阅读说明：本技术 预测拮抗剂方案下受试者卵巢低反应概率的系统及指导***起始用药剂量选择的系统 (System for predicting the probability of hyporesponsiveness of a subject's ovary under an antagonist regimen and system for guiding the selection of initial dosage of gonadotropins ) 是由 李蓉 徐慧玉 冯国双 韩勇 乔杰 于 2018-06-05 设计创作，主要内容包括：本发明涉及一种预测拮抗剂方案下受试者卵巢低反应概率的系统以及指导促性腺激素起始用药剂量选择的系统。所述用于预测卵巢低反应概率的系统包括：数据采集模块,其用于获取受试者的年龄、抗缪勒氏管激素(AMH)水平、卵泡刺激素(FSH)水平、窦卵泡计数(AFC)的数据；以及计算卵巢低反应发生概率的模块,其用于将数据采集模块中的获取的信息进行计算从而计算出该受试者发生卵巢低反应的概率,并根据预测的低反应概率给予外源性促性腺激素(Gn)起始剂量建议。(The present invention relates to a system for predicting the probability of a subject's ovarian hyporesponsiveness under an antagonist regimen and for guiding the selection of an initial dosage of gonadotropin. The system for predicting ovarian hypo-response probability comprises: a data acquisition module for acquiring data of age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, Antral Follicle Count (AFC) of the subject; and a module for calculating the incidence probability of ovarian hyporeaction, which is used for calculating the acquired information in the data acquisition module so as to calculate the probability of ovarian hyporeaction of the subject, and giving an exogenous gonadotropin (Gn) initial dose recommendation according to the predicted probability of hyporeaction.)

1. a system for predicting the probability of an ovarian hypo-response in a subject, comprising:

A data acquisition module for acquiring data of age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, Antral Follicle Count (AFC) of the subject;

and the module for calculating the incidence probability of the ovarian hyporeaction is used for calculating the acquired information in the data acquisition module so as to calculate the probability of the ovarian hyporeaction of the subject.

2. the system of claim 1, wherein,

the subject is a subject who is administered exogenous gonadotropin (Gn) on day 2 or day 3 of the menstrual cycle and is administered an antagonist of gonadotropin releasing hormone (GnRH) 5 to 7 days after the administration of exogenous gonadotropin (Gn).

3. The system of claim 1, wherein,

in the module for calculating the incidence of ovarian hyporesponsiveness, the probability of ovarian hyporesponsiveness in the subject is calculated using two classification variables into which data on the age of the subject, the anti-mullerian hormone (AMH) level of the subject, the Follicle Stimulating Hormone (FSH) level of the subject, and the Antral Follicle Count (AFC) of the subject are converted.

4. The system of claim 3, wherein,

in the module for calculating the probability of occurrence of ovarian hyporesponsiveness, a cutoff point of age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, and sinus follicle count (AFC) is detected using a Receiver Operating Characteristic (ROC) curve, and the age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, and sinus follicle count (AFC) are converted into two classification variables based on a cut point value at the cutoff point, thereby calculating the probability of occurrence of ovarian hyporesponsiveness in the subject using the two classification variables.

5. the system of claim 4, wherein,

The anti-mullerian hormone (AMH) level refers to the anti-mullerian hormone concentration in venous blood of the female subject from 2 to 4 days of menstruation, the Follicle Stimulating Hormone (FSH) level refers to the follicle stimulating hormone concentration in venous blood of the female subject from 2 to 4 days of menstruation, and the Antral Follicle Count (AFC) refers to the number of all visible follicles with a diameter of 2 to 8mm in both ovaries when the female subject is subjected to vaginal B-super counting for 2 to 4 days of menstruation.

6. the system of claim 4 or 5,

The cutoff value for the age was 35 years, the cutoff value for the anti-mullerian hormone (AMH) level was 0.93ng/ml, the cutoff value for the Follicle Stimulating Hormone (FSH) level was 9.1IU/L, and the cutoff value for the Antral Follicle Count (AFC) was 8.

7. the system of any one of claims 1 to 6,

The module for calculating the incidence of ovarian hyporesponsiveness stores in advance a formula for calculating the incidence of ovarian hyporesponsiveness, which is fitted based on two classification variables into which the data of the subject's subject age, the subject's anti-mullerian hormone (AMH) level, the subject's Follicle Stimulating Hormone (FSH) level, and the subject's sinus follicle count (AFC) are converted, in an existing database.

8. The system of claim 7, wherein,

The formula is the following formula one:

Wherein i is any value selected from-1.786 to-0.499, a is any value selected from 0.063 to 1.342, b is any value selected from-2.542 to-1.056, c is any value selected from 0.548 to 1.838, and d is any value selected from-2.133 to-0.51, wherein i is preferably-1.143, a is preferably 0.703, b is preferably-1.799, c is preferably 1.193, and d is preferably-1.322.

9. A system for directing the initial dosing of exogenous gonadotropin (Gn) to a patient, comprising:

A data acquisition module for acquiring data of age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, Antral Follicle Count (AFC) of the subject;

a module for calculating the incidence probability of ovarian hyporeaction, which is used for calculating the information acquired in the data acquisition module so as to calculate the probability of ovarian hyporeaction of the subject;

the grouping module is prestored with a grouping basis, and groups the test subjects with the ovarian hyporeaction probability calculated by the module for calculating the ovarian hyporeaction occurrence probability according to the grouping basis; and

a recommending module for an initial dosage of exogenous gonadotropin (Gn) recommending an initial dosage of Gn for the group into which the subject is classified based on the grouping module.

10. The system of claim 9, wherein,

The subject is a subject who is administered an exogenous ovulation-promoting drug (Gn) on day 2 or day 3 of the menstrual cycle, and is administered an antagonist of gonadotropin-releasing hormone (GnRH) 5 to 7 days after the administration of the exogenous ovulation-promoting drug.

11. The system of claim 9, wherein,

The grouping basis pre-stored in the grouping module is a grouping basis established for the occurrence of the ovarian hypo-reaction probability according to whether the interaction between the exogenous ovulation-promoting drug (Gn) starting dose and the predicted ovarian hypo-reaction probability is meaningful or not by utilizing the existing data.

12. The system of claim 11, wherein,

The grouping basis prestored in the grouping module is as follows:

The probability of the subject developing an ovarian hypo-response is < 5%;

The probability of ovarian hyporesponsiveness of a subject is more than or equal to 5 percent and less than 20 percent;

The probability of ovarian hyporesponsiveness of a subject is more than or equal to 20% and less than 50%;

The probability of the low ovarian response of the testee is more than or equal to 50 percent.

13. the system of claim 10, wherein,

In the module for calculating the incidence of ovarian hyporesponsiveness, the probability of ovarian hyporesponsiveness in the subject is calculated using two classification variables into which data on the age of the subject, the anti-mullerian hormone (AMH) level of the subject, the Follicle Stimulating Hormone (FSH) level of the subject, and the Antral Follicle Count (AFC) of the subject are converted.

14. The system of claim 13, wherein,

In the module for calculating the probability of occurrence of ovarian hyporesponsiveness, a cutoff point of age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, and sinus follicle count (AFC) is detected using a Receiver Operating Characteristic (ROC) curve, and the age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, and sinus follicle count (AFC) are converted into two classification variables based on a cut point value at the cutoff point, thereby calculating the probability of occurrence of ovarian hyporesponsiveness in the subject using the two classification variables.

15. The system of claim 14, wherein,

The anti-mullerian hormone (AMH) level refers to the anti-mullerian hormone concentration in venous blood of the female subject taken 2-4 days of menstruation, the Follicle Stimulating Hormone (FSH) level refers to the follicle stimulating hormone concentration in venous blood of the female subject taken 2-4 days of menstruation, and the Antral Follicle Count (AFC) refers to the number of all visible follicles with a diameter of 2-8mm in both ovaries when the female subject was taken 2-4 days of menstruation at vaginal B-super count.

16. The system of claim 14 or 15,

The cutoff value for the age was 35 years, the cutoff value for the anti-mullerian hormone (AMH) level was 0.93ng/ml, the cutoff value for the Follicle Stimulating Hormone (FSH) level was 9.1IU/L, and the cutoff value for the Antral Follicle Count (AFC) was 8.

17. the system of any one of claims 9-16,

the module for calculating the incidence of ovarian hyporesponsiveness stores in advance a formula for calculating the incidence of ovarian hyporesponsiveness, which is fitted based on two classification variables into which the data of the subject's subject age, the subject's anti-mullerian hormone (AMH) level, the subject's Follicle Stimulating Hormone (FSH) level, and the subject's sinus follicle count (AFC) are converted, in an existing database.

18. the system of claim 17, wherein,

the formula is the following formula one:

Wherein i is any value selected from-1.786 to-0.499, a is any value selected from 0.063 to 1.342, b is any value selected from-2.542 to-1.056, c is any value selected from 0.548 to 1.838, and d is any value selected from-2.133 to-0.51, wherein i is preferably-1.143, a is preferably 0.703, b is preferably-1.799, c is preferably 1.193, and d is preferably-1.322.

Technical Field

The present invention relates to a system for predicting ovarian hyporesponsiveness in a subject under a regimen of administration of an antagonist, and a system for directing the initial dosage range of gonadotropins (Gn).

Background

In the process of controlled ovulation induction (COS), the number of eggs obtained is considered as a strong predictor of success or failure of pregnancy after IVF-ET (in vitro fertilization-embryo transfer) surgery. A study of over 40 million people in Europe, published in the authoritative magazine "Human Reproduction", showed that the appropriate number of eggs obtained significantly improved live productivity compared to the lower number of eggs obtained on the day of egg retrieval. In the COS process, the main problem facing the patient is insufficient number of eggs obtained, i.e. low ovarian response, which results in higher cycle abrogation rates and poor pregnancy outcome, e.g. lower embryo planting rates, pregnancy rates and live birth rates. Predicting ovarian response prior to COS and administering an appropriate initial dose of exogenous ovulation-promoting drug (Gn) is currently the only clinically accepted effective method to avoid ovarian hyporesponsiveness. A variety of markers have been used worldwide to assess ovarian hyporesponsiveness, including age, follicle stimulating hormone (bFSH) levels at 2-4 days of menstruation, Antral Follicle Count (AFC), anti-mullerian hormone (AMH), and estrogen levels at 2-4 days of menstruation (bE2), among others. In recent years, AMH is considered as the best index for predicting ovarian reserve, so that a group tries to explore AMH and other indexes combined to predict low response of the ovary from abroad, but the research is based on a gonadotropin releasing hormone (GnRH) long scheme, mainly aiming at Caucasian race, and different from China in population, dietary habits and the like.

Disclosure of Invention

As described above, judging whether or not a subject is ovarian hypo-response is a very important task for a clinician or the like. Furthermore, the selection of different starting doses of gonadotropin (Gn) for different patients in order to obtain the best number of eggs obtained on the day of taking eggs in an in vitro fertilization embryo transfer (IVF-ET) cycle is the most important clinical decision for the procreation physician. However, to date there are no standards or guidelines internationally instructing clinicians how to select an appropriate Gn start dose for different patients. There is also no system that would help a clinician judge the probability of an ovarian hypo-response occurring in a subject. In the past, clinicians generally selected the initial dose of Gn based on their clinical experience based on past history of ovarian response, age, BMI, AFC, and serum FSH levels over 2-4 days of menstruation in women. Therefore, the present invention is intended to provide a system capable of accurately, conveniently and quickly predicting ovarian hyporesponsiveness, and a system capable of accurately, conveniently and quickly guiding administration of drugs to ovarian hyporesponsiveness patients.

in particular, the invention relates to the following:

1. a system for predicting the probability of an ovarian hypo-response in a subject, comprising:

A data acquisition module for acquiring data of age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, Antral Follicle Count (AFC) of the subject;

and the module for calculating the incidence probability of the ovarian hyporeaction is used for calculating the acquired information in the data acquisition module so as to calculate or predict the probability of the ovarian hyporeaction of the subject.

2. The system of item 1, wherein,

The subject is a subject who is administered an exogenous ovulation-promoting drug (Gn) on day 2 or day 3 of the menstrual cycle, and an antagonist of gonadotropin-releasing hormone (GnRH) on days 5 to 7 after the administration of the exogenous gonadotropin (Gn).

3. The system of item 1 or 2, wherein,

In the module for calculating the incidence of ovarian hyporesponsiveness, the probability of ovarian hyporesponsiveness in the subject is calculated using two classification variables into which data on the age of the subject, the anti-mullerian hormone (AMH) level of the subject, the Follicle Stimulating Hormone (FSH) level of the subject, and the Antral Follicle Count (AFC) of the subject are converted.

4. The system according to any one of items 1 to 3, wherein,

In the module for calculating the probability of occurrence of ovarian hyporesponsiveness, a cutoff point of age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, and sinus follicle count (AFC) is detected using a Receiver Operating Characteristic (ROC) curve, and the age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, and sinus follicle count (AFC) are converted into two classification variables based on a cut point value at the cutoff point, thereby calculating the probability of occurrence of ovarian hyporesponsiveness in the subject using the two classification variables.

5. The system according to any one of items 1 to 4, wherein,

the anti-mullerian hormone (AMH) level refers to the anti-mullerian hormone concentration in venous blood of the female subject from 2 to 4 days of menstruation, the Follicle Stimulating Hormone (FSH) level refers to the follicle stimulating hormone concentration in venous blood of the female subject from 2 to 4 days of menstruation, and the Antral Follicle Count (AFC) refers to the number of all visible follicles with a diameter of 2 to 8mm in both ovaries when the female subject is subjected to vaginal B-super counting for 2 to 4 days of menstruation.

6. The system according to any one of items 1 to 5, wherein,

the cutoff value for the age was 35 years, the cutoff value for the anti-mullerian hormone (AMH) level was 0.93ng/ml, the cutoff value for the Follicle Stimulating Hormone (FSH) level was 9.1IU/L, and the cutoff value for the Antral Follicle Count (AFC) was 8.

7. The system according to any one of items 1 to 6, wherein,

The module for calculating the incidence of ovarian hyporesponsiveness stores in advance a formula for calculating the incidence of ovarian hyporesponsiveness, which is fitted based on two classification variables into which the data of the subject's subject age, the subject's anti-mullerian hormone (AMH) level, the subject's Follicle Stimulating Hormone (FSH) level, and the subject's sinus follicle count (AFC) are converted, in an existing database.

8. The system of item 7, wherein,

the formula is the following formula one:

Wherein i is any value selected from-1.786 to-0.499, a is any value selected from 0.063 to 1.342, b is any value selected from-2.542 to-1.056, c is any value selected from 0.548 to 1.838, and d is any value selected from-2.133 to-0.51, wherein i is preferably-1.143, a is preferably 0.703, b is preferably-1.799, c is preferably 1.193, and d is preferably-1.322.

9. A system for guiding gonadotropin dosing determination in a patient, comprising:

A data acquisition module for acquiring data of age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, Antral Follicle Count (AFC) of the subject;

a module for calculating the incidence probability of ovarian hyporeaction, which is used for calculating the acquired information in the data acquisition module so as to calculate or predict the probability of ovarian hyporeaction of the subject;

The grouping module is prestored with a grouping basis, and groups the test subjects with the ovarian hyporeaction probability calculated by the module for calculating the ovarian hyporeaction occurrence probability according to the grouping basis; and

a recommending module for an initial dose of exogenous gonadotropin (Gn) recommending an initial dosing of Gn based on the grouping module grouping the groups of subjects.

10. the system of item 9, wherein,

the subject is a subject who is administered an exogenous ovulation-promoting drug (Gn) on day 2 or day 3 of the menstrual cycle, and an antagonist of gonadotropin-releasing hormone (GnRH) on days 5 to 7 after the administration of the exogenous gonadotropin (Gn).

11. The system of clauses 9 or 10, wherein,

The grouping basis pre-stored in the grouping module is a grouping basis established for the occurrence probability of low ovarian response according to whether the interaction between the Gn initial dose and the predicted low ovarian response probability is meaningful or not by utilizing the existing database.

12. The system of item 11, wherein,

The grouping basis prestored in the grouping module is as follows:

the probability of the subject developing an ovarian hypo-response is < 5%;

The probability of ovarian hyporesponsiveness of a subject is more than or equal to 5 percent and less than 20 percent;

The probability of ovarian hyporesponsiveness of a subject is more than or equal to 20% and less than 50%;

The probability of ovarian hyporesponsiveness of the subject is less than or equal to 50 percent.

13. the system according to any one of items 9 to 12, wherein,

In the module for calculating the incidence of ovarian hyporesponsiveness, the probability of ovarian hyporesponsiveness in the subject is calculated using two classification variables into which data on the age of the subject, the anti-mullerian hormone (AMH) level of the subject, the Follicle Stimulating Hormone (FSH) level of the subject, and the Antral Follicle Count (AFC) of the subject are converted.

14. The system according to any one of items 9 to 13, wherein,

in the module for calculating the probability of occurrence of ovarian hyporesponsiveness, a cutoff point of age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, and sinus follicle count (AFC) is detected using a Receiver Operating Characteristic (ROC) curve, and the age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, and sinus follicle count (AFC) are converted into two classification variables based on a cut point value at the cutoff point, thereby calculating the probability of occurrence of ovarian hyporesponsiveness in the subject using the two classification variables.

15. The system according to any one of items 9 to 14, wherein,

The anti-mullerian hormone (AMH) level refers to the anti-mullerian hormone concentration in venous blood of the female subject taken 2-4 days of menstruation, the Follicle Stimulating Hormone (FSH) level refers to the follicle stimulating hormone concentration in venous blood of the female subject taken 2-4 days of menstruation, and the Antral Follicle Count (AFC) refers to the number of all visible follicles with a diameter of 2-8mm in both ovaries when the female subject was taken 2-4 days of menstruation at vaginal B-super count.

The system of any of claims 9-15, wherein,

the cutoff value for the age was 35 years, the cutoff value for the anti-mullerian hormone (AMH) level was 0.93ng/ml, the cutoff value for the Follicle Stimulating Hormone (FSH) level was 9.1IU/L, and the cutoff value for the Antral Follicle Count (AFC) was 8.

17. The system according to any one of items 9 to 16, wherein,

The module for calculating the incidence of ovarian hyporesponsiveness stores in advance a formula for calculating the incidence of ovarian hyporesponsiveness, which is fitted based on two classification variables into which the data of the subject's subject age, the subject's anti-mullerian hormone (AMH) level, the subject's Follicle Stimulating Hormone (FSH) level, and the subject's sinus follicle count (AFC) are converted, in an existing database.

18. the system of any one of items 9 to 17, wherein,

The formula is the following formula one:

Wherein i is any value selected from-1.786 to-0.499, a is any value selected from 0.063 to 1.342, b is any value selected from-2.542 to-1.056, c is any value selected from 0.548 to 1.838, and d is any value selected from-2.133 to-0.51, wherein i is preferably-1.143, a is preferably 0.703, b is preferably-1.799, c is preferably 1.193, and d is preferably-1.322.

19. A method for predicting the probability of an ovarian hypo-response in a subject, comprising:

A data acquisition step in which data of the age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, sinus follicle count (AFC) of the subject is acquired;

And a step of calculating a probability of occurrence of an ovarian hyporesponsiveness, in which a calculation is performed using the age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, and sinus follicle count (AFC) data acquired in the step of acquiring data, thereby calculating or predicting a probability of occurrence of an ovarian hyporesponsiveness in the subject.

20. the method of item 19, wherein,

The subject is a subject who is administered an exogenous ovulation-promoting drug (Gn) on day 2 or day 3 of the menstrual cycle, and an antagonist of gonadotropin-releasing hormone (GnRH) on days 5 to 7 after the administration of the exogenous gonadotropin (Gn).

21. The method of item 19 or 20, wherein,

In the step of calculating the probability of the occurrence of an ovarian hyporesponsiveness, data of the age of the subject, the anti-mullerian hormone (AMH) level of the subject, the Follicle Stimulating Hormone (FSH) level of the subject, and the Antral Follicle Count (AFC) of the subject are converted into two classification variables, and the converted two classification variables are used to calculate or predict the probability of the occurrence of an ovarian hyporesponsiveness of the subject.

22. The method according to any one of items 19 to 21, wherein,

in the calculating of the probability of occurrence of an ovarian hyporesponsiveness step, a cutoff point of age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, and sinus follicle count (AFC) is detected using a Receiver Operating Characteristic (ROC) curve, and the age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, and sinus follicle count (AFC) are converted into two classification variables based on the cutoff point value at the cutoff point, thereby calculating the probability of occurrence of an ovarian hyporesponsiveness in the subject using the two classification variables.

23. The method according to any one of items 19 to 22, wherein,

The anti-mullerian hormone (AMH) level refers to the anti-mullerian hormone concentration in venous blood of the female subject from 2 to 4 days of menstruation, the Follicle Stimulating Hormone (FSH) level refers to the follicle stimulating hormone concentration in venous blood of the female subject from 2 to 4 days of menstruation, and the Antral Follicle Count (AFC) refers to the number of all visible follicles with a diameter of 2 to 8mm in both ovaries when the female subject is subjected to vaginal B-super counting for 2 to 4 days of menstruation.

24. the method of any one of items 19 to 23, wherein,

the cutoff value for the age was 35 years, the cutoff value for the anti-mullerian hormone (AMH) level was 0.93ng/ml, the cutoff value for the Follicle Stimulating Hormone (FSH) level was 9.1IU/L, and the cutoff value for the Antral Follicle Count (AFC) was 8.

25. the method of any one of items 19 to 24, wherein,

in the step of calculating the incidence of ovarian hyporesponsiveness, the calculation is performed using a formula for calculating the incidence of ovarian hyporesponsiveness, which is previously fitted based on two classification variables into which the subject age, the subject anti-mullerian hormone (AMH) level, the subject Follicle Stimulating Hormone (FSH) level, and the subject sinus follicle count (AFC) of the subject are converted in the existing database.

26. The method of any one of items 18 to 25, wherein,

In calculating the probability of occurrence of ovarian hyporesponsiveness, the probability of ovarian hyporesponsiveness is calculated from the data of age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, sinus follicle count (AFC) of the subject obtained in the data collection step and having been converted to two categorical variables using the following formula one:

wherein i is any value selected from-1.786 to-0.499, a is any value selected from 0.063 to 1.342, b is any value selected from-2.542 to-1.056, c is any value selected from 0.548 to 1.838, and d is any value selected from-2.133 to-0.51, wherein i is preferably-1.143, a is preferably 0.703, b is preferably-1.799, c is preferably 1.193, and d is preferably-1.322.

27. a method for directing medication to an ovarian hypo-responsive patient, comprising:

A data acquisition step in which data of the age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, sinus follicle count (AFC) of the subject is acquired;

calculating a probability of occurrence of an ovarian hyporesponsiveness, in which the probability of occurrence of an ovarian hyporesponsiveness in the subject is calculated using the age of the subject, the anti-mullerian hormone (AMH) level of the subject, the Follicle Stimulating Hormone (FSH) level of the subject, and the sinus follicle count (AFC) data of the subject, which are acquired in the data acquisition step;

Grouping according to pre-stored groups and the calculated probability of low ovarian response of the testee; and recommending the initial dosage of Gn to the subjects according to the grouping condition.

28. the method of item 27, wherein,

the subject is a subject who is administered with an exogenous ovulation-promoting drug (Gn) on day 2 or day 3 of the menstrual cycle, and an antagonist of gonadotropin-releasing hormone (GnRH) on day 5 to day 7 after the administration of the exogenous ovulation-promoting drug (Gn).

29. The method of clauses 27 or 28, wherein,

the pre-stored grouping basis is a grouping basis established for the occurrence of the ovarian hypo-response probability according to whether the interaction between the Gn initial dose and the predicted ovarian hypo-response probability is meaningful or not by utilizing the existing database.

30. the method of any one of items 27 to 29, wherein,

the pre-stored grouping basis is:

The probability of the subject developing an ovarian hypo-response is < 5%;

The probability of ovarian hyporesponsiveness of a subject is more than or equal to 5 percent and less than 20 percent;

The probability of ovarian hyporesponsiveness of a subject is more than or equal to 20% and less than 50%;

the probability of ovarian hyporesponsiveness of the subject is less than or equal to 50 percent.

31. The method of any one of items 27 to 30, wherein,

In the step of calculating the probability of the occurrence of an ovarian hyporesponsiveness, the probability of the occurrence of an ovarian hyporesponsiveness in the subject is calculated using two classification variables into which data on the age of the subject, the anti-mullerian hormone (AMH) level of the subject, the Follicle Stimulating Hormone (FSH) level of the subject, and the Antral Follicle Count (AFC) of the subject are converted.

32. the method of any one of items 27 to 31, wherein,

in calculating the probability of occurrence of an ovarian hyporesponsiveness, the cutoff points of age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, and sinus follicle count (AFC) are detected using a Receiver Operating Characteristic (ROC) curve, and the age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, and sinus follicle count (AFC) are converted into two classification variables based on the cutoff values at the cutoff points, thereby calculating the probability of occurrence of an ovarian hyporesponsiveness in the subject using the two classification variables.

33. The method of any one of items 27 to 31, wherein,

The anti-mullerian hormone (AMH) level refers to the anti-mullerian hormone concentration in venous blood of the female subject from 2 to 4 days of menstruation, the Follicle Stimulating Hormone (FSH) level refers to the follicle stimulating hormone concentration in venous blood of the female subject from 2 to 4 days of menstruation, and the Antral Follicle Count (AFC) refers to the number of all visible follicles with a diameter of 2 to 8mm in both ovaries when the female subject is subjected to vaginal B-super counting for 2 to 4 days of menstruation.

34. the method of any one of items 27 to 33, wherein,

the cutoff value for the age was 35 years, the cutoff value for the anti-mullerian hormone (AMH) level was 0.93ng/ml, the cutoff value for the Follicle Stimulating Hormone (FSH) level was 9.1IU/L, and the cutoff value for the Antral Follicle Count (AFC) was 8.

35. The method of any one of items 27 to 34, wherein,

In the step of calculating the incidence of ovarian hyporesponsiveness, the calculation is performed using a formula for calculating the incidence of ovarian hyporesponsiveness, which is previously fitted based on two classification variables into which the subject age, the subject anti-mullerian hormone (AMH) level, the subject Follicle Stimulating Hormone (FSH) level, and the subject sinus follicle count (AFC) of the subject are converted in the existing database.

36. the method of any one of items 27 to 35, wherein,

in calculating the probability of occurrence of ovarian hyporesponsiveness, the probability of ovarian hyporesponsiveness is calculated from the data of age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, sinus follicle count (AFC) of the subject obtained in the data collection step and having been converted to two categorical variables using the following formula one:

Wherein i is any value selected from-1.786 to-0.499, a is any value selected from 0.063 to 1.342, b is any value selected from-2.542 to-1.056, c is any value selected from 0.548 to 1.838, and d is any value selected from-2.133 to-0.51, wherein i is preferably-1.143, a is preferably 0.703, b is preferably-1.799, c is preferably 1.193, and d is preferably-1.322.

Effects of the invention

Since serum AMH levels perform well in predicting ovarian responses in GnRH antagonist regimens, the present invention contemplates a reliable system for predicting ovarian hyporesponsiveness and an effective system for directing the administration of drugs to patients with ovarian hyporesponsiveness, using such a system to classify subjects into different groups based on the probability of occurrence of ovarian hyporesponsiveness, and then assigning a dosing regimen to the subject based on the group of subjects.

In particular, the system for predicting ovarian hyporesponsiveness of a subject of the present invention may be used in the present invention to predict the probability of a subject developing ovarian hyporesponsiveness in the first place. By utilizing the system, the occurrence probability of the low ovarian response can be predicted, so that the ovarian reserve can be evaluated, the evaluation index of the current clinical ovarian reserve is also the index for predicting the low ovarian response, and a clinician is also a diagnosis standard for using the low ovarian response when the diagnosis of the ovarian reserve reduction is made. Since the definition of ovarian reserve refers to the number of primordial follicles in the ovarian cortex, the number of primordial follicles cannot be evaluated non-invasively, and can only be evaluated by the number of follicles mobilized per menstrual cycle, whereas fewer follicles mobilized during the IVF-ET cycle (hypo-reactive ovaries), suggesting a decreased ovarian reserve function. Thus, predicting ovarian hyporesponsiveness may be used to assess ovarian reserve function in order for women to rationally schedule fertility, in addition to giving certain dosing guidelines.

Further, by using the system for guiding the administration of the ovarian hyporeaction patient of the invention, the probability of the ovarian hyporeaction of the subject is firstly calculated, and then the classification of the probability of the ovarian hyporeaction of the subject can be realized through a grouping module, wherein the preset grouping standard of the system is as follows: the low reaction probability of the testee is less than 5%, the probability of ovary low reaction of the testee is less than 20%, the probability of ovary low reaction of the testee is less than 50%, and the low reaction probability is more than or equal to 50%. After grouping, a recommended dose module can be used to achieve a recommended starting dose of exogenous ovulation-promoting drugs (Gn) to subjects belonging to different groups.

The system of the present invention can prompt the physician to gradually increase the Gn initial dose in order from low to high according to the predicted probability of low response occurrence of the patient to achieve the best cost effectiveness ratio, thereby improving the ovarian response level of the patient with a shorter treatment period and a lower treatment cost.

the inventor of the invention predicts the ovarian hyporesponsiveness by applying four indexes of AFC (alpha-aminobutyric acid) of AMH (adenosine monophosphate) level at 2-4 days of menstruation, age, FSH (follicle stimulating hormone) level at 2-4 days of menstruation and vaginal B ultrasonic count at 2-4 days of menstruation for the first time in an antagonist scheme, groups people according to the interaction relation between the predicted incidence probability of the ovarian hyporesponsiveness and the initial dose of exogenous gonadotropin (Gn), and gives a recommendation of the initial dose of Gn.

drawings

Various other advantages and benefits of the present application will become apparent to those of ordinary skill in the art upon reading the following detailed description of the preferred embodiments. The drawings are only for purposes of illustrating the preferred embodiments and are not to be construed as limiting the application. It is obvious that the drawings described below are only some embodiments of the application, and that for a person skilled in the art, other drawings can be derived from them without inventive effort. Also, like parts are designated by like reference numerals throughout the drawings.

figure 1 ROC curve analysis for age variables.

FIG. 2 ROC curve analysis for the variation in AMH levels from day 2 to day 4 of menstruation.

FIG. 3 ROC curve analysis of the variation of serum FSH levels over 2-4 days of menstruation.

FIG. 4 ROC curve analysis of vaginal B-ultrasound AFC level variation over 2-4 days of menstruation.

FIG. 5 ROC curve analysis of a model predicting ovarian hypo-response (LOR) probability.

fig. 6 regression model plots of Gn starting dose, predicted probability of LOR, and interaction effect between them.

Detailed Description

Specific embodiments of the present invention will be described in more detail below with reference to the accompanying drawings. While specific embodiments of the invention are shown in the drawings, it should be understood that the invention may be embodied in various forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

It should be noted that certain terms are used throughout the description and claims to refer to particular components. As one skilled in the art will appreciate, various names may be used to refer to a component. This specification and claims do not intend to distinguish between components that differ in name but not function. In the following description and in the claims, the terms "include" and "comprise" are used in an open-ended fashion, and thus should be interpreted to mean "include, but not limited to. The description which follows is a preferred embodiment of the invention, but is made for the purpose of illustrating the general principles of the invention and not for the purpose of limiting the scope of the invention. The scope of the present invention is defined by the appended claims.

Several factors involved in infertility in this application are defined below. Endometriosis refers to a common gynecological disease in women, wherein activated endometrial cells are planted in a position except endometrium. The endometrial cells should grow in the uterine cavity, but because the uterine cavity is communicated with the pelvic cavity through the fallopian tube, the endometrial cells can enter the pelvic cavity through the fallopian tube to grow ectopically. The main pathological changes of endometriosis are ectopic intimal periodic hemorrhage and fibrosis of surrounding tissues, formation of ectopic nodules, and main symptoms of dysmenorrhea, chronic pelvic pain, abnormal menstruation and infertility. Lesions can spread to all pelvic tissues and organs, are most common in parts such as ovary, uterine rectum pouch, uterosacral ligament and the like, and can also occur in abdominal cavity, thoracic cavity, limbs and the like. Tubal infertility refers to the fact that tubal obstruction or dysfunction is the main cause of female infertility due to the important functions of the fallopian tube in transporting sperm, picking up ovum, and transporting fertilized ovum to uterine cavity. The reasons for tubal obstruction or dysfunction are acute and chronic salpingitis. Furthermore, infertility of unknown cause is defined as a couple who has a history of repeated pregnancy failure although the results of standard tests such as ovulation test, fallopian tube patency and semen analysis show normality.

continuous variables: in statistics, variables can be classified into continuous variables and classified variables according to whether the variable values are continuous or not. The variable which can be arbitrarily valued in a certain interval is called continuous variable, the numerical value is continuous, and two adjacent numerical values can be infinitely divided, i.e. an infinite number of numerical values can be obtained. For example, the specification size of the produced part, the height, weight, chest circumference and the like measured by a human body are continuous variables, and the numerical values can be obtained only by a measuring or metering method. Conversely, values that can only be calculated in natural or integer units are discrete variables. For example, the number of businesses, employees, equipment, etc. can only be counted in units of a meter, and the value of such variables is typically obtained by a counting method.

categorical variables refer to variables in terms of geographic location, demographics, etc., which function to group survey respondents. The description variables describe the difference between a certain customer group and other customer groups. Most categorical variables are also descriptive variables. Categorical variables can be divided into two broad categories, unordered categorical variables and ordered categorical variables. Wherein, unordered classification variable (unordered classification variable) refers to the degree and order of difference between the classified classes or attributes. It can be classified into two categories, such as sex (male and female), drug reaction (negative and positive), etc.; ② a plurality of classifications, such as blood type (O, A, B, AB), occupation (worker, agriculture, business, school, soldier), etc. And there is a degree of difference between the categories of the ordered categorical variable (the ordered categorical variable). For example, the urine glucose assay results are classified according to-, + +; the curative effects are classified according to cure, obvious effect, improvement and ineffectiveness. For the ordered classification variables, the variables are firstly grouped according to the grade sequence, the number of observation units of each group is counted, a frequency table of the ordered variables (each grade) is compiled, and the obtained data is called grade data.

The variable types are not invariable and conversion between the various types of variables is possible depending on the needs of the study. For example, the hemoglobin (g/L) is a primary numerical variable, and if the hemoglobin is divided into two categories according to the normal hemoglobin and the low hemoglobin, the two categories can be analyzed according to the two categories; if the blood is classified into five grades according to severe anemia, moderate anemia, mild anemia, normal and hemoglobin increase, the analysis can be performed according to grade data. The classifier data may also be quantified, e.g., the patient's nausea response may be expressed as 0, 1, 2, 3, and may be analyzed as numerical variable data (quantitative data).

The present invention relates to a system for predicting the probability of an ovarian hypo-response in a subject, comprising:

a data acquisition module for acquiring data of age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, Antral Follicle Count (AFC) of the subject;

And the module for calculating the incidence probability of the ovarian hyporeaction is used for calculating the acquired information in the data acquisition module so as to calculate the probability of the ovarian hyporeaction of the subject.

in the system of the present invention, the subject is a subject who is administered exogenous gonadotropin (Gn) on day 2 or day 3 of the menstrual cycle and is administered an antagonist of gonadotropin-releasing hormone (GnRH) 5 to 7 days after the administration of exogenous gonadotropin (Gn).

the ovarian hyporesponsiveness in the present invention means that under the conditions of the subject who is administered exogenous gonadotropin (Gn) on day 2 or day 3 of the menstrual cycle and is administered an antagonist of gonadotropin-releasing hormone (GnRH) 5 to 7 days after the administration of exogenous gonadotropin (Gn), less than 5 (i.e., 0 to 4) oocytes are obtained on the day of egg acquisition, and the probability of occurrence of the ovarian hyporesponsiveness is predicted by the data calculated by the system of the present invention.

In particular, exogenous gonadotropin (Gn) therapy is initiated on day 2 or day 3 of the menstrual cycle. Initial dose is based on age, BMI (i.e. body Mass index)the weight kilogram number is divided by the height meter number squared, and the number is selected according to the standard of measuring the body fat-thin degree and health or not which are commonly used internationally), FSH and AFC levels in 2-4 days per month. During ovulation induction, the Gn initial dose is based on ultrasound observation and serum E₂level to adjust. GnRH antagonist treatment starts on day 5-7 of stimulation when the growing follicle is 10-12mm in diameter. When at least 2 dominant follicles (> 18mm in diameter) were visible by ultrasound, 5000-. Ova were removed 36 hours after hCG administration. Transferring 1-3 embryos or performing embryo cryopreservation. Then, a luteinizing progesterone support is provided.

in a specific embodiment, in the present invention directed to an antagonist regimen, the exogenous gonadotropin (Gn) is exogenous human recombinant follicle stimulating hormone (rFSH).

In the module for calculating the probability of occurrence of ovarian hyporesponsiveness, the probability of occurrence of ovarian hyporesponsiveness in a subject is calculated or predicted using two classification variables into which data on subject age, subject anti-mullerian hormone (AMH) level, subject Follicle Stimulating Hormone (FSH) level, subject Antral Follicle Count (AFC) are converted.

Anti-mullerian hormone (AMH) is a hormone secreted by the granulosa cells of ovarian small follicles, and female babies at fetal stage make AMH from 9 months of stool, and the higher the number of small follicles in the ovaries, the higher the concentration of AMH; on the contrary, when the follicles are gradually consumed with age and various factors, the AMH concentration is also decreased, and the closer to the menopause, the AMH tends to be 0.

follicle Stimulating Hormone (FSH) is a hormone secreted by anterior pituitary basophils and is composed of glycoproteins, which primarily function to promote follicular maturation. FSH promotes proliferative differentiation of follicular granular layer cells and promotes overall ovarian growth. And acting on the seminal tubules of testis to promote spermatogenesis. FSH is secreted in humans in pulses, and in women varies with the menstrual cycle. The determination of FSH in serum has important significance for diagnosing and treating infertility and endocrine diseases, such as understanding pituitary endocrine function, indirectly understanding ovarian functional state, evaluating ovarian reserve and ovarian reactivity, and making ovulation-promoting drug dosage.

antral Follicle Count (AFC) refers to the number of all visible follicles with a diameter of 2-8mm in both ovaries on 2-4 days of menstruation. AFC can be measured and counted by ultrasound on follicles.

in the present invention, the anti-mullerian hormone (AMH) level refers to the concentration of anti-mullerian hormone in a serum sample of venous blood from a female subject taken 2-4 days a.menstrual period, the Follicle Stimulating Hormone (FSH) level refers to the concentration of follicle stimulating hormone in a serum sample of venous blood from a female subject taken 2-4 days a.menstrual period, and the Antral Follicle Count (AFC) refers to the number of all visible follicles with a diameter of 2-8mm in both ovaries when the female subject was subjected to vaginal B-super counting for 2-4 days a.menstrual period.

In the module for calculating the probability of occurrence of ovarian hyporesponsiveness, a cutoff point of age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, and sinus follicle count (AFC) is detected using a Receiver Operating Characteristic (ROC) curve, and the age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, and sinus follicle count (AFC) are converted into two classification variables based on a cut point value at the cutoff point, so that the probability of occurrence of ovarian hyporesponsiveness in the subject is calculated by substituting the above formula with all of the two classification variables.

Although in the prior art, researchers have attempted to use some of the above parameters for analysis, by using Receiver Operating Characteristic (ROC) curves to detect demarcation points for age, anti-Mullerian hormone (AMH) levels, Follicle Stimulating Hormone (FSH) levels, sinus follicle count (AFC), and converting age, anti-mullerian hormone (AMH) level, Follicle Stimulating Hormone (FSH) level, and Antral Follicle Count (AFC) into two categorical variables according to the cut point value of the cut point, it was therefore an unexpected discovery of the present inventors to utilize all of the two categorical variables to be substituted into the above formula to calculate the probability of a subject developing an ovarian hypo-response, by transforming the 4 variables into the two-classification variables, the probability of ovarian hyporesponsiveness of the subject can be predicted more accurately by performing data analysis using the two-classification variables, and the model stability is better. Grouping subjects can also be more effectively achieved by accurately predicting the probability of an ovarian hypo-response occurring, thereby more effectively directing the initial dosing of exogenous gonadotropins (Gn).

In the present invention, the cut-point value for age was 35 years, the cut-point value for anti-mullerian hormone (AMH) level was 0.93ng/ml, the cut-point value for Follicle Stimulating Hormone (FSH) level was 9.1IU/L, and the cut-point value for Antral Follicle Count (AFC) was 8.

the module for calculating the incidence of ovarian hyporesponsiveness stores in advance a formula for calculating the incidence of ovarian hyporesponsiveness, which is fitted based on two classification variables into which the data of the subject's subject age, the subject's anti-mullerian hormone (AMH) level, the subject's Follicle Stimulating Hormone (FSH) level, and the subject's sinus follicle count (AFC) are converted, in an existing database.

In the present invention, the existing database refers to a database composed of subjects who are currently receiving treatment or who have previously received treatment and meet the following inclusion and exclusion criteria, and there is no provision for the sample size of the database, but the larger the sample size of the database is, the better the sample size is, for example, 100 subjects, 200 subjects, 300 subjects, preferably 400 subjects or more, and more preferably 500 subjects or more. In a specific embodiment, an existing database of 561 samples is employed.

The inclusion and exclusion criteria are, respectively, the inclusion criteria: women aged 20-45 years have a Body Mass Index (BMI) of less than or equal to 30, six consecutive menstrual cycles of 25-45 days, and normal bilateral ovarian morphology is assessed by vaginal ultrasonography, i.e., the number of IVF/ICSI-ET cycles is less than or equal to 2. Exclusion criteria were: hydrosalpinx, unilateral ovarian AFC >20, polycystic ovarian syndrome, other untreated metabolic or endocrine diseases, previous surgery on the ovary or uterine cavity, intrauterine abnormalities, within 3 months of pregnancy, smoking, couples who have previously undergone radiotherapy or chemotherapy with oral contraceptives or other hormones within the previous two months, and who have previously undergone genetic diagnosis for PGD (preimplantation embryonic genetic diagnosis)/PGS (preimplantation genetic screening) treatment.

In selecting a sample of the database, subjects capable of inclusion in the database need to meet both the inclusion and exclusion criteria described above.

The module for calculating the incidence probability of the low ovarian response calculates the probability of the low ovarian response according to the data acquired in the data acquisition module by using the following formula:

Wherein i is any value selected from-1.786 to-0.499, a is any value selected from 0.063 to 1.342, b is any value selected from-2.542 to-1.056, c is any value selected from 0.548 to 1.838, and d is any value selected from-2.133 to-0.51, wherein i is most preferably-1.143, most preferably a is 0.703, most preferably b is-1.799, most preferably c is 1.193, and most preferably d is-1.322.

In addition, the system for guiding the administration of drugs to the ovarian hyporeaction patients, which is related by the invention, comprises the data acquisition module and the module for calculating the incidence probability of ovarian hyporeaction, and also comprises the following components:

The grouping module is prestored with a grouping basis, and groups the test subjects with the ovarian hyporeaction probability calculated by the module for calculating the ovarian hyporeaction occurrence probability according to the grouping basis; specifically, the population is divided into four groups according to the predicted low reaction probability according to a preset database, and the subjects are automatically allocated to corresponding groups by the system after obtaining the calculated low reaction probability, and

A recommending module for an initial dosage of exogenous gonadotropin (Gn) recommending an initial dosage of Gn for the group into which the subject is classified based on the grouping module.

The pre-stored grouping basis is a grouping basis established for the occurrence probability of low ovarian response by utilizing the existing database according to whether the interaction between the Gn initial dose and the predicted low ovarian response probability is meaningful or not.

that is, in the present invention, the subjects in the existing database are used to establish grouping bases for the occurrence probability of low ovarian response according to whether the interaction between the Gn initial dose and the predicted low ovarian response probability of the subjects is meaningful, in the present invention, different grouping criteria are tried first, and in combination with the distribution of the Gn initial dose and the predicted low ovarian response probability, a plurality of grouping modes are tried in a way that the grouping intervals are from small to large, and the interaction of the grouping modes in the present invention is found to be meaningful through multiple fitting.

In one embodiment of the present invention, the grouping module calculates the predicted probability of LOR of a certain subject based on the prediction model of the above formula one, and classifies the calculated probability according to the pre-stored grouping basis, wherein the grouping basis is to classify the predicted probability of low reaction into the following four categories, namely:

prediction probability (p) of LOR < 5%;

the prediction probability (p) of the LOR is more than or equal to 5 percent and less than 20 percent;

The prediction probability (p) of the LOR is more than or equal to 20 percent and less than 50 percent;

A prediction probability (p) of LOR being 50% or more,

and controlling the initial dose of Gn according to the result of the classification.