Application of butyric acid in preparation of medicine for treating polycystic ovarian syndrome

Abstract

The invention relates to application of butyric acid in preparation of a medicine for treating polycystic ovarian syndrome. According to the application disclosed by the invention, the treatment mechanism of the butyric acid for treating the polycystic ovarian syndrome is researched for the first time, and it is found that the specific butyric acid receptor Gpr109a of granular cells on an ovary can be remarkably increased and ferroptosis of the granular cells on the ovary can be inhibited by oral administration of the butyric acid, so that the cyst number of a PCOS mouse is reduced, the luteum number is increased, and the purpose of treating the PCOS is achieved. It is found that the effective dosage of butyric acid in the medicine is 302.5 mg / kg-907.5 mg / kg-90. 5 mg / kg-90. 5 mg / kg-90. 5 mg / kg-90. 5 mg / kg-90. 5 mg / kg-90. 5 mg / kg-90. 5 mg / kg-90. 5 mg / kg-90. 5 mg / kg-90. 5 mg / kg-90. 5 mg / kg-90. 5 mg / kg-90. 5 mg / kg-90. 5 mg / kg-90. 5 mg / kg-90. 5 mg / kg-90. 5 mg / kg-90. 5 mg / male hormones return to normal, and the like. A brand new thought is provided for research and development of medicines for treating the polycystic ovarian syndrome, and the application prospect is wide.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and in particular relates to the application of butyric acid in preparing a medicine for treating polycystic ovary syndrome. Background Art

[0002] Polycystic ovary syndrome (PCOS) is a common endocrine disease that affects 6%-10% of women of childbearing age. The main characteristics of PCOS are androgen excess, ovulatory dysfunction, and polycystic ovaries. In addition, PCOS is often accompanied by metabolic disorders such as insulin resistance (IR), glucose intolerance, and obesity. Although research on PCOS has been carried out for a long time, because its etiology and pathophysiological mechanisms are still unclear, there is no drug specifically for PCOS at home and abroad. Several existing treatments also have certain side effects. ① For patients in adolescence or childbearing age who have no fertility requirements and have menstrual disorders due to ovulation disorders, the cyclical use of progesterone may cause endocrine disorders, obesity or bone decalcification; oral contraceptives (OCPs) can only cause artificial "menstruation" for PCOS patients, protect the endometrium stimulated by a single estrogen due to long-term anovulation, and reduce acne and hirsutism caused by high androgen in PCOS. It cannot "cure" PCOS by itself. Irregular menstruation and amenorrhea will still occur after discontinuation of the drug, and short-acting combined oral contraceptives can cause irritation of the gastric mucosa, causing symptoms of loss of appetite, nausea and vomiting. ② When treating high androgen hormones, spironolactone is used when the OCP treatment is ineffective, and it takes at least 6 months to take effect. The treatment cycle is long, and when used in large doses, breast tenderness, menstrual disorders, headaches or polyuria may occur, and it may also cause hypotension and hyperkalemia. ③ For patients with severe obesity and lipid metabolism disorders, the diagnosis and treatment guidelines recommend the use of metformin or insulin sensitizers. The most common side effect of long-term use of metformin is gastrointestinal reactions, which may cause abdominal distension, nausea, vomiting, loss of appetite, abdominal pain, diarrhea, and weight loss. Rare adverse reactions include rash, hypoglycemia, dizziness, etc., and lactic acidosis may occur in rare cases. Insulin sensitizers such as troglitazone have common side effects such as gastrointestinal symptoms, such as nausea, vomiting, abdominal distension, diarrhea, and upper abdominal pain. There may be edema, respiratory tract infection, and reversible jaundice (liver biopsy shows an atopic drug reaction). In March 2000, the US FDA notified the withdrawal of this variety.

[0003] Butyrate is a short-chain fatty acid produced by intestinal flora. Existing studies have shown that butyrate has important metabolic regulatory functions. It can play a systemic role by stimulating the production of intestinal hormones such as glucagon-like peptide-1 (GLP-1) and participate in the regulation of glucose and lipid metabolism in the body. Butyrate is closely related to the health of the body and is of great significance for regulating intestinal health, inhibiting inflammation and cancer. Butyrate is often added in the breeding industry to protect the healthy growth of animals, such as preventing diarrhea in weaned piglets, regulating the intestinal flora of chickens and enhancing their immunity. Existing studies have reported that butyryl starch can relieve the symptoms of PCOS in rats by activating the colon GPR41 receptor, promoting PYY secretion and acting on the HPO axis. Although butyryl starch can enrich butyrate-producing bacteria in the intestines of rats, thereby further increasing the level of butyrate in the intestines, butyrate has not yet been directly used to treat polycystic ovary syndrome, and there are no related reports on the mechanism of direct application of butyrate to treat PCOS. Summary of the invention

[0004] The present invention discloses the use of butyric acid or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating polycystic ovary syndrome. The drug is for oral administration, and is measured in terms of butyric acid used for adults. The effective dose of butyric acid in the drug is 302.5 mg / kg-907.5 mg / kg day, and the optimal dose of butyric acid in the drug is 605 mg / kg day. The butyric acid achieves the purpose of treating polycystic ovary syndrome by inhibiting the ferroptosis state of ovarian granulosa cells.

[0005] Furthermore, the pharmaceutically acceptable salt thereof is sodium butyrate.

[0006] Furthermore, the drug also includes a pharmaceutically acceptable carrier and / or excipient.

[0007] Furthermore, the pharmaceutically acceptable carrier and / or excipient includes a diluent, a binder, a surfactant, a humectant, an adsorption carrier, a lubricant, a filler, and a disintegrant.

[0008] The beneficial effects of the present invention are:

[0009] The present invention explores the therapeutic mechanism of butyric acid in the treatment of PCOS for the first time, and finds that oral butyric acid can significantly increase the specific butyric acid receptor Gpr109a of granulosa cells on the ovaries, inhibit the ferroptosis of ovarian granulosa cells, thereby reducing the number of cysts in PCOS mice and increasing the number of corpora lutea, achieving the purpose of treating PCOS. Studies have shown that oral butyric acid for at least 21 days, based on the butyric acid dosage used by adults, the effective dose of butyric acid in the drug is 302.5mg / kg-907.5mg / kg˙day, and the optimal dose of butyric acid in the drug is 605mg / kg˙day, which can effectively alleviate the related symptoms of PCOS, such as the disappearance of insulin resistance, the normalization of estrus cycle, the increase in ovulation, and the restoration of normal male hormones. This application provides a new idea for the research and development of drugs for the treatment of PCOS, and has broad application prospects. DETAILED DESCRIPTION

[0010] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0011] Experimental Statement

[0012] 1. Experimental animals: All experiments strictly abide by the Chinese Laboratory Animal Welfare Law and are approved by the Experimental Animal Ethics Committee of the College of Life Sciences of China Agricultural University. The C57 mice used in the experiment were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. and kept in the clean-grade experimental animal room of China Agricultural University. The experiment set up no less than 25 mice in each group. The animal room maintained an ambient temperature of 22-24℃, and the lighting environment was 12h light and 12h dark alternately. The mice were free to eat and drink water.

[0013] 2. Modeling drugs

[0014] Preparation of dehydroepiandrosterone: DHEA (specification: 10g / bottle, CAS: 53-43-0) and sesame oil (specification: 1000ml / bottle, CAS: 8008-74-0) were purchased from Sigma-Aldrich and prepared in the ratio of 45mg DHEA to 10ml sesame oil. The drug was used after it was completely dissolved.

[0015] Preparation of butyric acid: Sodium butyrate (specification: 250 g / bottle, CAS: 156-54-7) was purchased from Sigma-Aldrich. Butyric acid was prepared according to the ratio of 1.1 g butyrate to 100 mL water and used after the drug was completely dissolved.

[0016] Preparation of metformin: Metformin was purchased from TCI (Shanghai) Chemical Industry Development Co., Ltd. and prepared in the ratio of 2 g metformin to 30 ml PBS. It was used after the drug was completely dissolved.

[0017] 3. Model construction: To induce PCOS, 3-week-old female prepubertal C57 mice were subcutaneously injected with 6 mg / 100 g DHEA daily. The control group mice were injected with 0.2 ml sesame oil daily, and the model was successfully established after 21 days of treatment. The hallmarks of successful PCOS mouse modeling are estrous cycle disorders, high androgen, polycystic ovaries, anovulation, and symptoms of glucose tolerance and insulin resistance.

[0018] 4. The values ​​in all the following tables are mean + standard error. * Compared with the control group, the results were statistically significant; ** There was statistically significant difference compared with the control group; *** It means that there is extremely significant statistical significance compared with the control group; # Compared with the placebo group, the ## Compared with the placebo group, there was a statistically significant ### The difference was statistically significant compared with the placebo group.

[0019] Example 1: Exploration of the optimal concentration of butyric acid

[0020] 1. Experimental groups:

[0021] The PCOS mice with successful modeling were randomly divided into 5 groups, including placebo group, 2.75g / kg butyrate group, 5.5g / kg butyrate group, 8.25g / kg butyrate group and metformin group.

[0022] 2. Dosage method:

[0023] Control group: normal mice were fed with purified water;

[0024] Placebo group: PCOS mice were fed with pure water;

[0025] Butyrate group: PCOS mice were gavaged with different doses of butyrate every day, which were 2.75g / kg, 5.5g / kg and 8.25g / kg;

[0026] Metformin group: PCOS mice were intragastrically administered with metformin solution at a dose of 50 mg / 100 g body weight / day.

[0027] 3. Observation content and methods

[0028] After 21 days of intragastric administration, the fasting blood glucose level of each mouse was tested, and the estrus cycle was determined by vaginal smear experiment. Five mice in each group were intraperitoneally injected with PMSG and HCG and then killed by cervical dislocation. The number of MⅡ stage oocytes was counted in the ampulla, and the ovaries of five mice in each group were obtained for HE staining and ovarian morphology was observed.

[0029] 4. Experimental results:

[0030] (1) The mice in the control group, placebo group, and groups treated with different concentrations of butyrate were all well developed, with shiny fur, no significant differences in behavioral signs, and were sensitive.

[0031] (2) Estrous cycle test: After intragastric administration of different concentrations of butyric acid, the estrous cycle disorder caused by PCOS was improved. According to the significant difference comparison of the time of the estrous cycle, the three butyric acid administration groups and the placebo group showed significant differences. The experimental data are shown in Table 1.

[0032] Table 1 Effect test of different doses of butyrate on the estrus cycle of PCOS mice

[0033]

[0034] (3) Ovulation statistics: As shown in Table 2, the significant decrease in the number of ovulations in PCOS-induced mice was improved by feeding butyric acid at doses of 2.75 g / kg, 5.5 g / kg, and 8.25 g / kg. Among them, the increase in the number of MⅡ oocytes was the most significant after feeding with 5.5 g / kg butyric acid.

[0035] Table 2 Effect of different doses of butyrate on the number of ovulations in PCOS mice

[0036] Group n Ovulation number Control group 5 23±6.58 Placebo group 6 <![CDATA[8±3.78 ** ]]> 2.75g / kg butyrate group 5 15±3.11 5.5g / kg butyrate group 5 <![CDATA[27±3.96 ### ]]> 8.25g / kg butyrate group 5 <![CDATA[17±7.79 # ]]> Metformin group 5 <![CDATA[24±5.07 ### ]]>

[0037] (4) Determination of fasting blood glucose level: After fasting for 12 hours, the mice were injected with 2 g / kg of glucose, and their blood glucose levels were measured at 0 min, 15 min, 30 min, 60 min, and 90 min, respectively. It was found that the glucose tolerance of PCOS mice was restored after feeding with 2.75 g / kg, 5.5 g / kg, and 8.25 g / kg of butyrate. Three days later, after fasting for 12 hours, the mice were injected with 1 IU / kg of insulin, and their blood glucose levels were measured at 0 min, 15 min, 30 min, 60 min, 90 min, and 120 min, respectively. The results are shown in Tables 3 and 4. It was found that feeding PCOS mice with 2.75 g / kg, 5.5 g / kg, and 8.25 g / kg of butyrate could improve their insulin resistance symptoms.

[0038] Table 3 Effect of different doses of butyrate on glucose tolerance in PCOS mice

[0039]

[0040] The examples of the present application use the common hypoglycemic drug metformin as a positive control experiment. It can be seen that butyric acid also has a hypoglycemic effect, and as time goes on, the hypoglycemic effect of the 5.5 g / kg experimental group is better than that of the metformin group.

[0041] Table 4 Effect of different doses of butyrate on insulin tolerance in PCOS mice

[0042]

[0043] (5) Observation of mouse ovarian morphology: The mouse ovaries were removed by cervical dissection, fixed with 4% paraformaldehyde overnight, dehydrated with different concentrations of ethanol, embedded in paraffin and fixed, and sliced ​​with a microtome. The morphological changes of the mouse ovaries were observed under a microscope after HE staining. It was found that 5.5g / kg and 8.25g / kg butyric acid treatment had a certain improvement effect on the abnormal morphology of the mouse ovaries, and the results are shown in Table 5.

[0044] Table 5 Effects of different doses of butyrate on the number of cysts and corpora lutea in PCOS mice

[0045] Group n Number of cysts Number of corpora lutea Control group 5 0 6.6±0.89 Placebo group 5 <![CDATA[5.4±1.14 ** ]]> <![CDATA[3.2±0.45 ** ]]> 2.75g / kg butyrate group 5 <![CDATA[1.6±0.55 ## ]]> <![CDATA[6.2±1.09 ## ]]> 5.5g / kg butyrate group 5 <![CDATA[2.2±0.84 ## ]]> <![CDATA[6±1.58 ## ]]> 8.25g / kg butyrate group 5 <![CDATA[2.4±0.54 ## ]]> <![CDATA[5.8±1.48 ## ]]> Metformin group 5 <![CDATA[2.4±0.89 ## ]]> <![CDATA[5.6±5.1 2## ]]>

[0046] In summary, daily oral administration of 2.75g / kg, 5.5g / kg and 8.25g / kg butyric acid had a certain improvement effect on estrous cycle disorders, anovulation, insulin resistance and abnormal ovarian morphology in PCOS mice, and the effect of 5.5g / kg was more significant, indicating that butyric acid has a certain therapeutic effect on PCOS.

[0047] Example 2: Study on the therapeutic effect of butyrate on PCOS mice

[0048] 1. Experimental groups:

[0049] The PCOS mice with successful modeling were randomly divided into two groups, a placebo group and a butyrate group with 7 mice in each group.

[0050] 2. Dosage method:

[0051] Control group: mice drank normal water;

[0052] Placebo group: PCOS mice drank normal water;

[0053] Butyrate group: PCOS mice were gavaged with 5.5 g / kg butyrate every day.

[0054] 3. Observation content and methods

[0055] After 21 days of intragastric administration, the fasting blood glucose level of each mouse was tested, and the estrus cycle was determined by vaginal smear experiment; 7 mice in each group were intraperitoneally injected with PMSG and HCG and then killed by cervical dislocation, and the number of MⅡ stage oocytes was counted from the ampulla; serum of the remaining mice was taken to test the level of sex hormones, and the ovaries were embedded in paraffin, and the number of corpora lutea and cysts was counted after sectioning and HE staining.

[0056] (1) General:

[0057] The mice in the control group, placebo group, and butyrate group were all well developed, with shiny fur, no significant differences in behavior, and were responsive.

[0058] (2) Estrous cycle test: After taking 5.5g / kg butyric acid orally, the estrous cycle disorder caused by PCOS was improved. According to the significant difference comparison of different estrous cycle time, the butyric acid group showed significant difference compared with the control group and the placebo group. The experimental data are shown in Table 6.

[0059] Table 6 Effect test of butyric acid on estrus cycle of PCOS mice

[0060]

[0061] (3) Ovulation statistics: As shown in Table 7, the number of ovulations in mice caused by PCOS decreased significantly. After daily oral administration of 5.5 g / kg butyrate for 21 days, there was a significant difference between the butyrate group and the control group and the placebo group, and the number of MⅡ oocytes increased significantly.

[0062] Table 7 Effect of butyric acid on the number of ovulations in PCOS mice

[0063] Group n Ovulation number Control group 7 20±3 Placebo group 7 <![CDATA[10±4 ** ]]> Butyrate group 7 <![CDATA[25±3 ## ]]>

[0064] (4) Determination of fasting blood glucose level: After fasting for 12 hours, the mice were injected with 2 g / kg of glucose, and their blood glucose levels were measured at 0 min, 15 min, 30 min, 60 min, and 90 min, respectively. It was found that the glucose tolerance of PCOS mice was significantly improved in the 5.5 g / kg butyrate group. Three days later, after fasting for 12 hours, the mice were injected with 1 IU / kg of insulin, and their blood glucose levels were measured at 0 min, 15 min, 30 min, 60 min, 90 min, and 120 min, respectively. The symptoms of insulin resistance of PCOS mice were significantly improved in the 5.5 g / kg butyrate group. The results are shown in Tables 8 and 9.

[0065] Table 8 Butyrate for glucose tolerance test in PCOS

[0066]

[0067] Table 9 Insulin tolerance test of butyrate in PCOS mice

[0068]

[0069] (5) Determination of serum sex hormone content: For estrus cycle determination, when mice are in the estrus cycle, the eyeballs are removed to collect blood, and the blood is centrifuged at 3000rpm at room temperature to collect serum. The ELISA kit is used to detect the content of T, LH, FSH, and AMH in the serum. The results are shown in Table 10. After oral administration of butyric acid, compared with the placebo group, the butyric acid group T, AMH, and LH were significantly reduced, and FSH was significantly increased. In short, the levels of several sex hormones in the butyric acid group mice were restored to the same level as normal mice.

[0070] Table 10 Effect of butyrate on serum sex hormone levels in PCOS mice

[0071] Group n T (ng / ml) FSH (U / l) LH (U / l) AMH (pg / ml) Control group 4 0.15±0.01 3.61±0.41 7.36±0.53 425.44±52.304 Placebo group 4 <![CDATA[0.37±0.04 *** ]]> <![CDATA[2.42±0.38 *** ]]> <![CDATA[13.53±1.02 *** ]]> <![CDATA[617.64±83.96 *** ]]> Butyrate group 4 <![CDATA[0.25±0.03 ### ]]> <![CDATA[4.15±0.71 ### ]]> <![CDATA[9.34±1.64 ### ]]> <![CDATA[482.52±76.38 # ]]>

[0072] (6) Ovarian follicle count: As shown in Table 11, compared with the control group, the number of cysts in the placebo group increased and the number of corpora lutea decreased significantly; while the number of cysts in the butyrate group decreased and the number of corpora lutea increased, which was significantly different from the placebo group. This indicates that oral butyrate can effectively improve the polycystic ovaries of PCOS mice.

[0073] Table 11 Effect of butyrate on the number of cysts and corpora lutea in PCOS mice

[0074] Group n Number of cysts Number of corpora lutea Control group 7 0.14±0.38 5.86±0.90 Placebo group 7 <![CDATA[3.71±0.49 ** ]]> <![CDATA[2.29±0.95 *** ]]> Butyrate group 7 <![CDATA[1.86±0.69 ## ]]> <![CDATA[4.00±1.15 ## ]]>

[0075] Example 3: Study on the therapeutic mechanism of butyrate in PCOS mice

[0076] (1) Detection of changes in butyrate receptor gene on ovarian granulosa cells: In order to explore the mechanism of action of butyrate in treating PCOS, this example detected the changes in butyrate receptor mRNA on ovarian granulosa cells of mice after intragastric administration of butyrate in Example 2. It was found that compared with the placebo group mice, the specific butyrate receptor Gpr109a on ovarian granulosa cells of mice increased significantly after intragastric administration of butyrate, while other short-chain fatty acid receptors did not change significantly, as shown in Table 12.

[0077] Table 12 Effects of butyrate on the level of butyrate receptor gene in granulosa cells of PCOS mice

[0078]

[0079]

[0080] (2) In vitro use of human ovarian granulosa cell line KGN to verify the mechanism of action of butyrate: Preliminary experiments speculated that butyrate may inhibit ferroptosis of granulosa cells by binding to butyrate receptors on ovarian granulosa cells, thereby reducing ovarian cysts. Therefore, the ferroptosis inducer RSL3 was used to construct a KGN ferroptosis model, and then different concentrations of butyrate were added. It was found that 800 μM butyrate could significantly inhibit RSL3-induced ferroptosis and increase cell proliferation, as shown in Table 13.

[0081] Table 13 Inhibitory effect of butyrate on ferroptosis of granulosa cells in PCOS mice

[0082] Group n Cell proliferation rate (%) Control group 7 99.13±0.04 RSL3 Group 7 52.72±0.05*** RSL3+600μM butyrate group 7 <![CDATA[62.82±0.02 ### ]]> RSL3+800μM butyrate group 7 <![CDATA[66.73±0.02 ### ]]> RSL3+1mM butyrate group 7 <![CDATA[63.26±0.02 ### ]]> RSL3+5mM butyrate group 7 56.58±0.02

[0083] In summary, the present application detected the expression of butyrate receptors on ovarian granulosa cells and found that the specific receptor Gpr109a for butyrate on the ovarian granulosa cells of mice gavaged with butyrate was significantly increased. Butyrate inhibited the ferroptosis of ovarian granulosa cells by binding to the butyrate receptors on the ovarian granulosa cells, thereby reducing the number of cysts and increasing the number of corpora lutea in PCOS mice, ultimately achieving the purpose of treating PCOS.

[0084] Example 4: Comparative experiment of gavage of butyric acid and butyryl starch on PCOS mice

[0085] By orally administering the same dose of butyric acid to mice, we verified whether the technical effects of butyric acid solution and butyric starch in the treatment of PCOS are the same.

[0086] The preparation method of butyryl starch is as follows: weigh 10g of corn starch with a dry weight, add it to 15ml of water, stir it magnetically at room temperature, and prepare a starch milk with a mass fraction of 40%; continue to stir at a constant temperature of 40°C, and continue to drop 0.75mol / LNaOH solution into the starch milk to maintain the pH value at about 8.5: at a constant temperature of 40°C, continue to drop 0.5mL of acid anhydride into the starch milk while continuing to drop 0.75mol / LNaOH solution to maintain the pH value at about 8.5, and the time is controlled within 90min; after the addition of acid anhydride is completed, continue to stir the starch milk for 2h to maintain the pH value at about 8.5; use 1molLHC1 solution to adjust the pH of the starch milk to about 5.7; let the starch milk settle, pour off the supernatant, add distilled water to wash the precipitate, centrifuge at 6000rpm for 5min, repeat this step 3 times, collect the precipitate and add 30ml of water. The butyric acid content in the butyryl starch obtained by the above-mentioned preparation method is 5.5 g / kg. The specific conversion method is as follows: the butyric anhydride content in the butyryl starch prepared by the above-mentioned method is 16 g / L, and the relative molecular mass of butyric anhydride is 158.195. Therefore, the butyric anhydride content is 100 mM. One molecule of butyric acid can release 2 molecules of butyric acid, so the butyric acid content released is 200 mM. After conversion, the dosage for each mouse is 5.5 g / kg.

[0087] The experimental groups are as follows:

[0088] Control group: normal mice were fed with purified water;

[0089] Placebo group: PCOS mice were fed with pure water;

[0090] Butyrate group: PCOS mice were intragastrically administered with butyrate solution every day, with a dose of 5.5 g / kg in terms of butyrate;

[0091] Butyryl starch group: PCOS mice were intragastrically administered with butyryl starch every day at a dose of 5.5 g / kg calculated as butyric acid.

[0092] After 21 days of intragastric administration, the fasting blood glucose level of each mouse was tested, and the estrus cycle was determined by vaginal smear experiment. Five mice in each group were intraperitoneally injected with PMSG and HCG and then killed by cervical dislocation. The number of MⅡ stage oocytes was counted in the ampulla, and the ovaries of five mice in each group were obtained for HE staining and ovarian morphology was observed.

[0093] Experimental results:

[0094] (1) The mice in the control group, placebo group, butyrate group, and butyryl starch group were all well developed, with shiny fur, no significant differences in behavioral signs, and were sensitive.

[0095] (2) Estrous cycle: As shown in Table 14, both butyric acid and butyryl starch can effectively improve the estrus cycle disorder of mice caused by PCOS.

[0096] Table 14 Effect test of butyric acid and butyryl starch on the estrus cycle of PCOS mice

[0097]

[0098] (3) Ovulation number: As shown in Table 15, the ovulation number of PCOS-induced mice decreased significantly. After oral administration of butyric acid, the ovulation number increased significantly, while the same dose of butyryl starch did not increase the ovulation number of PCOS mice.

[0099] Table 15 Test on the effect of butyric acid and butyryl starch on ovulation induction in PCOS mice

[0100] Group n Ovulation number Control group 3 13±2.31 Placebo group 3 <![CDATA[4.67±0.33 ** ]]> Butyrate group 3 <![CDATA[16±2.08 ### ]]> Butyryl starch group 3 5.33±0.33

[0101] (4) Ovarian cyst and corpus luteum counts: As shown in Table 16, compared with the placebo group, the number of cysts in the butyric acid group decreased and the number of corpus luteum increased, while there was no significant difference in the butyryl starch group, indicating that oral administration of 5.5 g / kg butyric acid instead of butyryl starch can effectively improve the polycystic ovary of PCOS mice.

[0102] Table 16 Effects of butyric acid and butyryl starch on the number of cysts and corpora lutea in PCOS mice

[0103] Group n Number of cysts Number of corpora lutea Control group 3 0 5.67±0.67 Placebo group 3 <![CDATA[4.33±0 *** ]]> <![CDATA[1.33±0.33 ** ]]> Butyrate group 3 <![CDATA[0.66±0.33 ### ]]> <![CDATA[5.67±0.88 ## ]]> Butyryl starch group 3 <![CDATA[4±0.58 *** ]]> <![CDATA[2±0.58 ** ]]>

[0104] (5) Fasting blood glucose measurement: After fasting for 12 hours, mice were injected with 2g / kg glucose, and blood glucose levels were measured at 0min, 15min, 30min, 60min, and 90min, respectively. It was found that the glucose tolerance of PCOS mice was restored after feeding with butyric acid; 3 days later, mice were fasted for 12 hours and injected with 1IU / kg insulin, and blood glucose levels were measured at 0min, 15min, 30min, 60min, 90min, and 120min, respectively. The results are shown in Tables 17 and 18. It was found that directly feeding butyric acid to PCOS mice can improve their insulin resistance symptoms. However, the same dose of butyryl starch had no significant effect on improving the symptoms of glucose tolerance and insulin resistance in PCOS mice.

[0105] Table 17 Effects of butyric acid and butyryl starch on glucose tolerance in PCOS mice

[0106]

[0107] Table 18 Effects of butyric acid and butyryl starch on insulin resistance in PCOS mice

[0108]

[0109] In summary, for the application of butyric acid in the preparation of drugs for the treatment of polycystic ovary syndrome, under the condition of the same optimal intake of 5.5g / kg and continuous feeding for 21 days, the therapeutic effect of direct oral administration of butyric acid is better than that of butyryl starch. Although butyryl starch can improve the estrous cycle disorders of mice caused by PCOS, it cannot increase the number of ovulations of PCOS mice, improve the polycystic ovaries of PCOS mice, and has no obvious effect on improving the symptoms of glucose tolerance and insulin resistance in PCOS mice. Therefore, butyrate needs to be taken directly orally in the treatment of polycystic ovary syndrome. The best technical effect can be obtained by taking 5.5g / kg per day in mice. According to the conversion coefficient table of animal and human body weight per kilogram, the conversion coefficient W for humans and mice is 0.11. The butyrate dosage used by mice in this experiment is 2.75g / kg-8.25g / kg. According to the formula, the dosage of animal B (g / kg) = W × the dosage of animal A (g / kg), the dosage of butyrate used by normal adults should be 302.5mg / kg-907.5mg / kg˙day, of which the optimal dosage is 605mg / kg˙day. The butyrate achieves the purpose of treating polycystic ovary syndrome by inhibiting the iron death state of ovarian granulosa cells.

[0110] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the embodiments should be considered exemplary and non-restrictive in all respects, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims be included in the present invention.

[0111] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. Use of butyric acid or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating polycystic ovary syndrome, characterized in that: The drug is taken orally, and is measured in butyrate for adults. The effective dose of butyrate in the drug is 302.5 mg / kg-907.5 mg / kg day. The butyrate achieves the purpose of treating polycystic ovary syndrome by inhibiting the ferroptosis of ovarian granulosa cells.

2. The use of butyric acid or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for treating polycystic ovary syndrome, characterized in that: The effective dosage of the butyric acid in the medicine is 605 mg / kg / day.

3. The use of butyric acid or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating polycystic ovary syndrome according to claim 1, characterized in that: The pharmaceutically acceptable salt thereof is sodium butyrate.

4. Use of butyric acid or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for treating polycystic ovary syndrome, characterized in that: The medicine further comprises a pharmaceutically acceptable carrier and / or excipient.

5. Use of butyric acid or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating polycystic ovary syndrome according to claim 4, characterized in that: The pharmaceutically acceptable carriers and / or excipients include diluents, binders, surfactants, wetting agents, adsorption carriers, lubricants, fillers, and disintegrants.

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