Traditional Chinese medicine composition for regulating growth of sexual precocious children

Abstract

The invention belongs to the technical field of traditional Chinese medicines, and particularly relates to a traditional Chinese medicine composition for regulating growth of sexual precocious children. The traditional Chinese medicine composition is prepared from the following components in parts by weight: 15 parts of radix rehmanniae, 15 parts of radix paeoniae alba, 15 parts of semen cassiae, 12 parts of roasted rhizoma atractylodis macrocephalae, 9 parts of semen myristicae, 15 parts of radix curcumae, 15 parts of corn stigma, 6 parts of rhizoma galangae, 6 parts of fructus amomi, 15 parts of semen boitae and 6 parts of semen ziziphi spinosae. The traditional Chinese medicine composition for the liver-nourishing and spleen-tonifying therapy has a remarkable clinical curative effect on treating the problem of sexual precocity, and the result shows that the liver-nourishing and spleen-tonifying compound can be used for inhibiting the sexual precocity and promoting the rapid growth of the height at the same time, so that a relatively ideal final height of a child is achieved.

Description

Technical Field

[0001] The present invention belongs to the technical field of traditional Chinese medicine, and particularly relates to a traditional Chinese medicine composition for regulating the growth of children with precocious puberty. Background Art

[0002] Precocious puberty (PP) in children refers to the appearance of sexual characteristics in girls before 7.5 years old and boys before 9 years old. Precocious puberty is one of the most common endocrine diseases in children and has attracted increasing attention from parents. The incidence rate in girls is higher than that in boys. Precocious puberty leads to accelerated bone maturation and premature epiphyseal fusion, resulting in short final stature and / or failure to reach the genetic target height range. According to the data of the World Health Organization (WHO), the global incidence rate of precocious puberty is about 1-3%, and it has been on the rise in recent years. GnRHa is the standard treatment method for CPP, but there are certain side effects and limitations in GnRHa treatment. During GnRHa treatment, a decrease in growth rate can be observed, even lower than the pre-pubertal level.

[0003] The efficacy of precocious puberty depends on age, bone age, the rate of pubertal progression, the rate of height increase, psychosocial factors, and the expected final height; the final height of girls with precocious puberty under 6 years old can increase significantly after GnRHa treatment, but it cannot improve the final height of girls with precocious puberty over 8 years old. In girls aged 6-8 years old, the final adult height (FAH) only increases slightly after treatment. Girls over 11 years old continuing GnRHa treatment cannot improve the final height, and even the final height may decrease; the reduction of GH and IGF-1 secretion during GnRHa treatment leads to a decrease in height growth rate, even lower than the pre-pubertal level, and usually rhGH needs to be used in combination with GnRHa.

[0004] Therefore, it is particularly important to explore a safe and effective alternative therapy. At present, the treatment of precocious puberty in traditional Chinese medicine mostly focuses on treating yin deficiency and internal heat, and liver depression transforming into fire. However, children are in a state of delicate yin and yang. "The liver is often excessive", "the spleen is often insufficient", "the kidney is often deficient", and during the growth and development period, "kidney qi should be prosperous" and "kidney qi should be solid". Clinically, for children with precocious puberty due to liver-spleen disharmony, the method of soothing the liver and strengthening the spleen is used for treatment, so that the acquired spleen is healthy and the congenital kidney can be nourished. When the spleen is healthy, the essence is sufficient, the kidney qi becomes increasingly abundant day by day, and the liver is nourished by the essence and the liver qi is smooth, promoting the normal growth and development of children and avoiding the risk of damaging the spleen and suppressing the liver by bitter cold herbs. Summary of the Invention

[0005] In order to overcome the problems existing in the prior art, on the basis of the "therapy of clearing and discharging and suppressing the liver", a traditional Chinese medicine compound with the "therapy of soothing the liver and strengthening the spleen" has been established. Through more than ten years of clinical exploration of the "therapy of soothing the liver and strengthening the spleen" for children with precocious puberty, a relatively complete treatment plan has gradually taken shape. Clinically, the legislative principle of the "therapy of soothing the liver and strengthening the spleen" is based on the fact that the spleen is healthy in the acquired stage, so that the congenital endowment can be nourished, the kidney qi is abundant, the liver qi is smooth, and the essence is sufficient. Thus, during the growth and development process of children, the kidney qi is abundant, the liver qi is smooth, and the essence transported by the healthy spleen is continuous, promoting the normal growth and development of children and avoiding the risk of damaging the spleen and suppressing the liver by bitter and cold herbs.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0007] A traditional Chinese medicine composition for regulating the growth of children with precocious puberty, and the formula is as follows:

[0008] Rehmannia glutinosa, Paeonia lactiflora, Cassia obtusifolia, stir-fried Atractylodes macrocephala, Nutmeg, Curcuma aromatica, Corn silk, Galangal, Amomum villosum, Semen Platycladi, Semen Ziziphi Spinosae.

[0009] Preferably, by weight, the formula is as follows:

[0010] 15 parts of Rehmannia glutinosa, 15 parts of Paeonia lactiflora, 15 parts of Cassia obtusifolia, 12 parts of stir-fried Atractylodes macrocephala, 9 parts of Nutmeg, 15 parts of Curcuma aromatica, 15 parts of Corn silk, 6 parts of Galangal, 6 parts of Amomum villosum, 15 parts of Semen Platycladi, 6 parts of Semen Ziziphi Spinosae.

[0011] The use of the traditional Chinese medicine composition for regulating the growth of children with precocious puberty in the preparation of a traditional Chinese medicine preparation for regulating the growth of children with precocious puberty.

[0012] Preferably, the preparation is a traditional Chinese medicine granule preparation or traditional Chinese medicine decoction pieces.

[0013] Compared with the prior art, the technical solution provided by the present invention has the following beneficial effects or advantages:

[0014] The traditional Chinese medicine compound of the present invention can regulate IGF-1. IGF-1 plays an important role in both fetal and postnatal growth. In the circulation, 75% of IGF-1 binds to IGFBP-3 and ALS to form a ternary complex, and its half-life is extended to about 16 hours; IGFBP-3 is the main binding protein of IGF-1, transporting more than 90% of IGF-1, and IGFBP-3 plays an important role in the functional regulation of IGF-1; IGFBP-3 is a growth hormone-dependent hormone, which decreases when growth hormone is deficient and increases simultaneously when growth hormone increases. Higher height is related to higher concentrations of IGF-I and IGFBP-3. The results show that after the treatment with the compound for soothing the liver and strengthening the spleen, the serum E2 and T levels in children decreased significantly, while IGF-1 and IGFBP3 increased significantly compared with those before treatment. Among them, IGF-1 increased by about 25-40% compared with that before treatment, and IGFBP3 increased by about 15-30%. After treatment, girls grew at a growth rate of about 9 cm / year, and boys grew at a growth rate of 12 cm / year, indicating that the therapy of soothing the liver and strengthening the spleen has the curative effect of promoting the rapid growth of children while inhibiting precocious puberty. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The drawings are used to provide a further understanding of the present invention, and constitute a part of the specification. Together with the embodiments of the present invention, they are used to explain the present invention, but do not constitute a limitation to the present invention.

[0016] In the drawings:

[0017] Figure 1 Before and after treatment: (a) Change in the bone age-age ratio of girls, (b) Change in the bone age-age ratio of boys, (c) Change in the growth rate of the bone age-age ratio of boys, (d) Change in the growth rate of the bone age-age ratio of girls, (e) Change in the height SSD of boys, (f) Change in the height SSD of girls;

[0018] Figure 2 Changes in reproductive glands before and after treatment: (a) Uterine volume, (b) Ovarian volume, (c) Follicle size, (d) Testicular volume;

[0019] Figure 3 Changes in serum sex hormone levels before and after treatment: (a) LH in girls, (b) FSH in girls, (c) Prl in girls, (d) Estradiol in girls, (e) LH in boys, (f) FSH in boys, (g) Prl in boys, (h) Testosterone in boys;

[0020] Figure 4 Changes in serum IGF-1 and IGFBP3 before and after treatment: (a) IGF-1 in girls, (b) IGFBP3 in girls, (c) IGF-1 in boys, (d) IGFBP3 in boys. DETAILED DESCRIPTION OF THE INVENTION

[0021] The following will describe the preferred embodiments of the present invention in conjunction with the attached Figures 1 - 4 It should be understood that the preferred embodiments described herein are only for the purpose of illustrating and explaining the present invention, and are not intended to limit the present invention.

[0022] In the following embodiments, the test methods and detection methods are conventional methods unless otherwise specified; the reagents and materials can be obtained on the market unless otherwise specified.

[0023] Example 1

[0024] A traditional Chinese medicine composition for regulating the growth of children with precocious puberty, by weight, the prescription is: 15 parts of Rehmannia glutinosa, 15 parts of Paeonia lactiflora, 15 parts of Cassia obtusifolia, 12 parts of stir-fried Atractylodes macrocephala, 9 parts of Nutmeg, 15 parts of Curcuma aromatica, 15 parts of Corn silk, 6 parts of Alpinia officinarum, 6 parts of Amomum villosum, 15 parts of Semen Platycladi, 6 parts of Semen Ziziphi Spinosae.

[0025] The traditional Chinese medicine composition of the present invention takes Rehmannia glutinosa, Paeonia lactiflora, and Atractylodes macrocephala as the monarch drugs. Rehmannia glutinosa is sweet and cold, and belongs to the heart, liver, and kidney meridians. It can clear heat in various meridians, nourish yin and reduce yang. The liver is in charge of storing blood, and children have "excessive liver qi". Paeonia lactiflora is sweet, pungent, and warm, nourishing blood, softening the liver, astringing yin, and suppressing liver yang, "restraining liver qi", "descending qi". Atractylodes macrocephala is sweet and warm, belonging to the spleen meridian, strengthening the spleen and replenishing qi, and having the effect of drying dampness, "supporting the spleen and stomach, dispersing dampness". The three are combined to nourish the liver, soften the liver, and strengthen the spleen, and prevent the dampness generated by Rehmannia glutinosa and Paeonia lactiflora. They work together to achieve the effect of softening the liver and strengthening the spleen. It is reported in the literature that the Chinese medicine components in the combination of the three can inhibit the expression of ESR, AR, and Ptgs2. The ministerial drugs are Nutmeg, which is pungent and warm, with the effects of astringing the intestines and stopping diarrhea, warming the middle and promoting qi movement, and slowly restraining the descending and purging effects of Paeonia lactiflora. Curcuma aromatica is pungent, bitter, and cold, belonging to the liver, heart, and lung meridians, promoting qi and relieving depression, rising first and then descending. Amomum villosum is pungent in taste and warm in nature; belonging to the spleen, stomach, and kidney meridians, "it can rise and fall, with more descending than rising", promoting qi movement and regulating the middle, harmonizing the stomach, and awakening the spleen. The three are combined to regulate the liver qi, make the liver qi rise and fall in an orderly manner, avoid excessive rising of liver qi, achieve smooth liver qi, a healthy spleen, and the spleen can transport water essence. The Chinese medicine components of the three can inhibit ESR, CYP17A1, and PTX3, and promote the expression of CYP1A1, SIRT1, and GHSR. The adjuvant drugs are Corn silk, which is sweet, light, and flat in nature, belonging to the bladder, liver, and gallbladder meridians, clearing the liver and gallbladder, and Alpinia officinarum, which is pungent and hot, warming the middle and dispelling cold, regulating qi, to restrict the coldness of Rehmannia glutinosa and Paeonia lactiflora, and prevent the endogenous generation of cold-dampness; Pyridoxine in Corn silk can increase the secretion of IGF-1 and IGFBP3, and Quercetin in Amomum villosum promotes the secretion of IGFBP3; the guiding drugs are Semen Platycladi, which is sweet and flat in nature, belonging to the heart, kidney, and large intestine meridians, and Semen Ziziphi Spinosae, which is sweet and flat, entering the heart, spleen, liver, and gallbladder meridians, nourishing the liver, calming the heart, and soothing the nerves. The two are used together to nourish the liver and soothe the nerves, and the sleep is peaceful, which is beneficial to "the growth of yin", maintaining the secretion function of children's growth hormone at night. Looking at the whole formula, it is intended to promote the normal growth and development of children in the puberty stage through the method of strengthening the spleen and softening the liver according to the physiological characteristics of "excessive liver qi".

[0026] Clinical research:

[0027] 1. General Information This study included 62 children with precocious puberty who received traditional Chinese medicine treatment at the Children's Hospital Affiliated to Fudan University from October 2023 to May 2024, including 38 girls and 24 boys. This study was reviewed by the Ethics Committee of the Children's Hospital Affiliated to Fudan University (No.: Fuer Luncha

[2024] No. 202).

[0028] 2. Diagnostic criteria

[0029] 2.1 The Western medicine diagnostic criteria are formulated with reference to the "Expert Consensus on the Diagnosis and Treatment of Central Precocious Puberty (2022)": 1) Early appearance of sexual characteristics, that is, breast development before 7.5 years old or menarche before 10.0 years old in girls, and testicular enlargement before 9.0 years old in boys; 2) Enlarged gonads, B-ultrasound shows that the volume of the uterus and ovaries of girls is enlarged and follicles with a diameter of ≥4mm can be seen in the ovaries, and the testicular volume of boys is ≥4mL; 3) Serum gonadotropin and sex hormones reach puberty levels; 4) Bone age is advanced, and the bone age exceeds the actual age by ≥1 year; 5) There is linear growth acceleration, and the annual growth rate is higher than that of healthy children of the same age.

[0030] 2.2 TCM Diagnostic Criteria The diagnostic criteria for spleen deficiency and liver hyperactivity type precocious puberty were formulated with reference to the "Guidelines for Clinical Diagnosis and Treatment of Pediatrics in TCM·Precocious Puberty (Revised)": 1) Conform to precocious puberty; 2) Sallow complexion, poor appetite, easy emotional excitement, unrefreshing sleep, difficulty falling asleep, frequent dreams, dry or soft stools; 3) Pale red tongue, white and greasy fur, thin or stringy pulse; Secondary symptoms: 1) No fever in the five hearts, no hot flashes, no fear of heat; 2) No red cheeks, no night sweats, no irritability; 3) Occasionally accompanied by obvious bad breath in the morning, or poor appetite in the morning, or no appetite in the morning;

[0031] 3. Inclusion criteria 1) Meet the Western medical diagnosis criteria for precocious puberty; 2) Meet the TCM diagnosis criteria for precocious puberty; 3) Voluntarily take Chinese medicine treatment; 4) Have not received other Chinese medicine or Chinese patent medicine treatment in the past 3 months;

[0032] 4. Exclusion criteria 1) Space-occupying lesions on cranial MRI; 2) Accompanied by other endocrine abnormalities; 3) Genetic diseases accompanied by precocious puberty; 4) Unable to take Chinese medicine orally;

[0033] 5. Treatment Method: The Chinese medicine compound is made of Siwu Decoction combined with Baizhu Paste (adapted from "Fushou Jingfang", which is composed of 11 Chinese medicines such as raw rehmannia, white peony, cassia seed, stir-fried Baizhu, nutmeg, turmeric, corn silk, galangal, amomum, cypress seed, and spiny jujube seed. Take 100 ml each time, twice a day, morning and evening, for 6 consecutive months.

[0034] 6. Observation indicators: height, bone age, sex hormone level, uterus, ovary, follicle and testicle size of children before and after treatment.

[0035] 7. Statistical methods were used to collate the data of the children's height, age, bone age, B-ultrasound, blood biochemistry, sex hormones, IGF-1, and IGFBP3, and calculate the height increase rate, bone age - age ratio, and the volumes of the ovaries, uterus, follicles, and testes before and after treatment; the changes in sex hormones E2, T, LH, FSH, PRL, IGF, and IGFBP3 before and after treatment. In this study, Prism Version 9.5.0 was used for data analysis, and the t-test was used before and after treatment.

[0036] 8. Results

[0037] 8.1 Bone age and height changes:

[0038] As Figure 1 , the results showed that the bone age - age ratio of the children decreased after treatment with soothing the liver and strengthening the spleen (Boys: 1.17 ± 0.02 Vs. 1.10 ± 0.02, p < 0.05; Girls: 1.23 ± 0.02 Vs. 1.13 ± 0.02, p < 0.05), and the growth rate of the children increased significantly compared with that before treatment (boys: 6.86 ± 0.67 Vs. 12.65 ± 1.05 cm / y, p < 0.05,

[0039] girls: 6.95 ± 0.32 Vs. 8.81 ± 0.44 cm / y, p < 0.05), and the height SSD

[0040] (boys: 0.15 ± 0.15 vs. 0.60 ± 0.14,

[0041] p < 0.05; girls 0.02 ± 0.17 vs. 0.64 ± 0.20, p < 0.05) decreased significantly compared with that before treatment.

[0042] 8.2 Changes in the development of secondary sexual characteristics during puberty:

[0043] Figure 2 , the results showed that there was no significant increase in the uterus (3.05 ± 0.26 vs. 2.84 ± 0.17 ml, p > 0.05), ovaries (2.48 ± 0.99 vs. 2.71 ± 0.15 ml, p > 0.05), follicles (4.29 ± 0.13 vs. 4.28 ± 0.16 mm, p > 0.05), and testes (4.23 ± 0.41 vs. 4.24 ± 0.44 ml, p > 0.05) of the children before and after treatment.

[0044] 8.3 Changes in sex hormones:

[0045] As Figure 3, after treatment, the levels of estradiol in girls (121.5±9.87 vs. 89.74±10.01 pmol / L, p<0.05) and testosterone in boys (5.33±0.57 vs. 3.31±0.59 pmol / L, p<0.05) decreased, while LH

[0046] (girls: 1.78±0.25 vs. 2.15±0.41 IU / L, p>0.05; boys: 2.10±0.21 vs. 2.02±0.11 IU / L, p>0.05), Prl

[0047] (girls: 220.4±16.53 vs. 194.6±20.58 IU / L, p>0.05; boys: 172.2±18.53 vs. 161.3±12.44 IU / L, p>0.05) showed no significant changes; the levels of FSH in girls

[0048] (girls: 4.06±0.25 vs. 5.35±0.49 IU / L, p<0.05;

[0049] boys: 3.67±0.32 vs. 3.94±0.29 IU / L, p>0.05) increased after treatment.

[0050] 8.4 Changes in IGF-1 and IGFBP3:

[0051] Such as Figure 4 , after treatment, the serum IGF-1

[0052] (girls: 189.7±7.88 vs. 273.6±23.58 ng / mL, p<0.05; boys: 265.8±18.09 vs. 329.8±19.48 ng / mL, p<0.05), IGFBP3

[0053] (girls: 5.03±0.09 vs. 6.50±0.26 μg / L, p<0.05; boys: 5.56±0.19 vs. 6.43±0.26 μg / L, p<0.05) increased significantly compared with before treatment.

[0054] Conclusion:

[0055] This study shows that the method of soothing the liver and strengthening the spleen can inhibit the sexual development and increase the growth rate of precocious puberty children with liver deficiency and hyperactive liver by regulating the liver and spleen functions and improving the endocrine environment of children.

[0056] Traditional Chinese medicine believes that precocious puberty is closely related to the liver and kidney, and the treatment mainly focuses on clearing heat and purging fire with bitter and cold herbs [13-17], but after long-term treatment with bitter-cold herbs for purging fire, children are prone to manifestations of spleen deficiency such as sallow complexion. On the other hand, bitter-cold herbs for purging fire have certain efficacy in inhibiting the progression of precocious puberty, but the improvement of growth rate is not obvious; children with relatively large bone age and short height often need to choose combined treatment with GnHa and GH, but some children give up the combined treatment with GnHa and GH due to genetic factors, economy or concerns about side effects. Clinically, there is an urgent need to explore traditional Chinese medicine therapies that can increase the growth rate while inhibiting the rapid increase of bone age in children with precocious puberty.

[0057] Research shows that the traditional Chinese medicine compound of the present invention can regulate IGF-1. IGF-1 plays an important role in growth both in the fetal period and after birth. In the circulation, 75% of IGF-1 binds to IGFBP-3 and ALS to form a ternary complex, and the half-life is extended to about 16 hours; IGFBP-3 is the main binding protein of IGF-1, transporting more than 90% of IGF-1, and IGFBP-3 plays an important role in the functional regulation of IGF-1; IGFBP-3 is a growth hormone-dependent hormone, which decreases when growth hormone is deficient and increases simultaneously when growth hormone increases. Higher height is related to higher concentrations of IGF-I and IGFBP-3. The results show that after treatment with the compound for soothing the liver and strengthening the spleen, the serum E2 and T levels in children decreased significantly, and both IGF-1 and IGFBP3 increased significantly compared with those before treatment. Among them, IGF-1 increased by about 25-40% compared with that before treatment, and IGFBP3 increased by about 15-30%. After treatment, girls grew at a growth rate of about 9 cm / year, and boys grew at a growth rate of 12 cm / year, indicating that the therapy of soothing the liver and strengthening the spleen has the efficacy of promoting the rapid growth of children while inhibiting precocious puberty.

[0058] As described above, the basic principles, main features and advantages of the present invention are preferably described. The above embodiments and the description are only descriptions of the preferred embodiments of the present invention. The present invention is not limited by the above embodiments. Without departing from the spirit and scope of the present invention, various changes and improvements made by those of ordinary skill in the art to the technical solutions of the present invention shall fall within the protection scope determined by the present invention.

Claims

1. A Chinese medicine composition for regulating the growth of children with precocious puberty, characterized in that: The formula is: Raw rehmannia, white peony root, cassia seed, stir-fried atractylodes, nutmeg, turmeric, corn silk, galangal, amomum villosum, cypress seed, and jujube seed.

2. A Chinese medicine composition for regulating the growth of children with precocious puberty according to claim 1, characterized in that: By weight, the formula is: 15 parts of Radix Rehmanniae, 15 parts of Radix Paeoniae Alba, 15 parts of Semen Cassiae, 12 parts of stir-fried Atractylodes Macrocephalae, 9 parts of Myristica Fragrance, 15 parts of Curcuma Radix, 15 parts of Stigma Corni, 6 parts of Alpinia Officinarum, 6 parts of Amomum Villosum, 15 parts of Semen Platycladi, and 6 parts of Semen Ziziphi Spinosae.

3. The Chinese medicine composition for regulating the growth of children with precocious puberty as claimed in any one of claims 1 to 2, characterized in that: Use of a traditional Chinese medicine preparation for preparing growth-regulating children with precocious puberty.

4. The Chinese medicinal preparation for regulating the growth of children with precocious puberty according to claim 3, characterized in that: The Chinese medicine preparation is a granule preparation or a Chinese medicine decoction piece.

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