Traditional Chinese medicine composition for treating polycystic ovarian syndrome infertility and application thereof

Abstract

The invention relates to a traditional Chinese medicine composition for treating polycystic ovarian syndrome infertility and application thereof, the traditional Chinese medicine composition can be used for treating polycystic ovarian syndrome infertility, has the effects of warming kidney and regulating thoroughfare, raising yang and discharging turbid, smoothing veins, harmonizing yin and yang, combining essence and blood and knotting embryos to promote follicular development when being applied to a patient with polycystic ovarian syndrome infertility, and has the effects of promoting follicular growth and promoting blood circulation. The ovum quality is improved, the abortion rate is reduced, and the pregnancy outcome is improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of traditional Chinese medicine, and particularly relates to a traditional Chinese medicine composition for treating polycystic ovary syndrome infertility and application thereof. BACKGROUND

[0002] Polycystic ovary syndrome (PCOS) is a reproductive disorder and endocrine metabolic disorder syndrome with highly heterogeneous clinical manifestations, which is closely related to female infertility, and the incidence is about 5%-15%. In the past 30 years, the global incidence of PCOS has increased dramatically, and the prevalence of infertility caused by PCOS in women of childbearing age has doubled from 1990 to 2019. Data shows that about 80% of anovulatory infertility is attributed to PCOS, and the abortion rate of PCOS women is as high as 60%. The risk of abortion and gestational diabetes mellitus (GDM) in PCOS patients during pregnancy is significantly increased. Even with the help of in vitro fertilization / intracytoplasmic sperm injection (IVF / ICSI), compared with non-PCOS, the number of high-quality embryos, available embryos and high-quality blastocyst formation of PCOS patients is still significantly reduced, and the cumulative live birth rate of the first IVF / ICSI cycle is significantly reduced (see PCOS and Role of Cumulus Gene Expression in Assessing Oocytes Quality). As can be seen, low pregnancy rate, high abortion rate and low live birth rate are the common reproductive problems faced by PCOS patients, and the reason for this predicament is the abnormal follicular development and decreased oocyte quality of PCOS patients, which seriously affects the pregnancy outcome and is a difficult problem to be solved in the field of reproductive medicine.

[0003] Modern Chinese medicine discusses the etiology and pathogenesis of PCOS from the liver, spleen and kidney, which is a deficiency in the root and excess in the branch. The pathogenesis is characterized by deficiency of spleen and kidney, and internal resistance of phlegm and dampness.

[0004] Deficiency of kidney essence is the basis of PCOS. The kidney stores essence and is the source of Tianqi reproduction. As the Neijing says: "When a person is born, essence is formed first. Essence is the embryo of the preheaven, and the seed of life." Traditional medicine believes that the physiological function of women's kidney qi-Tianqi-chongren-uterus runs normally, and kidney essence can only be transformed into Tianqi, and the blood of viscera and blood can support chongren, so that the blood sea is full and discharged on time, and the fetus is nurtured. If the kidney essence is insufficient, the source of the menstrual water is lacking, which affects the secretion of Tianqi, causes amenorrhea, and is difficult to nurture offspring. Therefore, deficiency of kidney essence plays a crucial role in the pathogenesis of PCOS.

[0005] Spleen deficiency and phlegm-dampness is the key factor of PCOS. Spleen governs blood, and is responsible for transformation, which is the source of qi and blood. If the spleen fails to transport and transform, water-dampness will flow into the lower jiao, accumulate and produce phlegm, which will block the chong and ren channels and the uterus, leading to infertility and other diseases, and become an important pathological link of PCOS.

[0006] Liver qi not being comfortable is an important predisposing factor of PCOS. Liver stores blood, governs dispersion, and manages emotions. According to the Canon of Internal Medicine, "When a woman is 27 years old, the kidney essence arrives, the ren channel is unblocked, and the chong channel is full, and the menstrual period comes regularly. If the heart is not comfortable, the liver is not unblocked, the spleen fails to transport and transform, qi is blocked and blood is stasis, and phlegm is produced, leading to irregular menstruation, and eventually to amenorrhea. If the five emotions are not in harmony, they will all be transformed into fire, which will scorch the true yin and gradually deplete the blood sea, so the menstrual period will not come regularly, and eventually to amenorrhea." The liver likes to be unblocked and hates to be depressed, and emotional factors play an important role in the pathogenesis of PCOS.

[0007] In the prior art, CN118304358A discloses a traditional Chinese medicine compound composition for treating polycystic ovary syndrome and its application. The composition is prepared from amethyst 1-20, radix leonuri 1-15, platycladus orientalis 1-15, acorus gramineus 1-15, polygala 1-12, radix rehmanniae preparata 1-12, angelica sinensis 1-12, medlar 1-12, salvia miltiorrhiza 1-10, dioscorea 1-10, poria cocos 1-10, and chuanxiong 1-9. The whole prescription focuses on treating the kidney, nourishing the essence and blood of the kidney, and guiding the qi and blood, so as to achieve the mutual interaction of the heart and kidney, and the harmony of qi and blood. It highlights the application of drugs for the chong and ren channels. CN105596495A discloses a traditional Chinese medicine compound for treating adolescent polycystic ovary syndrome, which is prepared from radix astragali 30-35, panax quinquefolium 20-25, salvia miltiorrhiza 15-20, fructus crataegi 15-20, poria cocos 15-20, rhizoma atractylodis 20-25, and citrus reticulata 15-20. The whole prescription tonifies qi and spleen, and resolves phlegm and promotes blood circulation, and treats adolescent PCOS by adjusting the constitution. CN103006971A also discloses a compound preparation for treating polycystic ovary syndrome and a preparation method thereof, which is mainly composed of fried gardenia, gentiana, madder, radix lithospermi, radix paeoniae, salvia miltiorrhiza, prepared rhubarb, and radix cyathulae, and treats polycystic ovary syndrome by the method of clearing liver and purging fire, and cooling and activating blood. However, the current traditional Chinese medicine prescription still focuses on tonifying the kidney and tonifying qi and blood, and cannot well solve the problem of infertility in polycystic ovary syndrome. SUMMARY

[0008] Therefore, the purpose of the present application is to provide a traditional Chinese medicine composition for promoting follicular development and improving oocyte quality in patients with polycystic ovary syndrome, and its application. The traditional Chinese medicine composition has the effects of warming the kidney and regulating the chong channel, and ascending yang and draining turbidity, and can promote follicular development, improve oocyte quality, reduce the abortion rate, and improve the pregnancy outcome, etc., and is a safe and effective pure traditional Chinese medicine preparation.

[0009] This invention provides a traditional Chinese medicine composition for treating infertility caused by polycystic ovary syndrome. The composition is made from the following raw materials in parts by weight: deer antler 5-20 parts, plantain seed 20-50 parts, polygonatum rhizome 5-25 parts, bupleurum root 5-25 parts, immature bitter orange peel 5-25 parts, poria cocos 10-30 parts, white hyacinth bean 5-25 parts, euryale seed 20-60 parts, phellodendron bark 1-10 parts, cat's claw herb 1-10 parts, cinnamon twig 1-10 parts, alisma rhizome 5-25 parts, and amethyst 5-25 parts.

[0010] Preferably, the traditional Chinese medicine composition is made from the following raw materials in parts by weight: 5-15 parts deer antler, 25-40 parts plantain seed, 5-20 parts polygonatum, 5-20 parts bupleurum, 5-20 parts immature bitter orange peel, 10-20 parts poria cocos, 5-20 parts white hyacinth bean, 20-50 parts euryale seed, 1-9 parts phellodendron bark, 1-9 parts cat's claw herb, 1-9 parts cinnamon twig, 5-20 parts alisma rhizome, and 5-20 parts amethyst.

[0011] Preferably, the traditional Chinese medicine composition is made from the following raw materials in parts by weight: 8-15 parts deer antler, 25-35 parts plantain seed, 5-15 parts polygonatum, 5-15 parts bupleurum, 5-15 parts immature bitter orange peel, 10-18 parts poria cocos, 5-15 parts white hyacinth bean, 20-40 parts euryale seed, 3-9 parts phellodendron bark, 3-9 parts cat's claw herb, 3-9 parts cinnamon twig, 8-15 parts alisma rhizome, and 8-15 parts amethyst.

[0012] Preferably, the traditional Chinese medicine composition is made from the following raw materials in parts by weight: 10 parts deer antler, 30 parts plantain seed, 10 parts polygonatum, 10 parts bupleurum, 10 parts immature bitter orange peel, 15 parts poria cocos, 10 parts white hyacinth bean, 30 parts euryale seed, 6 parts phellodendron bark, 6 parts cat's claw herb, 6 parts cinnamon twig, 10 parts alisma rhizome, and 10 parts amethyst.

[0013] The fox nuts mentioned are stir-fried fox nuts, and the plantain seeds are salted plantain seeds.

[0014] Among them, deer antler is the unossified, densely haired young antler of the male sika deer or red deer, belonging to the Cervidae family. It enters the kidney and liver meridians. It is warm in nature and sweet and salty in taste. Its functions and indications are: to invigorate kidney yang, nourish essence and blood, strengthen tendons and bones, regulate the Chong and Ren meridians, and promote the healing of sores and carbuncles. It is used for impotence and premature ejaculation, infertility due to cold uterus, emaciation, fatigue, aversion to cold, dizziness, tinnitus and deafness, cold pain in the lower back and spine, weakness of tendons and bones, metrorrhagia and leukorrhea, and non-healing carbuncles.

[0015] Plantain seed is slippery and diuretic, sweet in taste, cold in nature, and non-toxic. It enters the bladder, spleen, and kidney meridians, and is most effective in clearing the urinary tract, its function being specifically to promote urination. When the urinary tract is cleared, the seminal tract naturally closes. When the seminal tract is kept closed, the seminal tract becomes abundant over time, and when the seminal tract is abundant, it can be released, leading to fertility. The *Compendium of Materia Medica* states, "Plantain seed...strengthens yin and benefits essence, enabling fertility." Plantain seed clears the urinary tract and consolidates the seminal tract, thus enabling fertility. This is actually a function of clearing blockages and purging within tonification, not that plantain seed has the function of tonifying the kidneys and replenishing essence. The *New Compilation of Materia Medica* also records, "When the urinary tract is open, the seminal tract closes, naturally the spirit is strong, and fertility can be achieved through intercourse, not that plantain seed can spontaneously fertilize."

[0016] Polygonatum sibiricum, with a neutral nature and a sweet taste, has the effects of replenishing middle qi, moistening the heart and lungs, and strengthening the muscles and bones. It is used to treat deficiency syndromes with cold or heat, hemoptysis due to pulmonary tuberculosis, anorexia after illness, weakness of muscles and bones, rheumatic pain, and leprosy and tinea. "Ben Cao Bian Du" states: "Polygonatum sibiricum is a nourishing and greasy product. Taking it for a long time can make people not feel hungry. If a person has dampness due to spleen deficiency, it is not suitable to take it, for fear that it will cause stuffiness in the diaphragm. This medicine tastes as sweet as maltose, has a neutral nature and a moist texture, and is the genuine product for nourishing the yin of the spleen." In the formula, Poria cocos, Euryale ferox and other herbs for strengthening the spleen and promoting diuresis to eliminate dampness are used. They can not only restrict the greasy nature of Polygonatum sibiricum, but also strengthen the transportation and transformation of the middle jiao, so that the tonic effect is not stagnant. It is especially suitable for the syndrome of spleen deficiency with dampness retention, which exactly conforms to the formula principle of "tonifying while dredging, nourishing without being greasy", enabling the nourishing yin function of Polygonatum sibiricum to be fully exerted without the drawback of stagnation.

[0017] Poria cocos strengthens the spleen and promotes diuresis to eliminate dampness. It tastes sweet and bland, has a neutral nature, and is non-toxic. "Shen Nong's Herbal Classic" states that Poria cocos "promotes diuresis to eliminate dampness, strengthens the spleen, calms the mind, supplements qi, eliminates phlegm, and removes dampness. It is used to treat spleen deficiency, anorexia, diarrhea, edema, phlegm turbidity, rheumatism... and strengthen the body." The results of modern pharmacological research have confirmed that Poria cocos has effects such as anti-inflammatory and antioxidant.

[0018] Bupleurum chinense is bitter and cool, enters the liver and gallbladder meridians, and has the effects of reconciling the exterior and interior, soothing the liver, and ascending yang. It is used to treat alternating chills and fevers, fullness and pain in the chest and hypochondrium, bitter taste in the mouth and deafness, headache and dizziness, malaria, diarrhea with rectal prolapse, irregular menstruation, and uterine prolapse. "Compendium of Materia Medica of Yunnan" states: "It is an important medicine for inducing sweating and relieving the exterior syndrome in cold damage, expelling pathogenic factors of the six meridians that alternate between cold and heat, treating flaccidity and paralysis, removing pathogenic heat in the liver, consumptive fever, promoting the qi stagnation in the reverse flow of the liver meridian, relieving the pain of the liver qi on the left hypochondrium, treating women's menorrhagia due to blood heat, and regulating menstruation. The tender stamens are used for inducing sweating, and the roots are used for treating deficiency heat and regulating menstruation." "Explanation of the Herbal Classic" states: "Bupleurum chinense is a medicine for the exterior of the Shaoyang meridian. It mainly treats qi stagnation in the heart, abdomen, stomach, and intestines, food accumulation, cold and heat pathogenic factors, promoting the transformation of the old and the generation of the new, and removing restlessness in the heart due to cold damage. It pertains to the foot Shaoyang gallbladder meridian. The gallbladder is a pure organ without entry or exit, and sweating, vomiting, and purging are not applicable. Its meridian is in the half-exterior and half-interior, so the treatment method follows reconciliation, such as the Minor Bupleurum Decoction. Its nature is ascending and dispersing, belonging to yang, so it can reach the exterior and disperse pathogenic factors. When pathogenic factors are stagnated, there will be restlessness in the heart; when pathogenic factors are dispersed, the restlessness will be resolved spontaneously. When yang qi sinks, there will be food accumulation; when yang qi ascends, the clear qi will ascend, and when the qi of the spleen and stomach moves along the yang meridian, the food accumulation will be dispersed spontaneously. All phlegm-heat accumulation, pathogenic reverse qi in the chest, and wandering qi among the five zang-organs are the diseases caused by the excess heat pathogen of the Shaoyang meridian."

[0019] Fructus Aurantii has a bitter, pungent, and sour taste, and is slightly cold; it has the effects of regulating qi and relieving distension, promoting qi movement and relieving flatulence, and is used for qi stagnation in the chest and hypochondrium, fullness and pain, indigestion, internal retention of phlegm-fluid, and visceral ptosis. Fructus Aurantii contains components such as volatile oil, flavonoids, and alkaloids, and has effects such as anti-inflammatory, antioxidant, and regulating smooth muscle, and is clinically used to assist in the treatment of diseases such as functional dyspepsia and chronic gastritis.

[0020] Hyacinth bean, sweet and neutral in nature, enters the spleen and stomach meridians, and has the effects of strengthening the spleen and harmonizing the middle jiao, relieving summer heat and dampness. It treats summer heat and dampness causing vomiting and diarrhea, spleen deficiency causing nausea and vomiting, poor appetite and chronic diarrhea, water retention and thirst, leukorrhea, and infantile malnutrition. The Compendium of Materia Medica states: "Hard-shelled white hyacinth beans have plump seeds that are white with a slight yellow tinge. They have a fishy and fragrant aroma and are warm and neutral in nature, thus being a grain for the spleen. They enter the Taiyin Qi level, unblock the three jiaos, and can transform clear Qi into turbid Qi. Therefore, they are specifically used to treat diseases of the middle jiao, relieve summer heat and dampness, and detoxify. Soft-shelled and blackish-brown hyacinth beans are slightly cool in nature and can be eaten, also regulating the spleen and stomach."

[0021] Euryale ferox, sweet and astringent, neutral in nature, enters the spleen and kidney meridians. It has the effects of tonifying the kidneys and securing essence, strengthening the spleen and stopping diarrhea, and dispelling dampness and stopping leukorrhea. It is used for nocturnal emission, frequent urination, chronic diarrhea due to spleen deficiency, leukorrhea, and vaginal discharge. The *Compendium of Materia Medica* states: "Euryale ferox is sweet and bland, possessing the true flavor of earth, and is a medicine for the spleen and kidneys. The spleen dislikes dampness, and the kidneys dislike dryness. Euryale ferox is bland, sweet, and fragrant, thus not harming dampness; its sticky texture and astringent taste, yet smooth and moist, do not harm dryness. While medicines for the spleen and kidneys often have opposite effects, this one complements them, hence its special value."

[0022] Phellodendron bark, bitter and cold in nature, enters the kidney and bladder meridians. It has the effects of clearing heat, drying dampness, purging fire, and detoxifying. It treats dysentery, diarrhea, diabetes, jaundice, weakness, nocturnal emission, urinary tract infections, hemorrhoids, hematochezia, leukorrhea, steaming bone fever, red and swollen eyes, sores in the mouth and tongue, and carbuncles and boils.

[0023] Cinnamon twig enters the heart, lung, and bladder meridians. It is pungent, sweet, and warm in nature. It has the effects of inducing sweating and relieving muscle tension, warming and unblocking the meridians, assisting yang and transforming qi, and calming and descending qi. It is used for colds due to wind-cold, abdominal pain due to cold, amenorrhea due to blood stasis, joint pain, phlegm retention, edema, palpitations, and abdominal distension.

[0024] Cat's Claw Herb has the effects of resolving phlegm and dissipating nodules, detoxifying and reducing swelling. It is often used for scrofula, boils and carbuncles, and snake and insect bites.

[0025] The principal ingredient of the herbal composition of this invention consists of deer antler and plantain seed. The assistant ingredients consist of polygonatum rhizome, bupleurum root, immature bitter orange peel, poria cocos, white hyacinth bean, and euryale seed. The adjuvant ingredients consist of phellodendron bark, cat's claw herb, and cinnamon twig. The herbal composition of this invention can be formulated into preparations by adding a pharmaceutically acceptable drug carrier, wherein the preparation is selected from one of granules, tablets, capsules, decoctions, pills, ointments, and oral liquids.

[0026] This invention addresses the unique pathogenesis of infertile patients with polycystic ovary syndrome (PCOS), a condition characterized by congenital kidney yang deficiency, acquired liver and spleen dysfunction, and stagnation in the middle jiao, leading to the retention of dampness, phlegm, and turbidity in the lower jiao and obstruction of the Chong and Ren meridians.

[0027] Detailed pathogenesis analysis:

[0028] Based on years of clinical practice, our team has concluded that the pathogenesis of PCOS is congenital kidney yang deficiency, acquired liver and spleen dysfunction, stagnation in the middle jiao, which leads to the retention of dampness, phlegm and turbidity in the lower jiao and obstruction of the Chong and Ren meridians.

[0029] The concept of the lower jiao (lower burner) first appeared in the *Huangdi Neijing* (Yellow Emperor's Inner Classic). The *Lingshu* (Spiritual Pivot) states, "The lower jiao separates from the ileum, flows into the bladder, and seeps in… the lower jiao is like a ditch." Its physiological functions can be summarized as "excreting waste and regulating fluids," encompassing the kidneys, bladder, large intestine, and uterus. Its qi and blood circulation is characterized by "turbid yin returning downwards," and dampness tends to descend, thus phlegm and dampness easily stagnate here. PCOS patients are fundamentally due to congenital kidney deficiency, which leads to impaired fluid transformation. Combined with acquired spleen deficiency and liver stagnation, this results in impaired function of the middle jiao, leading to stagnation and the accumulation of dampness and phlegm in the lower jiao and uterus, obstructing the Chong and Ren meridians, ultimately causing female infertility.

[0030] The kidneys govern reproduction and are the foundation of innate essence. The essence stored in the kidneys is fundamental to reproductive function and menstruation. Most PCOS patients have congenital kidney yang deficiency. The kidneys reside in the lower jiao and are the foundation of primordial yang. Kidney yang deficiency leads to "weakness of the fire of the gate of life, unable to vaporize and transform fluids." When fluids lose their warmth, they easily condense into phlegm and dampness. The kidneys are the root of the five viscera. Insufficient kidney yang leads to malnourishment of the five viscera. Coupled with a daily diet of cold drinks, the spleen and stomach are easily damaged. Furthermore, the liver and kidneys share the same origin. The kidneys are responsible for storage, while the liver is responsible for free flow. The two, one opening and one closing, jointly govern the occurrence and cessation of menstruation. Kidney deficiency cannot nourish the liver. In addition, the fast pace and multiple sources of stress in modern society often lead to liver qi stagnation in women of childbearing age. The liver and spleen are both located in the middle jiao. When this occurs, the pivot mechanism is obstructed, clear yang fails to ascend, and turbid yin fails to descend. Dampness and turbidity descend along the meridians to the lower jiao, and phlegm and turbidity accumulate internally, leading to obstruction of the uterus and the Chong and Ren meridians, resulting in poor circulation of qi and blood in the Chong and Ren meridians. The uterus is a "special organ" that requires nourishment from qi and blood, and warmth from kidney yang. Internal accumulation of phlegm and dampness obstructs the nourishment of the uterus by qi and blood essence, and inhibits the vaporization and transformation of kidney yang, leading to impaired egg development and expulsion. This is what Xu Shuwei of the Song Dynasty described in his *Puji Benshifang* as "damp phlegm and phlegm-fluid accumulation in the uterus."

[0031] This invention's kidney-tonifying and phlegm-resolving formula uses deer antler and plantain seed as the principal ingredients. Deer antler tonifies kidney yang and nourishes essence and blood, thus warming the kidneys and regulating the Chong meridian. Plantain seed eliminates damp heat and phlegm, allowing dampness and turbidity to be expelled through urination. The combined use of these two ingredients establishes the overall therapeutic principle of this formula, which focuses on warming the kidneys and reducing turbidity.

[0032] Polygonatum, Bupleurum, Aurantium, Poria, White Hyacinth Bean, and Fried Euryale Seed are the assistant herbs. Fried Euryale Seed and Polygonatum nourish the kidneys and replenish essence, embodying the principle of seeking yang within yin, assisting the principal herbs in warming the kidneys. In addition, Fried Euryale Seed can also strengthen the spleen and eliminate dampness, protecting the qi of the spleen and stomach. Poria and White Hyacinth Bean strengthen the spleen and eliminate dampness, cutting off the source of phlegm production. The formation of phlegm is closely related to spleen and stomach weakness. Strengthening the earth element to control water ensures that when the spleen is healthy, dampness cannot be generated and phlegm cannot accumulate. Bupleurum and Aurantium soothe the liver and relieve depression, regulate the flow of qi and blood in the Chong and Ren meridians, and unblock the qi mechanism of the middle jiao. The combined use of these assistant herbs strengthens the spleen and soothes the liver, unblocks the qi mechanism of the middle jiao to resolve phlegm, and relieves the stagnation of the pivot.

[0033] The formula is supplemented with Phellodendron bark, Uncaria rhynchophylla, and Cinnamon twig. Phellodendron bark and Uncaria rhynchophylla clear heat and dissipate nodules, resolve phlegm and reduce turbidity. While eliminating dampness and resolving phlegm, it is necessary to prevent the stagnation of dampness from generating heat over time. Cinnamon twig warms and invigorates Yang Qi. When combined with Bupleurum, they work together to soothe the liver, relieve depression, and promote the upward movement of Shao Yang Qi, thus helping the clear Yang Qi to reach the exterior. Alisma rhizome and Amethyst serve as guiding herbs. Alisma rhizome promotes diuresis and eliminates turbidity, guiding phlegm, dampness, and stasis out through the water passages, thus providing an outlet for pathogens. Amethyst warms the uterus and dispels cold stagnation, acting as a guiding herb to direct other warming and tonifying herbs to the lower Jiao. The combined effects of all the herbs in the formula warm the kidneys, regulate the Chong meridian, and promote Yang Qi to eliminate turbidity.

[0034] Guided by the theory of the "Triple Burner," this formula employs a combination of tonification and purgation, opening and closing to warm the kidneys, regulate the Chong meridian, raise Yang, and expel turbidity. This replenishes the kidney essence in the lower burner and relieves stagnation in the middle burner. Consequently, the body's vital functions are strengthened, the uterine vessels are unobstructed, dampness and phlegm are eliminated, the lipid membrane opens, Yin and Yang harmonize, essence and blood unite, and the embryo forms, leading to fertilization and development. Clinically, this invention can promote follicle development, improve egg quality, reduce miscarriage rates, and improve pregnancy outcomes.

[0035] The present invention also provides a method for preparing the above-mentioned traditional Chinese medicine composition, wherein the raw materials of each traditional Chinese medicine are pulverized and then extracted with water or alcohol solution. The alcohol is one of methanol, ethanol, propanol or butanol, preferably ethanol.

[0036] The extraction is selected from one of the following: immersion extraction, percolation, and reflux extraction.

[0037] The ethanol solution is preferably a 40%-90% aqueous ethanol solution, more preferably 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% aqueous ethanol solution.

[0038] The present invention further provides the use of the above-mentioned traditional Chinese medicine composition in the preparation of a drug for polycystic ovary syndrome infertility, preferably in the preparation of a drug for improving sex hormone levels, increasing the number of primordial follicles, increasing the number of secondary follicles, increasing the number of antral follicles, or improving egg quality, or improving follicle development.

[0039] This invention also discloses that the traditional Chinese medicine composition can be prepared by any existing technology and by adding any other ingredients to improve infertility caused by polycystic ovary syndrome.

[0040] The beneficial effects of this invention are: it can treat infertility caused by polycystic ovary syndrome, and has the effects of warming the kidneys and regulating the Chong meridian, raising Yang and eliminating turbidity, unblocking the uterine vessels, promoting the interaction of Yin and Yang, and condensing essence and blood to form an embryo and promote fertility. When applied to patients with infertility caused by polycystic ovary syndrome, it can promote follicle development, improve egg quality, reduce miscarriage rate, and improve pregnancy outcome. It is a safe and effective pure Chinese medicine preparation. Attached Figure Description

[0041] Figure 1Vaginal smears of rats in the blank control group were observed for 4 consecutive days (a) proestrus, b) estrus, c) metestrus, d) estrus.

[0042] Figure 2 Vaginal smears of rats in the model group and each group treated with traditional Chinese medicine were observed for 4 consecutive days (no keratinized cells were observed, indicating the disappearance of the estrous cycle);

[0043] Figure 3 A kidney-tonifying and phlegm-resolving formula improved glucose and lipid metabolism levels in PCOS model mice;

[0044] Figure 4 The kidney-tonifying and phlegm-resolving formula improved PCOS and restored the proportion of normal oocytes in PCOS model mice.

[0045] Figure 5 Percentage of normal oocytes in each group of PCOS mice;

[0046] Figure 6 The kidney-tonifying and phlegm-resolving formula increased implantation sites in PCOS model mice;

[0047] Figure 7 Number of implantation sites in each group of PCOS mice. Detailed Implementation Plan

[0048] Example 1

[0049] Formula: 10g deer antler, 30g plantain seed, 10g polygonatum, 10g bupleurum, 10g immature bitter orange peel, 15g poria cocos, 10g white hyacinth bean, 30g euryale seed, 6g phellodendron bark, 6g cat's claw herb, 6g cinnamon twig, 10g alisma, 10g amethyst.

[0050] Preparation method: First, decoct the deer antler in water for 15 minutes, then add Polygonatum sibiricum, Bupleurum chinense, Citrus aurantium, Poria cocos, Dolichos lablab, Euryale ferox, Phellodendron chinense, Uncaria rhynchophylla, Cinnamomum cassia, Alisma plantago-aquatica, and amethyst and continue to decoct for 30 minutes. Then add Plantago asiatica and decoct for another 15 minutes. After filtering, collect the filtrate. Add water to the dregs and decoct for another 40 minutes. Collect the filtrate and combine the two filtrates to obtain the decoction.

[0051] Example 2

[0052] Formula: 10g deer antler, 35g plantain seed, 15g polygonatum rhizome, 15g bupleurum root, 10g immature bitter orange peel, 20g poria cocos, 10g white hyacinth bean, 25g euryale seed, 10g phellodendron bark, 6g cat's claw herb, 9g cinnamon twig, 10g alisma rhizome, 10g amethyst.

[0053] Preparation method: The above-mentioned medicinal materials are placed in an extraction tank, and water is added in three separate extractions. The first extraction involves adding 10-15 times the amount of water as the medicinal materials and extracting for 2.5-3.5 hours. The second extraction involves adding 8-12 times the amount of water as the medicinal materials and extracting for 1.5-2.5 hours. The third extraction involves adding 6-10 times the amount of water as the medicinal materials and extracting for 0.5-1.5 hours. The extracts are combined, filtered, and concentrated under reduced pressure to obtain a thick paste. Finally, the mixed powder of the medicinal materials is stirred and mixed evenly with the thick paste, then dried in a vacuum drying oven. After drying, the paste is removed, crushed, and further vacuum dried for 10-12 hours. After cooling to room temperature, a paste block is obtained.

[0054] Example 3

[0055] Formula: 10g deer antler, 25g plantain seed, 10g polygonatum, 15g bupleurum, 15g immature bitter orange peel, 25g poria cocos, 20g white hyacinth bean, 35g euryale seed, 9g phellodendron bark, 6g cat's claw herb, 6g cinnamon twig, 15g alisma, 6g amethyst.

[0056] Preparation method: Put the above-mentioned medicinal materials into an extraction tank, add 10 times the amount of 60% ethanol to extract for 2 hours, add 8 times the amount of 75% ethanol to extract for 1.5 hours, combine the extracts, combine the two filtrates, concentrate, dry and pulverize, add dextrin and magnesium stearate to make granules.

[0057] The formulation of this invention can also be prepared into various drug dosage forms such as powder, pills, tablets or capsules as needed.

[0058] Experimental example: Animal experiments

[0059] 1. Establishment of a DHEA-induced PCOS mouse model

[0060] After the experimental ICR mice were acclimatized to a normal diet for 7 days, the blank control group was injected subcutaneously with 0.09 mL of sesame oil + 0.01 mL of 95% ethanol daily for 20 days; the PCOS model group was injected subcutaneously with DHEA (6 mg / 100 g) dissolved in 0.09 mL of sesame oil + 0.01 mL of 95% ethanol daily for 20 days. The mice were weighed every 5 days and the dosage was recalculated.

[0061] Select male mice aged 6-8 weeks, weighing 25-35g, for breeding.

[0062] 2. Animal grouping and dosing regimen

[0063] Animals in the PCOS model group were randomly divided into 5 groups, with 20 animals in each group. These included a blank control group, a PCOS model group, a low-dose traditional Chinese medicine (TCM) group, a medium-dose TCM group, and a high-dose TCM group. The animals were labeled, weighed, and relevant data were recorded. The TCM groups received the medication (from Example 1) via gavage daily at doses of 12.65 g / kg·d, 25.53 g / kg·d, and 50.60 g / kg·d, respectively, once daily for 28 consecutive days. The control group and the model group received an equal volume of physiological saline via gavage based on body weight, once daily for 28 consecutive days.

[0064] Eight mice were taken from each group and caged with sexually mature male mice at a 1:1 ratio. The number of implantation sites after pregnancy was recorded in each group.

[0065] 3. Material Selection Plan

[0066] Serum preparation (6 animals per group): Blood was collected via the orbital cavity and placed in 1.5 mL EP tubes. The samples were incubated at room temperature for at least one hour (or 2 hours at 4°C) and centrifuged at 3000 rpm for 10 minutes. The supernatant was the serum, which was then transferred to a -80°C freezer for storage. This serum was used for the detection of sex hormones and glucose and lipid metabolism-related indicators.

[0067] Oocyte collection (n=6 per group): Oocytes were collected from mice in each group for testing. Mice in each group were intraperitoneally injected with 7.5 IU of PMSG, followed by 7.5 IU of HCG 46–48 hours later. Mice were euthanized by cervical dislocation 13–15 hours later, and the fallopian tubes were removed and placed in modified human tubal fluid medium (mHTF). Cumulus-oocyte complexes (COCs) were collected under a microscope. The COCs were digested with 0.1% hyaluronidase for 30 seconds, and oocytes were collected using a fine pipette and washed with PBS until all oocytes were fully exposed. The morphology of the mouse oocytes was observed under an inverted microscope.

[0068] Uterus of pregnant mice: After confirming pregnancy in each group of mice, the mice were euthanized by cervical dislocation, and the uteruses of the mice were collected to count the number of implantation sites.

[0069] 4. Model Evaluation

[0070] At the end of the modeling process, the control group mice maintained a regular estrous cycle, with an estrous cycle of 4-5 days. Irregular anucleate keratinocytes were visible throughout the field of view during estrus, appearing as "fallen leaves" in their accumulation. Figure 1 Meanwhile, mice in the model group and the traditional Chinese medicine groups remained in the interestrus phase, and vaginal smears showed predominantly white blood cells with no cyclical changes (see...). Figure 2Furthermore, compared with the control group, the model group mice exhibited severe disorders in glucose and lipid metabolism, with significantly elevated levels of triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), fasting insulin (FINS), fasting plasma glucose (FPG), and the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), with statistically significant differences (P < 0.05). Figure 3 As shown, * indicates P < 0.05 compared to the blank group, and Δ indicates P < 0.05 compared to the model group.

[0071] 5. Comparison of glucose and lipid metabolism in mice of different groups

[0072] Animal experiments showed that the kidney-tonifying and phlegm-resolving formula (BSHT) can improve glucose and lipid metabolism disorders in PCOS model mice. Compared with the model group, the medium-dose BSHT group significantly reduced TG levels in PCOS mice (P < 0.05), while the TG levels in the other BSHT groups were also reduced compared with the model group, but the differences were not statistically significant (P > 0.05). The high-dose BSHT group significantly reduced LDL levels in PCOS mice (P < 0.05), while the LDL levels in the other BSHT groups were not statistically significant compared with the model group (P > 0.05). The medium-dose and high-dose BSHT groups significantly reduced FINS and HOMA-IR levels in PCOS mice (P < 0.05), while the low-dose BSHT group also reduced FINS and HOMA-IR levels in PCOS mice, but the differences were not statistically significant (P > 0.05) (see...). Figure 3 ).

[0073] 6. Comparison of oocyte morphology among different groups of mice.

[0074] The kidney-tonifying and phlegm-resolving formula can restore the normal morphology of oocytes in DHEA-induced PCOS mouse models and increase the proportion of normal cells (see...). Figure 4 Compared with the model group, the percentage of normal oocytes in PCOS mice in each group treated with traditional Chinese medicine was significantly increased, and the difference was statistically significant (P < 0.05) (see...). Figure 5 ).

[0075] 7. Comparison of the number of pregnancies and implantation sites in each group of mice.

[0076] The kidney-tonifying and phlegm-resolving formula can significantly increase the number of implantation sites in PCOS model mice and promote their pregnancy (see...). Figure 6 Compared with the model group, the number of implantation sites in PCOS mice in each group of traditional Chinese medicine was significantly increased, and the difference was statistically significant (P < 0.05) (see...). Figure 7 ).

[0077] Typical Case 1

[0078] Patient Zhai, female, 24 years old, presented to our department on May 9, 2024, due to infertility. [Medical History] Previously regular menstrual cycles, but since biochemical pregnancy, menstrual flow has decreased, with blood clots (+), dysmenorrhea (++), relieved by heat. She also experiences breast tenderness during menstruation, lower back pain, poor appetite, abdominal distension after meals, normal sleep, sticky and incomplete bowel movements, normal urination, facial acne, and hair loss. LMP: May 8, 2024. Tongue: pale and swollen, with a white, greasy coating and teeth marks on the edges; sublingual veins are tortuous; pulse: deep and slippery. Height: 1.65m, weight: 68kg, BMI: 24.98kg / m². 2Previous follicle monitoring revealed delayed follicle development, with ovulation occurring around day 30-40 of the menstrual cycle. [Auxiliary Examinations] Gynecological ultrasound showed bilateral polycystic ovarian changes; sex hormone panel: FSH: 3 mIU / ml, LH: 4.05 mIU / ml, E2: 22.99 pg / ml, PRL: 17.46 ng / ml, T: 0.38 ng / ml, P: 0.22 ng / ml; AMH: 15.81 ng / mL; male partner's semen analysis: normal. [Preliminary Diagnosis] Western medicine diagnosis: secondary infertility; polycystic ovary syndrome; Traditional Chinese medicine diagnosis: infertility (spleen and kidney deficiency, phlegm and blood stasis obstructing the ovaries). [Initial Consultation Prescription] Traditional Chinese medicine was prescribed to warm the kidneys, regulate the Chong meridian, and promote Yang to eliminate turbidity. The prescription consisted of: deer antler 10g, plantain seed 30g, bupleurum 10g, immature bitter orange peel 10g, poria cocos 15g, white hyacinth bean 10g, euryale seed 30g, phellodendron bark 6g, cat's claw herb 6g, cinnamon twig 6g, alisma rhizome 10g, amethyst 10g, and polygonatum rhizome 10g. On May 30, 2024, the patient returned for a follow-up visit. Symptoms of lower back and sacral pain and sticky stools had improved, facial acne had decreased, recent sleep disturbances were poor, weight had not changed significantly, tongue was pale red with a slightly greasy white coating and teeth marks on the edges, and the pulse was deep and slippery. The prescription was modified by adding 15g of cornus officinalis and replacing poria cocos with poria cocos sclerotium. The patient continued this treatment. On June 21, 2024, the third consultation revealed that menstruation had started on June 10, 2024, with increased flow and a small amount of blood clots. Menstrual cramps had lessened, bowel movements were normal, sleep had improved, appetite was good, and postprandial abdominal distension had lessened. The tongue was red with a thin white coating, and the sublingual veins had disappeared. The pulse was slippery. Ultrasound monitoring of the follicles (day 12 of the menstrual cycle) showed a size of 14x14mm. The following day (day 14 of the menstrual cycle), a second monitoring showed a size of 17x16mm, indicating a significant improvement in follicle development compared to before treatment. The previous prescription, without the addition of Cornus officinalis, was continued. On July 15, 2024, the fourth consultation revealed that menstruation had not yet started. A self-tested urine pregnancy test was positive. On July 20, 2024, a blood HCG test showed 6197.73 mIU / mL, and P showed 20.5 ng / mL, indicating pregnancy. The patient had regular prenatal checkups, and her HCG levels were doubling well. An ultrasound showed that the fetus was developing well. Follow-up showed that the pregnancy was going smoothly, and she gave birth to a baby boy vaginally in our hospital's obstetrics department on April 19, 2025.

[0079] Typical Case 2

[0080] Patient Li, female, 33 years old, presented to our department on October 9, 2023, due to infertility. [Medical History] Menstrual cycles have become increasingly delayed over the past 5 years, occurring approximately every 30-150 days, with moderate flow, bright red color, and clots (+). She also experienced dysmenorrhea (+), severe breast tenderness before menstruation, lower abdominal pain, and lower back and sacral pain during menstruation, making sitting or standing difficult. Previous ultrasound monitoring at other hospitals failed to detect a dominant follicle. She is generally irritable and easily angered, has a good appetite, poor sleep with frequent dreams and easy awakening, normal bowel movements, and no facial acne or hirsutism. Her tongue is pale red with teeth marks on the edges, a thin white coating, and a wiry, slippery pulse. PMP: May 23, 2023; LMP: September 12, 2023 (dydrogesterone). BMI: 23.83 kg / m². 2

Auxiliary examinations

Preliminary diagnosis

Initial consultation order

[0081] Typical Case 3

[0082] Patient Zhang, female, 28 years old, visited our department on March 2, 2024. [Medical History] She usually has regular menstruation, but experiences lower back and knee pain, occasional tinnitus, cold hands and feet, weakness in the limbs, facial acne, good appetite, difficulty falling asleep, frequent dreams and easy awakening, dry stools (every 2-3 days), pale and swollen tongue with teeth marks on the edges, red tongue with a white, greasy coating, and a wiry, slippery pulse. LMP: February 29, 2024. BMI: 20.76 kg / m² 2

Auxiliary Examinations

Preliminary Diagnosis

[0083] Typical Case 4

[0084] Patient Wang, female, 29 years old, visited our department on January 10, 2024. [Medical History] Past menstrual history: irregular, moderate flow, bright red color, blood clots (++), dysmenorrhea (++), increased bowel movements during menstruation, accompanied by lumbosacral pain, difficulty sitting or standing, lower abdominal distension, facial acne, usually profuse vaginal discharge, fatigue, normal appetite and sleep, and normal bowel movements. Weight gain of 5 kg in the past year, significant hirsutism. Menstruation only occurs after taking Yasmin and Dydrogesterone. Previous ultrasound monitoring of follicles showed slow development to maturity, but no ovulation, eventually leading to luteinization. Tongue: pale and swollen with scattered petechiae, teeth marks on the edges, white and greasy coating, thready and deep pulse. LMP: December 6, 2023. BMI: 23.88 kg / m². 2 [Auxiliary Examinations] Sex hormone levels: FSH: 7.2 mIU / ml, LH: 17.2 mIU / ml; E2: 60.7 pg / ml; PRL: 15.0 ng / ml; T: 0.64 ng / ml, P: 0.32 ng / ml, TSH: 4.94 uIU / ml. Gynecological ultrasound: Polycystic ovary syndrome in both ovaries. [Preliminary Diagnosis] Western medicine diagnosis: Polycystic ovary syndrome; Traditional Chinese medicine diagnosis: Delayed menstruation (deficiency of both spleen and kidney, dampness and stagnation in the lower jiao). [Initial Consultation Orders] Traditional Chinese medicine treatment: warming the kidneys and regulating the Chong meridian, raising yang and clearing turbidity. Basic formula: Deer antler 10g, Plantago seed 30g, Polygonatum rhizome 10g, Bupleurum root 10g, Aurantium fruit 10g, Poria cocos 15g, White hyacinth bean 10g, Euryale seed 30g, Phellodendron bark 6g, Uncaria rhynchophylla 6g, Cinnamon twig 6g, Alisma rhizome 10g, Amethyst 10g. For those with blood stasis, add 10g of *Spatholobus suberectus* and 30g of *Leonurus japonicus*. On January 30, 2024, at the follow-up visit, the patient reported menstruation on January 24, 2024, with a small amount of blood clots, reduced dysmenorrhea, and improved fatigue. She still experienced lower back and sacral pain during menstruation. The previous prescription was modified by removing *Leonurus japonicus* and adding 30g of stir-fried *Coix lacryma-jobi*, to be continued. The patient was instructed to monitor follicles regularly during treatment. On February 22, 2024, at the third visit, the patient's vaginal discharge had decreased, and the previous prescription was continued. On March 18, 2024, at the fourth visit, the patient reported menstruation on March 6, 2024, with normal bowel movements during menstruation, no dysmenorrhea or blood clots, and no lower back and sacral pain. Ultrasound monitoring showed polycystic changes in both ovaries, with the largest follicle measuring 13x11mm. The previous prescription was modified by removing *Spatholobus suberectus*, to be continued. Monitoring on days 15 and 17 of the menstrual cycle showed that the largest follicles were 16x14mm and 19x18mm respectively. Monitoring on day 19 of the menstrual cycle showed that ovulation had occurred. On April 15, 2024, during the fifth visit, the patient reported that menstruation had not yet returned. A blood HCG test showed 4691.98 mIU / mL, indicating pregnancy. Subsequent follow-up showed a smooth pregnancy, and a cesarean section was performed on January 26, 2025, resulting in the delivery of a baby girl.

[0085] Typical Case 5

[0086] Patient Zhai, female, 31 years old, visited our department on March 10, 2024. [Medical History] Delayed menstruation, moderate flow, dark color, blood clots (+), dysmenorrhea (-), premenstrual breast tenderness, habitual aversion to cold, profuse vaginal discharge, clear and thin, odorless, good appetite, poor sleep, frequent dreams after sleep, fatigue and shortness of breath, no acne, obvious hirsutism. Previously treated with Diane-35, Yasmin, and dydrogesterone. Tongue: pale and swollen with teeth marks on the edges, red tip, white and greasy coating, deep and weak pulse. LMP: February 29, 2024. BMI: 23.03 kg / m². 2

Auxiliary Examinations

Preliminary Diagnosis

Initial Consultation Orders

Claims

1. A traditional Chinese medicine composition for treating infertility caused by polycystic ovary syndrome, characterized in that, The traditional Chinese medicine composition is made from the following raw materials in parts by weight: 5-20 parts deer antler, 20-50 parts plantain seed, 5-25 parts polygonatum, 5-25 parts bupleurum, 5-25 parts immature bitter orange peel, 10-30 parts poria cocos, 5-25 parts white hyacinth bean, 20-60 parts euryale seed, 1-10 parts phellodendron bark, 1-10 parts cat's claw herb, 1-10 parts cinnamon twig, 5-25 parts alisma rhizome, and 5-25 parts amethyst.

2. The traditional Chinese medicine composition according to claim 1, characterized in that, The traditional Chinese medicine composition is made from the following raw materials in parts by weight: 5-15 parts deer antler, 25-40 parts plantain seed, 5-20 parts polygonatum, 5-20 parts bupleurum, 5-20 parts immature bitter orange peel, 10-20 parts poria cocos, 5-20 parts white hyacinth bean, 20-50 parts euryale seed, 1-9 parts phellodendron bark, 1-9 parts cat's claw herb, 1-9 parts cinnamon twig, 5-20 parts alisma rhizome, and 5-20 parts amethyst.

3. The traditional Chinese medicine composition according to claim 1, characterized in that, The traditional Chinese medicine composition is made from the following raw materials in parts by weight: 8-15 parts deer antler, 25-35 parts plantain seed, 5-15 parts polygonatum, 5-15 parts bupleurum, 5-15 parts immature bitter orange peel, 10-18 parts poria cocos, 5-15 parts white hyacinth bean, 20-40 parts euryale seed, 3-9 parts phellodendron bark, 3-9 parts cat's claw herb, 3-9 parts cinnamon twig, 8-15 parts alisma rhizome, and 8-15 parts amethyst.

4. The traditional Chinese medicine composition according to claim 1, characterized in that, The traditional Chinese medicine composition is made from the following raw materials in parts by weight: 10 parts deer antler, 30 parts plantain seed, 10 parts polygonatum, 10 parts bupleurum, 10 parts immature bitter orange peel, 15 parts poria cocos, 10 parts white hyacinth bean, 30 parts euryale seed, 6 parts phellodendron bark, 6 parts cat's claw herb, 6 parts cinnamon twig, 10 parts alisma rhizome, and 10 parts amethyst.

5. The traditional Chinese medicine composition according to any one of claims 1-4, characterized in that, The fox nuts mentioned are stir-fried fox nuts, and the plantain seeds are salted plantain seeds.

6. The method for preparing the traditional Chinese medicine composition according to any one of claims 1-5, characterized in that, The raw materials of each Chinese herbal medicine are pulverized and then extracted with water or alcohol solution.

7. The preparation method according to claim 6, characterized in that, The alcohol is one of methanol, ethanol, propanol or butanol, preferably ethanol.

8. The preparation method according to claim 6, characterized in that, The extraction is selected from one of the following: immersion extraction, percolation, and reflux extraction.

9. The preparation method according to claim 7, characterized in that, The ethanol solution is preferably a 40%-90% aqueous ethanol solution.

10. Use of the traditional Chinese medicine composition according to any one of claims 1-5 in the preparation of a medicament for treating infertility caused by polycystic ovary syndrome.

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