Medicine for treating premature ovarian insufficiency and application

Abstract

The invention belongs to the technical field of traditional Chinese medicine, and particularly relates to a medicine for treating premature ovarian insufficiency and application, the medicine comprises a modified kidney-tonifying pill, and the modified kidney-tonifying pill is prepared from radix rehmanniae preparata, Chinese yam, poria cocos, wine-prepared fructus corni, angelica sinensis, fructus lycii, salted eucommia ulmoides, salted semen cuscutae, raspberry and mulberry according to the mass ratio of 2: 1: 1: 1: 1: 1: 1: 1: 1: 1: 1: 1: 1. Research finds that when a female progestational hormone sequential therapy is combined with the modified kidney-invigorating pill to treat a kidney deficiency type POI patient, clinical symptoms in multiple aspects of menstrual cycle, menstrual period, menstrual dose, soreness and weakness of waist and knees, dizziness and tinnitus, hectic fever and night sweat, sexual apathy and frequent urination at night can be remarkably improved, the serum FSH and LH levels are reduced, the E2 level is improved, and the traditional Chinese medicine composition is worthy of clinical popularization and has a wide application prospect. The theoretical basis and clinical guidance are provided for treating the kidney deficiency type POI through traditional Chinese medicine.

Description

Technical Field

[0001] The invention belongs to the technical field of traditional Chinese medicine, and specifically relates to a medicine for treating premature ovarian insufficiency and its application. Background Art

[0002] Premature Ovarian Insufficiency (POI) is a disease in which ovarian function gradually declines in women under 40 years old. Its main manifestations are abnormal menstruation (such as infrequent, frequent, delayed or amenorrhea), increased serum follicle-stimulating hormone (FSH) levels (FSH>25U / L for two consecutive tests, with an interval of at least 4 weeks) and decreased estrogen (E2) levels. POI not only affects women's fertility, but may also cause a series of health problems related to hormone disorders, such as hot flashes, night sweats, dizziness, tinnitus, sexual dysfunction, osteoporosis, and cardiovascular diseases, which seriously reduce women's quality of life.

[0003] Modern medicine has not yet fully clarified the cause of POI, but known factors include genetic factors, autoimmune factors, metabolic / enzyme dysfunction, iatrogenic factors (such as gynecological surgery, radiotherapy and chemotherapy), and environmental factors. Currently, hormone replacement therapy (HRT) is the most commonly used treatment in clinical practice. Although it can regulate the hormone levels in patients and improve related clinical symptoms to a certain extent, long-term use of HRT may increase the risk of breast cancer, ovarian cancer, and endometrial cancer. In addition, due to factors such as many adverse drug reactions, long treatment duration, and poor patient compliance, its clinical efficacy is not significant.

[0004] At the same time, traditional Chinese medicine has shown unique advantages in the treatment of POI. Although there is no specific name for "premature ovarian insufficiency" in traditional Chinese medicine, it can be classified into the categories of "scarce menstruation", "infertility", "late menstruation", "pre- and post-menopausal symptoms" according to its clinical manifestations. Traditional Chinese medicine believes that the onset of POI is closely related to kidney deficiency, and also involves dysfunction of multiple organs such as the heart, liver, and spleen. Based on this theory, traditional Chinese medicine has achieved good results in regulating patients' hormone levels and improving clinical symptoms through the treatment of tonifying the kidney and replenishing essence, soothing the liver and relieving depression, and strengthening the spleen and replenishing qi, using a variety of treatment methods such as Chinese herbal decoctions, paste prescriptions, acupuncture, and acupoint thread embedding, with fewer adverse reactions and easy for patients to accept.

[0005] However, there are many methods for treating POI with traditional Chinese medicine, but there is a lack of unified and standardized treatment plans, and the targeted treatment research for specific syndromes (such as kidney deficiency syndrome) is not in-depth enough. Therefore, it is necessary to combine the research results of modern medicine and the experience of traditional Chinese medicine treatment to develop an effective treatment method for kidney deficiency POI, so as to further improve the clinical efficacy and meet the treatment needs of patients. Summary of the invention

[0006] The purpose of the present invention is to provide a medicine for treating premature ovarian insufficiency and its application, which adopts estrogen-progestin sequential therapy combined with Jiawei Guishen Pills to treat patients with kidney deficiency type POI, and can significantly improve the clinical symptoms of menstrual cycle, menstrual period, menstrual volume, soreness of waist and knees, dizziness and tinnitus, hot flashes and night sweats, sexual frigidity, and frequent urination at night, reduce serum FSH and LH levels, and increase E2 levels, which is worthy of clinical promotion.

[0007] The objective of the present invention is achieved through the following technical solutions:

[0008] The invention provides a medicine for treating premature ovarian insufficiency, comprising Jiawei Guishen Pills.

[0009] Furthermore, the modified Guishen Pills are prepared from cooked rehmannia, yam, poria, wine-soaked cornus fruit, angelica, wolfberry, salt eucommia, salt dodder seed, rubus idaeus and mulberry in a mass ratio of 2:1:1:1:1:1:1:1:1:1:1:1.

[0010] Furthermore, the medicine also includes estradiol valerate and dydrogesterone tablets.

[0011] The present invention also provides an application of the modified Guishen Pills in the preparation of a medicine for treating premature ovarian insufficiency. The modified Guishen Pills are used in combination with an estrogen-progesterone sequential therapy to treat premature ovarian insufficiency.

[0012] Furthermore, the premature ovarian insufficiency is kidney deficiency type premature ovarian insufficiency.

[0013] Furthermore, the drug treats premature ovarian insufficiency by reducing the levels of serum sex hormones FSH and LH and increasing the level of E2.

[0014] Furthermore, the increasing of E2 level means that the E2 level can be further increased compared with the sequential estrogen-progestin therapy.

[0015] The applicant has found through experimental research that kidney deficiency is the key pathogenesis of POI. POI patients often show clinical symptoms of menstrual disorders and secondary infertility. The kidney is responsible for reproduction and is the innate foundation of the human body. When a woman grows to the age of fourteen, her kidneys are full of essence and qi, her menstruation is full, and she has reproductive function since then, which shows the importance of the kidney to women's menstruation and reproductive function. As Fu Qingzhu's Women's Medicine said: "Menstrual water originates from the kidney" and "Menstrual water comes from the kidney". If the kidney qi is depleted or the essence and blood in the kidney are insufficient, the material basis for maintaining women's reproductive function is lacking, and the uterus is difficult to be full, which leads to irregular menstruation and even amenorrhea, and eventually develops into POI. HRT, as a commonly used treatment measure for POI in clinical practice, can only relieve the patient's short-term clinical symptoms, and has poor efficacy for long-term harm. Traditional Chinese medicine has significant efficacy in improving the clinical symptoms and hormone levels of POI patients. In terms of treatment, it is advocated to use kidney tonification as the basic method to achieve the purpose of treating this disease by tonifying yin and benefiting yang, and to make up for the limitations of modern medicine in treating this disease.

[0016] The modified Guishen Pills adopted by the applicant are made by adding raspberries and mulberries to Guishen Pills based on many years of clinical experience. The prescription reuses Rehmannia as the main medicine, which is intended to nourish yin and blood, replenish essence and fill marrow, and relieve the deficiency of kidney yin; Cornus, Chinese yam, Eucommia, and Cuscuta are all ministerial medicines, among which Cornus nourishes the liver and kidney, Chinese yam nourishes both spleen and kidney, Eucommia nourishes kidney yang, strengthens tendons and bones, and Cuscuta nourishes kidney and fills essence, which together help the main medicine to nourish kidney yin; Lycium barbarum, raspberries, mulberries, Chinese angelica, and Poria are combined as adjuvant medicines, Lycium barbarum nourishes yin and blood, raspberries and mulberries nourish yin and yang, nourish blood and fill essence, Chinese angelica nourishes blood and promotes blood circulation, and Poria penetrates dampness and strengthens the spleen. The whole prescription is mainly to nourish kidney yin, and nourishes kidney yang, and plays the role of nourishing yin and kidney.

[0017] Specifically, Rehmannia glutinosa contains chemical components such as iridoid glycosides and amino acids. Its pharmacological effects mainly include improving the blood system, anti-aging, anti-oxidation, enhancing the body's immune function, anti-tumor, affecting the cardiovascular system, and preventing osteoporosis. Rehmannia glutinosa polysaccharides in Rehmannia glutinosa play an antioxidant role by directly or indirectly participating in the process of scavenging free radicals. Studies have shown that Rehmannia glutinosa polysaccharides can inhibit cell apoptosis and reduce the degree of oxidative damage. Experimental studies have found that Rehmannia glutinosa decoction in Rehmannia glutinosa can achieve the effect of regulating the body's endocrine system and delay aging by supplementing phytoestrogens. Because it has the ability to improve the body's hematopoietic ability, it has become a commonly used blood tonic in clinical practice. Studies have found that Rehmannia glutinosa polysaccharides in Rehmannia glutinosa can regulate the peripheral blood count, bone marrow hematopoietic stem cells, and bone marrow nucleated cells of model mice, thereby playing a hematopoietic role. It can delay the decline of peripheral blood count and bone marrow nucleated cells, and promote the proliferation and differentiation of hematopoietic stem cells.

[0018] The effective chemical component of yam, yam polysaccharide, has anti-inflammatory, anti-tumor, antioxidant, anti-aging, immune regulation, and blood lipid and blood sugar lowering effects. Yam polysaccharide can delay the oxidation of low-density lipoprotein. In addition, the higher the concentration, the stronger its reducing power. The saponin components contained in the rhizome of yam have an immunomodulatory effect and have significant clinical efficacy in the treatment of autoimmune diseases. Studies have found that yam total saponins can reduce the concentration of serum IL-2 and IFN-γ in mice with aplastic anemia and increase the concentration of IL-4, thereby playing an anti-apoptotic role. In addition, Chen Mengyu et al. found that yam polysaccharide can reduce fasting blood sugar, triglycerides and cholesterol in diabetic mouse models, indicating that yam polysaccharide has a blood sugar lowering effect to a certain extent.

[0019] Cornus officinalis contains iridoids and their glycosides, flavonoids and other effective chemical components. Modern pharmacology has confirmed that Cornus officinalis has many effects, such as improving immunity, anti-tumor, anti-inflammatory, antibacterial, antioxidant, hypoglycemic and anti-aging. A study conducted by Zhou Yingchun and other scholars showed that the iridoid glycosides in Cornus officinalis have anti-aging effects, increase the expression of rat neurotransmitter acetylcholinesterase (ChAT), and thus improve cognitive impairment in rats with vascular dementia (VD). In addition, Ji Tao's research found that Cornus officinalis leaf polysaccharides have excellent antioxidant effects, and the polyphenols in Cornus officinalis fruits also have powerful and effective antioxidant effects, which can play a good anti-aging effect.

[0020] Poria cocos is a commonly used Chinese medicinal material. Its main chemical components include polysaccharides and triterpenes. It is also rich in steroids, volatile oils, fatty acids and other substances. Modern pharmacological studies have shown that Poria cocos has significant effects in promoting water metabolism, regulating gastrointestinal function, calming, anti-tumor, protecting the liver, and anti-oxidation. Through the study of Poria cocos polysaccharides, Cheng Yue and other scholars found that this ingredient can scavenge free radicals and participate in the regulation of antioxidant enzymes, thereby reducing the body's oxidative stress response and the resulting damage, achieving antioxidant and anti-aging effects.

[0021] The chemical components of angelica mainly include polysaccharides, and are rich in volatile oils and organic acids. Modern pharmacological studies have shown that angelica plays an important role in immunoregulation, anti-tumor, and anti-oxidation. Studies have found that angelica polysaccharides can rebuild the hematopoietic function of mice with hematopoietic failure. In addition, angelica polysaccharides can weaken the oxidative damage caused by hydrogen peroxide (H2O2), increase cell activity, weaken cell apoptosis, and reduce the production of reactive oxygen species (ROS). The extracts of angelica can enhance the body's acquired immunity and innate immunity. The total acid and ferulic acid contained in it play an extremely important role in immunoregulation. They have the ability to increase the phagocytosis of tissue cells and promote the production of IL-2, thereby achieving the effect of enhancing humoral immunity. The neutral oil in angelica can not only delay the production of antibodies, but also has an anti-complement effect, which has a significant advantage in enhancing the body's humoral immunity. In addition, angelica can also enhance the activity of cytotoxic T cells. Its mechanism of action is that angelica lactone can regulate T cell subpopulations.

[0022] The main chemical components of wolfberry include alkaloids, polysaccharides, flavonoids and phenylpropanoids, and these components show a variety of biological activities such as liver and kidney protection, anti-tumor, anti-oxidation, anti-aging, anti-inflammatory, and hypoglycemic. Polysaccharides and flavonoid polyphenol compounds are the main antioxidant components in wolfberry, which can effectively remove excessive free radicals and exert antioxidant effects. In addition, both the water extract and the alcohol extract in wolfberry have certain antioxidant properties, and their antioxidant ability can achieve the effect of delaying aging. Lycium barbarum polysaccharides mainly achieve the protective effect on the reproductive system by improving hormone levels, delaying cell apoptosis, and regulating oxidative stress. It can increase the levels of serum sex hormones FSH, LH, E2 and T in rats with high adenine-induced kidney yang deficiency infertility model. In addition, Lycium barbarum polysaccharides can increase the ovarian reserve capacity of mice, improve the quality of oocytes and ovarian function. Its mechanism of action is to reduce the content of oxidative products of 8-OHDG and LPO and improve ovarian damage caused by repeated superovulation. Wang Hengquan et al. found that the oxidative stress level of female rats was regulated to some extent by Lycium barbarum polysaccharides, which reduced the apoptosis of germ cells by downregulating the expression of the Fas-FasL pathway, thereby playing a role in protecting the reproductive system.

[0023] According to modern pharmacological research, the main components of Eucommia ulmoides include lignans, flavonoids, terpenes and other components. Studies have found that Eucommia ulmoides has multiple effects, such as anti-inflammatory, neuroprotective, and immunomodulatory. At the same time, studies have found that Eucommia ulmoides can improve osteoporosis symptoms through oxidative stress, regulating and controlling amino acid metabolism and other methods. Other scholars have also conducted related research. For example, Zhao Liang et al. found through a study on ovariectomized osteoporotic rats that high-dose salt-roasted Eucommia ulmoides can promote the differentiation of osteoblasts in model rats, delay bone absorption, and accelerate bone formation, thereby improving osteoporosis symptoms and having a therapeutic effect.

[0024] The main active ingredients in Cuscuta are flavonoids. Modern pharmacological studies have found that Cuscuta has the effects of protecting the reproductive system, preventing osteoporosis, anti-aging, and regulating immunity. Among them, total flavonoids are the main substances in Cuscuta that play an estrogenic role. Studies have found that Cuscuta can significantly increase the levels of serum sex hormones (LH, FSH, E2) in rat models of kidney yang deficiency, and increase the expression levels of LHR, FSHR genes in rat ovaries and ER genes in uterine tissues to varying degrees. Huang Mingzhu et al. found that by inhibiting the apoptosis of ovarian granulosa cells and the imbalance of autophagy, the trend of ovarian dysfunction can be delayed. According to studies, total flavonoids in Cuscuta can activate the FSH-cAMP / PKA signaling pathway, showing a significant protective effect on rats with ovarian reserve dysfunction in the experiment.

[0025] According to research, the chemical components contained in raspberries include flavonoids, alkaloids, coumarins, terpenes and steroids. Modern pharmacological research results show that raspberries have multiple effects, including but not limited to anti-tumor, hypoglycemic, lipid-regulating, anti-thrombotic, antioxidant, anti-aging and anti-inflammatory effects. The ethyl acetate extract in raspberries has an inhibitory effect on the differential protein expression in patients with Alzheimer's disease, and its antioxidant capacity is also the best. Raspberries are rich in an estrogen-like substance that has the effect of regulating the female reproductive system. According to research, raspberry extracts can downregulate the level of luteinizing hormone-releasing hormone in the hypothalamus in aqueous solution, and reduce the levels of pituitary luteinizing hormone, follicle-stimulating hormone and gonadal estradiol, while increasing testosterone levels. In addition, raspberries contain a certain amount of antioxidant active substances, and their glycoprotein crude extracts can significantly increase the activity levels of superoxide dismutase and catalase in mice, and can effectively reduce the content of malondialdehyde in serum, liver and brain.

[0026] The chemical components of mulberry mainly include anthocyanins, phenolic acids and polysaccharides. Modern pharmacological studies have shown that this product has the effects of preventing Alzheimer's disease, inhibiting bacteria, anti-inflammatory, anti-tumor, anti-oxidation, lowering blood sugar and blood lipids. Mulberry polysaccharide (MFP) has an antioxidant effect. Experiments have shown that the antioxidant strength of mulberry polysaccharide is closely related to the uronic acid content and anthocyanin content it contains. The higher the content of these two, the better the antioxidant activity.

[0027] The beneficial effects of the present invention are:

[0028] Through research, the present invention finds that sequential estrogen-progesterone therapy combined with Jiawei Guishen Pills can significantly improve clinical symptoms such as menstrual cycle, menstrual period, menstrual volume, soreness of waist and knees, dizziness, tinnitus, hot flashes and night sweats, low libido, and frequent urination at night, reduce serum FSH and LH levels, and increase E2 levels. It is worthy of clinical promotion, and provides a theoretical basis and clinical guidance for the treatment of kidney deficiency type POI with traditional Chinese medicine. DETAILED DESCRIPTION

[0029] The present invention is described in more detail below in conjunction with the following embodiments. It should be understood that the implementation of the present invention is not limited to the following embodiments, and any modifications and / or changes made to the present invention will fall within the scope of protection of the present invention.

[0030] Among them, the specific drugs used in the following embodiments include estradiol valerate (purchased from Bayer Healthcare Co., Ltd. Guangzhou Branch, national medicine standard J20171038), dydrogesterone tablets (purchased from Abbott Biologicals BV in the Netherlands, national medicine standard HJ20170221) and modified Guishen Pills (prepared with cooked rehmannia, yam, poria, wine cornus, angelica, wolfberry, salt eucommia, salt dodder, raspberry and mulberry in a mass ratio of 2: 1: 1: 1: 1: 1: 1: 1: 1: 1, prepared by the preparation room of Ningxia Hui Autonomous Region Hospital of Traditional Chinese Medicine and Institute of Traditional Chinese Medicine in the present invention).

[0031] Example 1: Treatment of Kidney Deficiency Type Premature Ovarian Insufficiency with Modified Guishen Pills

[0032] 1. Methods

[0033] 1.1 Experimental methods

[0034] A total of 66 patients with kidney deficiency-type POI who visited the outpatient clinic of the Department of Gynecology and Obstetrics and Gynecology of the Ningxia Hui Autonomous Region Traditional Chinese Medicine Hospital and Institute of Traditional Chinese Medicine from October 2022 to October 2023 and met the inclusion and exclusion criteria were selected and divided into a control group and an observation group of 33 cases in each group according to the principle of random grouping. The control group used estrogen-progestin sequential therapy (estradiol valerate + dydrogesterone tablets), and the observation group took Jiawei Guishen Pills (estradiol valerate + dydrogesterone tablets + Jiawei Guishen Pills) on the basis of the above.

[0035] Since this embodiment belongs to a randomized controlled trial, the sample content required for this topic is estimated with reference to the estimation formula of sample content in "Medical Statistics" (Edited by Sun Zhenqiu and Xu Yongyong, 4th edition, People's Medical Publishing House): N=1641.4[(uα+uβ) / (sin-1√p1-sin-1√p2)]2 (where α=0.05, 1-β=0.80), (referring to relevant literature, the clinical effective rate of the Western medicine control group is 60.0%, and the estimated clinical effective rate of the Western medicine combined with Chinese medicine observation group is 90%), the minimum sample size (N) is 60 cases, and calculated based on a dropout rate of 10%, the final sample size included in the experiment is 66 cases, with 33 cases in the control group and 33 cases in the observation group.

[0036] In the control group, estradiol valerate was taken on the 5th day of the menstrual cycle, 1 mg each time, once a day, for 21 consecutive days. In the last 10 days, dydrogesterone tablets were taken every day, 10 mg each time, twice a day. Take it half an hour after a meal. After stopping the medication, if menstruation comes, continue to take the medication on the 5th day of the cycle; if menstruation does not come, stop the medication for 7 days and then continue to take the medication. Three menstrual cycles are one course of treatment, and one course of treatment is performed. One month after the end of treatment, the patient's serum sex hormone (FSH, LH, E2) levels are monitored, and the patient's TCM syndrome score and efficacy are evaluated.

[0037] The observation group was given Jiawei Guishen Pills combined with the control group. The dosage of western medicine was the same as before. Jiawei Guishen Pills were taken twice a day, 6g each time, orally after meals in the morning and evening. The Chinese medicine and western medicine were taken half an hour apart. Three menstrual cycles were one course of treatment, and one course of treatment was completed. One month after the end of treatment, the serum sex hormone (FSH, LH, E2) levels of the patients were monitored, and the clinical symptoms, TCM syndrome scores and efficacy of the patients were evaluated.

[0038] Before and after treatment, monitor the patient's general indicators such as body temperature, pulse, respiration, blood pressure, heart rate, and monitor the patient's blood routine, liver function, kidney function, urine routine, electrocardiogram and other safety indicators. At the same time, observe the improvement of POI patients' symptoms before and after medication, record the changes in TCM syndrome scores of POI patients before and after medication, and monitor the changes in serum sex hormone (FSH, LH, E2) levels of POI patients before and after medication.

[0039] 1.2 Evaluation Criteria

[0040] The TCM syndrome scoring table was formulated with reference to the "Guiding Principles for Clinical Research of New Chinese Medicines", "Standards for Diagnosis and Efficacy of TCM Diseases and Syndromes" and "TCM Gynecology". The TCM syndrome efficacy judgment standard was formulated with reference to the relevant standards of the "Guiding Principles for Clinical Research of New Chinese Medicines" (n is the efficacy index):

[0041] n = (total score before treatment - total score after treatment) / total score before treatment × 100%

[0042] ① Cured: Menstruation returns to normal, and the clinical manifestations corresponding to the kidney deficiency syndrome disappear or even completely disappear after treatment, with or without the return of laboratory test indicators to normal, n greater than 90%;

[0043] ② Markedly effective: Menstruation basically returns to normal, the corresponding clinical manifestations of kidney deficiency syndrome are significantly alleviated, with or without laboratory test indicators basically returning to normal, n is greater than or equal to 70% and less than 90%;

[0044] ③ Effective: Menstruation has improved or has not improved significantly, the corresponding clinical manifestations of kidney deficiency syndrome have improved compared with before, with or without slight improvement or not significant improvement in laboratory test indicators, n is greater than or equal to 30% and less than 70%;

[0045] ④ Ineffective: No improvement in menstruation, no change in the corresponding clinical manifestations of kidney deficiency syndrome, or even aggravation, with or without changes or aggravation in laboratory test indicators, n is less than 30%.

[0046] The safety evaluation standards refer to the "Guidelines for Clinical Research of New Chinese Medicines", as shown in Table 1:

[0047] Table 1 Safety evaluation criteria

[0048] Security classification Evaluation Criteria Level 0 Safe, no adverse reactions Level 1 Only mild adverse reactions, relatively safe, no treatment required, can continue to be tested Level 2 Moderate adverse reactions exist and need to be treated before continuing the trial Level 3 Discontinuation of the trial due to adverse reactions .

[0049] 1.3 Statistical methods

[0050] The statistical software SPSS26.0 was used to perform statistical analysis and processing of the data: the completed cases were collected and recorded, and they were sorted and entered into the corresponding database. The measurement data obeyed the normal distribution, expressed as mean ± standard deviation, and statistically processed by t test. If they did not obey the normal distribution, they were expressed as median and quartiles, and statistically processed by non-parametric test. The chi-square test was used for count data, and the rank sum test was used for rank data. All data in the study were statistically analyzed based on the two-sided test. P<0.01 indicated that the difference was statistically significant, P<0.05 indicated that the difference was statistically significant, and P>0.05 indicated that the difference was not statistically significant.

[0051] 2. Experimental results and conclusions

[0052] 2.1 Enrollment and Completion

[0053] A total of 66 patients with kidney deficiency were included in this study and randomly divided into an observation group (estrogen-progestin sequential therapy combined with Jiawei Guishen Pills) with 33 cases and a control group (estrogen-progestin sequential therapy) with 33 cases. During the treatment, 2 cases dropped out of the control group (1 case dropped out due to work reasons and 1 case dropped out due to poor compliance), and 1 case dropped out of the observation group (due to other diseases during the treatment process and termination of treatment), with a total dropout rate of 4.55%.

[0054] 2..2 General Data Analysis

[0055] 2.2.1 Comparison of age between the two groups of patients

[0056] The oldest patient in the control group was 39 years old and the youngest patient was 23 years old; the oldest patient in the observation group was 39 years old and the youngest patient was 22 years old. The Mann-Whitney U rank sum test showed that P>0.05 showed no statistical difference in the age of the two groups of patients, and they were comparable. The age distribution is shown in Tables 2 and 3.

[0057] Table 2 Overall age distribution

[0058] Grouping Number of cases 22-27 (years old) 28-31 (years old) 32-35 (years old) 36-39 (years old) Control group 31 9 5 7 10 Observation Group 32 14 3 6 9

[0059] Table 3 Age distribution

[0060]

[0061] Note: According to the rank sum test, Z=-0.848, P=0.40>0.05.

[0062] 2.2.2 Comparison of disease course between the two groups

[0063] The average course of disease in the control group was 10.97±2.14 months, and the average course of disease in the observation group was 11.25±1.95 months (see Table 4).

[0064] Table 4 Comparison of disease course

[0065]

[0066] Note: After two independent sample t-test, P>0.05, the difference is statistically insignificant and has a certain degree of comparability.

[0067] 2.2.3 Comparison of TCM syndrome scores between the two groups before treatment

[0068] The scores of each TCM syndrome and the total score of the two groups of patients before treatment were analyzed by rank sum test. All P values ​​were greater than 0.05, with no statistical difference and comparability (see Table 5).

[0069] Table 5 Comparison of TCM syndrome scores and total scores between the two groups of patients before treatment

[0070] TCM Syndrome Control group Observation Group Z P Menstrual cycle 4.0(2.0,4.0) 4.0(2.0,4.0) -0.185 0.853 menstruation 4.0(2.0,4.0) 4.0(2.0,4.0) -0.185 0.853 Menstrual flow 4.0(2.0,4.0) 4.0(4.0,4.0) -0.841 0.400 Weak waist and knees 4.0(2.0,4.0) 4.0(2.0,4.0) -0.871 0.384 Dizziness and tinnitus 4.0(2.0,4.0) 4.0(4.0,4.0) -1.222 0.222 Hot flashes and night sweats 4.0(4.0,4.0) 4.0(2.0,4.0) -1.013 0.311 Low libido 4.0(4.0,6.0) 4.0(2.0,4.0) -0.717 0.473 Frequent urination at night 2.0(2.0,2.0) 2.0(2.0,4.0) -0.821 0.411 Total points 28.0(24.0,32.0) 28.0(22.0,31.5) -0.083 0.934

[0071] 2.2.4 Comparison of serum sex hormone FSH, LH, and E2 levels between the two groups before treatment

[0072] The comparison results of serum sex hormone FSH, LH and E2 levels of the two groups of patients before treatment are shown in Table 6:

[0073] Table 6 Comparison of serum sex hormone FSH, LH, E2 levels between the two groups of patients before treatment

[0074]

[0075]

[0076] Note: Before treatment, the above parameters were compared by two independent sample t-tests, P>0.05, showing no statistical difference and comparable.

[0077] 2.3 Efficacy evaluation

[0078] 2.3.1 Comparison of TCM syndrome scores between the two groups before and after treatment

[0079] 2.3.1.1 Comparison of TCM syndrome scores in the control group before and after treatment

[0080] The rank sum test was used to analyze the scores of each syndrome and the total score before and after treatment. P < 0.05, the difference was statistically significant, see Table 7.

[0081] Table 7 Comparison of TCM syndrome scores and total scores before and after treatment in the control group

[0082] TCM Syndrome Before treatment After treatment Z P Menstrual cycle 4.0(2.0,4.0) 2.0(2.0,2.0) -4.363 0.000 menstruation 4.0(2.0,4.0) 2.0(2.0,2.0) -4.134 0.000 Menstrual flow 4.0(2.0,4.0) 2.0(2.0,2.0) -4.134 0.000 Weak waist and knees 4.0(2.0,4.0) 2.0(2.0,2.0) -3.934 0.000 Dizziness and tinnitus 4.0(2.0,4.0) 2.0(2.0,2.0) -3.945 0.000 Hot flashes and night sweats 4.0(4.0,4.0) 2.0(2.0,4.0) -3.787 0.000 Low libido 4.0(4.0,6.0) 2.0(2.0,4.0) -4.025 0.000 Frequent urination at night 2.0(2.0,2.0) 2.0(0.00,2.0) -4.000 0.000 Total points 28.0(24.0,32.0) 16.0(14.0,18.0) -4.868 0.000

[0083] 2.3.1.2 Comparison of TCM syndrome scores in the observation group before and after treatment

[0084] The rank sum test was used to analyze the scores of each syndrome and the total score before and after treatment. P < 0.05, the difference was statistically significant, see Table 8.

[0085] Table 8 Comparison of TCM syndrome scores and total scores in the observation group before and after treatment

[0086]

[0087]

[0088] 2.3.1.3 Comparison of TCM syndrome scores between the two groups after treatment

[0089] The rank sum test was used to analyze the score of each syndrome and the total score of the two groups after treatment. P<0.05, the difference was statistically significant, and the total score of TCM syndrome in the observation group decreased more significantly than that in the control group, see Table 9.

[0090] Table 9 Comparison of TCM syndrome scores and total scores between the two groups after treatment

[0091] TCM Syndrome Control group Observation Group Z P Menstrual cycle 2.0(2.0,2.0) 2.0(2.0,2.0) -2.081 0.037 menstruation 2.0(2.0,2.0) 2.0(2.0,2.0) -2.274 0.023 Menstrual flow 2.0(2.0,2.0) 2.0(2.0,2.0) -2.083 0.037 Weak waist and knees 2.0(2.0,2.0) 2.0(2.0,2.0) -2.036 0.042 Dizziness and tinnitus 2.0(2.0,2.0) 2.0(2.0,2.0) -2.070 0.038 Hot flashes and night sweats 2.0(2.0,4.0) 2.0(2.0,2.0) -1.986 0.047 Low libido 2.0(2.0,4.0) 2.0(2.0,2.0) -2.266 0.023 Frequent urination at night 2.0(0.00,2.0) 0.0(0.00,2.0) -2.197 0.028 Total points 16.0(14.0,18.0) 11.0(8.0,13.5) -5.113 0.000

[0092] 2.3.2 Comparison of serum sex hormone FSH, LH, and E2 levels between the two groups before and after treatment

[0093] 2.3.2.1 Comparison of serum sex hormone FSH, LH, and E2 levels in the control group before and after treatment

[0094] The paired sample t-test showed that the serum sex hormones FSH, LH and E2 in the control group before and after treatment were all P<0.05, and the differences were statistically significant, as shown in Table 10.

[0095] Table 10 Comparison of serum sex hormone FSH, LH and E2 levels in the control group before and after treatment

[0096] Serum sex hormones Before treatment After treatment t P FSH (IU / L) 33.01±4.07 18.43±4.28 26.80 0.000 LH (IU / L) 14.02±1.82 11.57±1.92 39.47 0.000 <![CDATA[E2(pmol / L)]]> 22.94±4.45 35.21±4.72 -21.12 0.000

[0097] 2.3.2.2 Comparison of serum sex hormone FSH, LH, and E2 levels in the observation group before and after treatment

[0098] The paired sample t-test showed that the serum sex hormones FSH, LH and E2 in the observation group before and after treatment were all P<0.05, and the differences were statistically significant, see Table 11.

[0099] Table 11 Comparison of serum sex hormone FSH, LH and E2 levels in the observation group before and after treatment

[0100] Serum sex hormones Before treatment After treatment t P FSH (IU / L) 32.24±3.46 13.84±2.40 37.33 0.000 LH (IU / L) 14.80±1.37 8.09±1.61 46.79 0.000 <![CDATA[E2(pmol / L)]]> 23.26±3.43 46.46±5.26 -36.48 0.000

[0101] 2.3.2.3 Comparison of serum sex hormones FSH, LH, and E2 levels between the two groups after treatment

[0102] After treatment, the serum sex hormones FSH, LH, and E2 in the two groups were tested by independent sample t test: P<0.05, and the difference was statistically significant. The difference of FSH, LH, and E2 in the two groups before and after treatment was tested by independent sample t test: P was less than 0.05, and the difference was statistically significant, indicating that both estrogen-progesterone sequential therapy and estrogen-progesterone sequential therapy combined with Jiawei Guishen Pills can reduce the levels of serum sex hormones FSH and LH and increase the level of E2, but the observation group is better than the control group in improving the level of sex hormones in patients, as shown in Table 12.

[0103] Table 12 Comparison of serum sex hormone FSH, LH, E2 levels between the two groups after treatment

[0104] Serum sex hormones Control group Observation Group t P FSH (IU / L) 18.43±4.28 13.84±2.40 5.235 0.000 LH (IU / L) 11.57±1.92 8.09±1.61 7.784 0.000 <![CDATA[E2(pmol / L)]]> 35.21±4.72 46.46±5.26 -8.929 0.000

[0105] 2.3.3 Comparison of clinical efficacy between the two groups

[0106] After treatment, among the 31 patients in the control group, 1 was significantly effective, 20 were effective, 10 were ineffective, and the total effective rate was 67.74%; among the 32 patients in the observation group, 3 were significantly effective, 25 were effective, 4 were ineffective, and the total effective rate was 87.50%, see Table 13 for details.

[0107] Table 13 Comparison of clinical efficacy between the two groups after treatment

[0108] Grouping Number of cases get well Significant effect efficient invalid Total effective rate (%) Control group 31 0(0) 1(3.22％) 20(64.52％) 10(32.26％) 67.74％ Observation Group 32 0(0) 3(9.375％) 25(78.125％) 4(12.50％) 87.50％

[0109] Note: The clinical efficacy of the two groups after treatment was tested by rank sum test, Z=-2.009, P=0.044<0.05, the difference was statistically significant. The treatment showed that the clinical efficacy of estrogen-progestin sequential therapy combined with Jiawei Guishen Pills in the treatment of patients with kidney deficiency type POI was better than that of estrogen-progestin sequential therapy alone.

[0110] Safety evaluation

[0111] Before and after treatment, the vital signs of the two groups of subjects were stable without major fluctuations. There were no abnormalities in blood routine, urine routine, liver function, kidney function and electrocardiogram, and no adverse drug reactions occurred.

[0112] 2.5 Conclusion

[0113] In this embodiment, a total of 66 cases were collected, and 63 effective cases completed this study (3 cases dropped out, 2 cases dropped out of the control group, and 1 case dropped out of the observation group), including 31 cases in the control group and 32 cases in the observation group. Before treatment, the two groups of patients were compared in terms of age, course of disease, TCM syndrome score and serum sex hormone (FSH, LH, E2) levels, and there was no statistically significant difference, so they were comparable.

[0114] 2.5.1 Comparison of TCM syndrome scores

[0115] After the treatment of the two groups of patients, the following results were obtained through rank sum test analysis:

[0116] ① Intra-group comparison: After comparison, the total score of TCM syndromes before and after treatment in the control group and the observation group was statistically significant (P<0.05), indicating that both estrogen-progesterone sequential therapy and estrogen-progesterone sequential therapy combined with Jiawei Guishen Pills can effectively reduce the total score of TCM syndromes in POI patients. The scores of TCM syndromes (menstrual cycle, menstrual period, menstrual volume, soreness of waist and knees, dizziness and tinnitus, hot flashes and night sweats, low libido, and frequent urination at night) in the two groups were statistically significant (P<0.05), indicating that both treatment methods can improve the clinical symptoms of POI patients.

[0117] ② Comparison between groups: After comparison, the total score of TCM syndromes in the two groups of patients after treatment was statistically different (P<0.05). The degree of decrease in the observation group was greater than that in the control group. In addition, there were statistically significant differences in the scores of TCM syndromes (menstrual cycle, menstrual period, menstrual volume, soreness of waist and knees, dizziness and tinnitus, hot flashes and night sweats, low libido, and frequent urination at night) between the two groups (P<0.05), indicating that the observation group was superior to the control group in reducing the scores of each TCM syndrome and the total score of the patients. This indicates that the estrogen-progesterone sequential therapy combined with Jiawei Guishen Pills is superior to the simple estrogen-progesterone sequential therapy in improving the TCM syndromes of patients with kidney deficiency-type POI.

[0118] 2.5.2 Comparison of serum sex hormone (FSH, LH, E2) levels

[0119] After 3 months of treatment, the two groups of patients were analyzed by t-test, and the results were as follows:

[0120] ① Intra-group comparison: After comparison, the serum sex hormones (FSH, LH, E2) of the two groups before and after treatment were statistically significant (P<0.05), and FSH and LH were lower than before treatment, and E2 was higher than before treatment, indicating that simple estrogen-progesterone sequential therapy and estrogen-progesterone sequential therapy combined with Jiawei Guishen Pills can effectively improve the serum sex hormone (FSH, LH, E2) levels in patients with kidney deficiency type POI, reduce FSH and LH, and increase E2.

[0121] ② Comparison between groups: After comparison, there were statistically significant differences in the levels of serum sex hormones (FSH, LH, E2) between the two groups after treatment (P<0.05), and there were statistically significant differences in the levels of serum sex hormones (FSH, LH, E2) between the two groups after treatment (P<0.05), indicating that estrogen-progestin sequential therapy combined with Jiawei Guishen Pills is superior to simple estrogen-progestin sequential therapy in reducing the levels of serum sex hormones FSH and LH and increasing the level of E2.

[0122] 2.5.3 Analysis and evaluation of clinical efficacy

[0123] The clinical efficacy of 63 patients in this application was analyzed. There were 31 cases in the control group, 0 cases were cured, 1 case was markedly effective, 20 cases were effective, 10 cases were ineffective, and the total effective rate was 67.74%. There were 32 cases in the observation group, 0 cases were cured, 3 cases were markedly effective, 25 cases were effective, 4 cases were ineffective, and the total effective rate was 87.5%. The observation group was better than the control group, and the difference was statistically significant (P<0.05).

[0124] The above results show that sequential estrogen-progesterone therapy combined with Jiawei Guishen Pills in the treatment of patients with kidney deficiency type POI can significantly improve the menstrual cycle, menstrual period, menstrual volume, soreness of the waist and knees, dizziness, tinnitus, hot flashes and night sweats, loss of libido, and frequent urination at night, reduce serum FSH and LH levels, and increase E2 levels, which is worthy of clinical promotion.

[0125] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the technical solution of the present invention, which should be covered by the scope of the claims of the present invention.

Claims

1. A drug for treating premature ovarian insufficiency, characterized in that: The medicine includes Jiawei Guishen Pills.

2. The drug according to claim 1, characterized in that The modified Guishen Pill is prepared from cooked rehmannia, yam, poria, wine-soaked cornus fruit, angelica, wolfberry, salt eucommia, salt dodder seed, raspberry and mulberry in a mass ratio of 2:1:1:1:1:1:1:1:1:1:1:

1.

3. The drug according to claim 1, characterized in that The medicine also includes estradiol valerate and dydrogesterone tablets.

4. The use of Jiawei Guishen Pills in the preparation of a medicine for treating premature ovarian insufficiency, characterized in that: The Jiawei Guishen Pill is used in combination with estrogen-progestin sequential therapy to treat premature ovarian insufficiency.

5. The use according to claim 4, characterized in that The premature ovarian insufficiency is kidney deficiency type premature ovarian insufficiency.

6. The use according to claim 4, characterized in that The drug treats premature ovarian insufficiency by reducing the levels of serum sex hormones FSH and LH and increasing the level of E2.

7. The use according to claim 6, characterized in that The improving E2 level means that the E2 level can be further improved compared with the estrogen-progestin sequential therapy.

Images