566 to 0.3940448, preferably 0.3634007, The system according to claim 19 or 20.

22. Based on the number of oocytes retrieved (predicted NRO) calculated in the first calculation and the ratio calculated in the second calculation, Equation 6 is used to calculate the adjusted dosage of the exogenous FSH drug to be administered to the subject, and Equation 6 is Adjusted dosage of exogenous FSH drug = round (predicted NROs calculated by Equation 4 / predicted ovarian sensitivity calculated by Equation 5, 0) The system according to claim 21.

23. A method for predicting the dosage of an exogenous FSH drug administered to a subject during a controlled ovarian stimulation cycle, comprising: A data collection step of acquiring the age, basic anti-Müllerian hormone (AMH) level, basic follicle-stimulating hormone (FSH) level or dynamic change (ΔINHB) of inhibin B level, and basic antral follicle count (AFC) data of the subject. Performing a first calculation on the data obtained by the data collection step to calculate the predicted number of retrieved oocytes (predicted NRO) of the subject in the ovulation induction cycle; performing a second calculation on the data obtained by the data collection module to calculate the ratio of the predicted number of retrieved oocytes (predicted NRO) of the subject in the ovulation induction cycle to the dose of exogenous FSH drug, that is, the predicted ovarian sensitivity; calculating the dose of exogenous FSH drug to be administered to the subject based on the predicted number of retrieved oocytes (predicted NRO) calculated in the first calculation and the ratio obtained in the second calculation, an exogenous FSH drug dose calculation step A method comprising.

24. The subject is a subject undergoing standard ovulation induction treatment, and the number of retrieved oocytes (NRO) of the subject is the number of mature oocytes with a diameter of 10 mm or more, preferably 15 mm or more, obtained after the subject has received ovulation induction treatment and after hCG injection is performed to induce follicle maturation after the diameters of 1 to 2 dominant follicles reach 18 mm or more during the ovarian stimulation process. The method according to claim 23.

25. In the data collection step, the obtained basal anti-Müllerian hormone (AMH) level is the concentration of anti-Müllerian hormone in the venous blood of the subject at any time point during the menstrual period before ovulation induction treatment. The method according to claim 23 or 24.

26. In the data collection step, the obtained basal follicle-stimulating hormone (FSH) level is the concentration of follicle-stimulating hormone in the venous blood of a female subject on the 2nd to 4th days of menstruation before ovulation induction treatment. The method according to any one of claims 23 to 25.

27. In the data collection step, the obtained basal antral follicle count (AFC) is the number of all follicles with a diameter of 2 to 10 mm visible by transvaginal B-ultrasound examination in both ovaries of a female subject on the 2nd day of menstruation. The method according to any one of claims 23 to 26.

28. In the data collection step, the obtained dynamic change in inhibin B level (ΔINHB) is the dynamic change in inhibin B level (ΔINHB) at the initial stage of ovulation induction treatment, preferably the difference between the serum inhibin B concentration on the 6th day of the menstrual cycle of a female subject receiving a GnRH antagonist regimen and the inhibin B concentration in the venous blood on the 2nd day of menstruation during the ovulation induction treatment cycle. The method according to any one of claims 23 to 27.

29. In the data collection step, data on the age of the subject, the level of basal anti-Müllerian hormone (AMH), the dynamic change in inhibin B level (ΔINHB), and the number of basal antral follicles (AFC) are obtained. In the exogenous follicle-stimulating hormone (FSH) drug dosage calculation step, a first calculation is performed on the data obtained by the data collection module to calculate the predicted number of retrieved oocytes (predicted NRO) of the subject in the ovulation induction cycle; a second calculation is performed on the data obtained by the data collection module to calculate the ratio of the predicted number of retrieved oocytes (predicted NRO) of the subject in the ovulation induction cycle to the adjusted dosage of the exogenous FSH drug, that is, the predicted ovarian sensitivity; based on the predicted number of retrieved oocytes (predicted NRO) calculated in the first calculation and the ratio obtained in the second calculation, the adjusted dosage of the exogenous FSH drug to be administered to the subject is calculated. The method according to any one of claims 23 to 28.

30. In the exogenous FSH drug dosage calculation step, in an existing database, formula 1 for calculating the predicted number of retrieved oocytes (predicted NRO) of the subject fitted based on the data of the age, basal anti-Müllerian hormone (AMH) level, dynamic change in inhibin B level (ΔINHB), basal antral follicle number (AFC), and actual number of retrieved oocytes of patients who received ovulation induction treatment with a standard GnRH antagonist regimen is pre-stored. The method according to claim 29.

31. In the exogenous FSH drug dosage calculation step, formula 1 is a calculation formula 1 fitted using the negative binomial distribution of the result variable for the data of the age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level, basal antral follicle number (AFC) data, and actual number of retrieved oocytes (result variable) of patients who received ovulation induction treatment with a standard GnRH antagonist regimen in an existing database. Formula 1 can calculate the predicted number of retrieved oocytes (predicted NRO) of the subject using the age data of the subject obtained in the data collection step, the basal anti-Müllerian hormone (AMH) level data of the subject, the basal follicle-stimulating hormone (FSH) level data of the subject, and the basal antral follicle number (AFC) data of the subject. The method according to claim 30.

32. Formula 1 is The predicted NRO = EXP(a + b * age* + c * basal FSH + d * LN[basal AMH] + f * LN[basal AFC]), and wherein a is any value selected from 1.5576128 to 2.6037078, preferably 2.0806603; b is any value selected from -0.019097 to 0.0044064, preferably -0.007345; c is any value selected from -0.045234 to -0.004054, preferably -0.024644; d is any value selected from 0.348168 to 0.4948875, preferably 0.4215277; f is any value selected from 0.0415663 to 0.2566199, preferably 0.1490931, The method according to claim 31.

33. In the exogenous FSH drug dosage calculation step, in an existing database, the age, basal anti-Müllerian hormone (AMH) level, basal follicle-stimulating hormone (FSH) level, basal antral follicle count (AFC) data of patients who received ovulation induction treatment with a standard GnRH antagonist regimen, and the ratio value data of the predicted number of oocytes retrieved (predicted NRO) calculated by Formula 1 and the average daily dosage of the exogenous FSH drug used by the patient are used for fitting. The predicted ovarian sensitivity of the subject, that is, a formula 2 for calculating the ratio value of the predicted number of oocytes retrieved (predicted NRO) to the initial dosage of the exogenous FSH drug is pre-stored. The average daily dosage of the exogenous FSH drug used by the patient is the ratio value of the total dosage of the exogenous FSH drug used by the patient during the past ovulation induction treatment period with a standard GnRH antagonist regimen and the number of days the exogenous FSH drug was used. The method according to claim 32.

34. In the exogenous FSH drug dosage calculation step, Formula 2 can calculate the predicted ovarian sensitivity of the subject, that is, the ratio value of the predicted number of oocytes retrieved (predicted NRO) to the initial dosage of the exogenous FSH drug of the subject, using the age data of the subject, the basal anti-Müllerian hormone (AMH) level data of the subject, the basal follicle-stimulating hormone (FSH) level data of the subject, and the basal antral follicle count (AFC) data of the subject obtained by the data collection module. The method according to claim 33.

35. Formula 2 is The predicted ovarian sensitivity of the subject, i.e., the initial dose of the predicted NRO / exogenous FSH agent calculated by the above formula 1 = EXP(g + h*age + i*basal FSH + j*LN[basal AMH] + k*basal AFC), and wherein g is any value selected from -3.167587 to -2.751518, preferably -2.959552; h is any value selected from -0.025951 to -0.016355, preferably -0.021153; i is any value selected from -0.048143 to -0.025727, preferably -0.036935; j is any value selected from 0.5174476 to 0.6075545, preferably 0.5625011; k is any value selected from 0.0241595 to 0.0365579, preferably 0.0303587, The method according to claim 33 or 34.

36. Based on the number of eggs retrieved (predicted NRO) calculated in the first calculation and the ratio value calculated in the second calculation, use formula 3 to calculate the initial dose of the exogenous FSH agent to be administered to the subject. Formula 3 is Initial dose of exogenous FSH agent = Round (predicted NROs calculated by formula 1 / predicted ovarian sensitivity calculated by formula 2, 0) The method according to claim 35.

37. In the data collection step, obtain data on the age, basal anti-Müllerian hormone (AMH) level, basal antral follicle count (AFC), and dynamic change (ΔINHB) of inhibin B level of the subject, In the exogenous FSH agent dose calculation step, perform a first calculation on the above data obtained by the data collection module to calculate the predicted number of eggs retrieved (predicted NRO) of the subject in the ovulation induction cycle; perform a second calculation on the above data obtained by the data collection module to calculate the ratio value between the predicted number of eggs retrieved (predicted NRO) of the subject in the ovulation induction cycle and the adjusted dose of the exogenous FSH agent, i.e., the predicted ovarian sensitivity; calculate the adjusted dose of the exogenous FSH agent to be administered to the subject based on the predicted number of eggs retrieved (predicted NRO) calculated in the first calculation and the ratio value obtained in the second calculation. The method according to any one of claims 23 to 28.

38. In the exogenous FSH drug dosage calculation step, Equation 4 for calculating the predicted number of retrieved oocytes (predicted NRO) of a subject fitted based on the data of age, basal anti-Müllerian hormone (AMH) level, basal antral follicle count (AFC), dynamic change in inhibin B level (ΔINHB), and actual number of retrieved oocytes of patients who received ovulation induction treatment with a standard GnRH antagonist regimen is pre-stored in an existing database. The method according to claim 37.

39. In the exogenous FSH drug dosage calculation step, Equation 4 is a calculation formula 4 fitted using the negative binomial distribution of the result variable for the data of age, basal anti-Müllerian hormone (AMH) level, basal antral follicle count (AFC) data, dynamic change in inhibin B level (ΔINHB), and actual number of retrieved oocytes (result variable) of patients who received ovulation induction treatment with a standard GnRH antagonist regimen in an existing database. Equation 4 can calculate the predicted number of retrieved oocytes (predicted NRO) of the subject using the subject's age data, basal anti-Müllerian hormone (AMH) level data, basal antral follicle count (AFC) data, and dynamic change in inhibin B level (ΔINHB) data obtained by the data collection module. The method according to claim 38.

40. Equation 4 is predicted NRO = EXP(w + m * age * + n * LN[basal AMH] + o * LN[ΔINHB] + p * LN[basal AFC]), where w is an arbitrary value selected from -0.447201 to 0.9161863, preferably 0.2344927; m is an arbitrary value selected from -0.017165 to 0.0039328, preferably -0.006616; n is an arbitrary value selected from 0.1318094 to 0.3113979, preferably 0.2216036; o is an arbitrary value selected from 0.1901643 to 0.3850919, preferably 0.2876281; p is an arbitrary value selected from 0.0541966 to 0.2338079, preferably 0.1440023. The method according to claim 39.

41. In the exogenous FSH drug dosage calculation step, in an existing database, the age of patients who received ovulation induction treatment with a standard GnRH antagonist regimen, the basal anti-Müllerian hormone (AMH) level, the basal antral follicle count (AFC), the dynamic change in inhibin B level (ΔINHB), and the ratio data of the predicted number of oocytes retrieved (predicted NRO) calculated by Equation 4 to the average daily dosage of the exogenous FSH drug used by the patient are used to fit the predicted ovarian sensitivity of the subject, that is, Equation 5 for calculating the ratio of the predicted number of oocytes retrieved (predicted NRO) to the adjusted dosage of the exogenous FSH drug is pre-stored. The average daily dosage of the exogenous FSH drug used by the patient is the ratio of the total dosage of the exogenous FSH drug used by the patient during the past ovulation induction treatment period with a standard GnRH antagonist regimen to the number of days the exogenous FSH drug was used. The method according to claim 40.

42. In the exogenous FSH drug dosage calculation step, in Equation 5, the age data of the subject, the basal anti-Müllerian hormone (AMH) level data of the subject, the basal antral follicle count (AFC) data of the subject, and the dynamic change in inhibin B level (ΔINHB) data of the subject obtained by the data collection module are used to calculate the predicted ovarian sensitivity of the subject, that is, the ratio of the predicted number of oocytes retrieved (predicted NRO) to the adjusted dosage of the exogenous FSH drug of the subject. The method according to claim 41.

43. Equation 5 is the predicted ovarian sensitivity of the subject, that is, predicted NRO / calculated by Equation 4 / adjusted dosage of exogenous FSH drug = EXP(q + r*age* + s*LN[basal AMH] + t*basal AFC + u*LN[ΔINHB]), where q is an arbitrary value selected from -5.63461 to -5.108612, preferably -5.371611; r is an arbitrary value selected from -0.0264 to -0.015183, preferably -0.020792; s is an arbitrary value selected from 0.2696292 to 0.3684551, preferably 0.3190421. t is an arbitrary value selected from 0.0273504 to 0.0399372, preferably 0.0336438; u is an arbitrary value selected from 0.3327566 to 0.3940448, preferably 0.3634007. The method according to claim 41 or 42.

44. Based on the predicted number of retrieved oocytes (predicted NRO) calculated in the first calculation and the ratio value calculated in the second calculation, Equation 6 is used to calculate the adjusted dose of exogenous FSH agent to be administered to the subject, and Equation 6 is Adjusted dose of exogenous FSH agent = Rounding (predicted NROs calculated by Equation 4 / predicted ovarian sensitivity calculated by Equation 5, 0) The method according to claim 43, wherein:

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