Climacteric disorder improver, climacteric disorder prevention agent, food composition for climacteric disorder improver, food composition for climacteric disorder prevention, method for determining crisis of climacteric disorder, and method for predicting crisis of climacteric disorder

Abstract

To provide a climacteric disorder improver, a climacteric disorder prevention agent, a food composition for improving climacteric disorder, a food composition for preventing climacteric disorder, a method for determining crisis of climacteric disorder, and a method for predicting crisis of climacteric disorder.SOLUTION: The invention provides, a climacteric disorder improver containing selenium compounds as an active ingredient, a climacteric disorder prevention agent containing selenium compounds as an active ingredient, a food composition for improving climacteric disorders containing selenium compounds as an active ingredient, a food composition for preventing climacteric disorders containing selenium compounds as an active ingredient, a method for determining the onset of climacteric disorders that includes a step of measuring the selenium concentration in the subject's sample, and a method for predicting the onset of climacteric disorders that includes a step of measuring the selenium concentration in the subject's sample.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an agent for improving climacteric disorder, an agent for preventing climacteric disorder, a food composition for improving climacteric disorder, a food composition for preventing climacteric disorder, a method for determining the onset of climacteric disorder, and a method for predicting the onset of climacteric disorder.

Background Art

[0002] Among the various symptoms that appear during menopause, symptoms not caused by organic changes are called menopausal symptoms, and a pathological condition that impairs daily life among these symptoms is defined as climacteric disorder. Regarding the cause of climacteric disorder, in the case of women, the main cause is the decline of ovarian function, and it has been reported that it appears due to the combined influence of physical changes associated with aging, psychosocial factors, and sociocultural environmental factors. That is, the definitive cause of female climacteric disorder is the decrease in female hormones accompanying the decline of ovarian function, and it has been reported that the secondary dysfunction of the hypothalamic-pituitary system causes various symptoms centered on autonomic nerve disorder symptoms (Non-Patent Document 1).

[0003] The hypothalamus, which is the body temperature regulation center, overall regulates the autonomic nerve and endocrine functions, and is the center for feeding, drinking (electrolyte balance), and circadian rhythm, playing an important role in maintaining the homeostasis of the living body. That is, the hypothalamus plays an important role in maintaining homeostasis. For example, "overeating" and "food preference" occur due to the influence on the feeding center, which affects lipid metabolism, sugar metabolism, and water metabolism, resulting in menopausal symptoms and body shape changes. Hot flashes and sweating are related to increased metabolism, irritability, and depression are also related to lipid metabolism, and leptin, which excites the sympathetic nerve from adipose tissue, is secreted. Stiff shoulders and headaches stimulate nerves due to water metabolism disorders and cause pain. In addition, stress and insomnia occur due to an increase in the hormone ACTH that constitutes the hypothalamic-pituitary-adrenal system. Since symptoms and constitutions vary greatly from person to person, for the treatment of climacteric disorder or symptoms, improvement of lifestyle habits, non-drug therapy, and drug therapy are carried out.

[0004] Menopause disorders include vasomotor symptoms such as hot flashes as physical symptoms, motor function symptoms such as shoulder stiffness, and mental symptoms such as irritability, anxiety, depression, decreased concentration, and forgetfulness. However, there are significant individual differences in the presence and degree of the symptoms of menopause disorders. In many cases, few symptoms appear, while on the other hand, there are also some women whose daily lives are severely affected and whose symptoms persist for more than a year. Therefore, depending on the presence or absence of symptoms and complications, drug therapy, psychotherapy, physical therapy, etc. are carried out (Non-Patent Document 2). In the drug therapy for menopause disorders, hormone replacement therapy, traditional Chinese medicine, and plant estrogens, gamma-oryzanol, vitamin E, tryptophan, etc. as complementary and alternative medicine have been tried. However, due to individual differences and the fact that the way and degree of the effects vary from person to person, there is currently no unified method.

Prior Art Documents

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0006] An object of the present invention is to provide an agent for improving menopause disorders, an agent for preventing menopause disorders, a food composition for improving menopause disorders, a food composition for preventing menopause disorders, a method for determining the onset of menopause disorders, and a method for predicting the onset of menopause disorders.

Means for Solving the Problems

[0007] The inventors have found that selenium compounds have excellent improving and preventive effects on various symptoms that appear during menopause, and that measuring the selenium concentration in a specimen can be used for the determination or prediction of the onset of menopausal disorders, thereby completing the present invention.

[0008] That is, the present invention includes the following aspects. [1] An agent for improving menopausal disorders containing a selenium compound as an active ingredient. [2] The agent for improving menopausal disorders according to [1], wherein the selenium compound is contained as a natural product, microorganism or food or drink containing selenium, or an extract of these natural products, microorganisms or food or drink. [3] A preventive agent for menopausal disorders containing a selenium compound as an active ingredient. [4] The preventive agent for menopausal disorders according to [3], wherein the selenium compound is contained as a natural product, microorganism or food or drink containing selenium, or an extract of these natural products, microorganisms or food or drink. [5] A food composition for improving menopausal disorders containing a selenium compound as an active ingredient. [6] The food composition for improving menopausal disorders according to [5], wherein the selenium compound is contained as a natural product, microorganism or food or drink containing selenium, or an extract of these natural products, microorganisms or food or drink. [7] The food composition for improving menopausal disorders according to [5] or [6], wherein the food composition for improving menopausal disorders is a health food, a food with function claims, a food for specified health use, a food for patients, a food with nutritional function claims, a dietary supplement, a supplement, a food for specified health use, a therapeutic milk or an enteral nutrient. [8] A food composition for preventing menopausal disorders containing a selenium compound as an active ingredient. [9] The food composition for preventing menopausal disorders according to [8], wherein the selenium compound is contained as a natural product, microorganism or food or drink containing selenium, or an extract of these natural products, microorganisms or food or drink.

[10] The food composition for preventing climacteric disorders according to [8] or [9], which is a health food, a food with function claims, a food for specified health use, a food for patients, a food with nutritional function claims, a dietary supplement, a supplement, a food for specified health use, a therapeutic milk or an enteral nutrition agent.

[11] A method for determining the onset of climacteric disorders, comprising the steps of measuring the selenium concentration in a specimen of a subject, comparing the selenium concentration with a reference value, and evaluating that the subject is highly likely to develop climacteric disorders when the selenium concentration is lower than the reference value.

[12] A method for predicting the onset of climacteric disorders, comprising the steps of measuring the selenium concentration in a specimen of a subject, comparing the selenium concentration with a reference value, and evaluating that the subject is highly likely to develop climacteric disorders when the selenium concentration is lower than the reference value.

Advantages of the Invention

[0009] There are provided an agent for improving climacteric disorders, an agent for preventing climacteric disorders, a food composition for improving climacteric disorders, a food composition for preventing climacteric disorders, a method for determining the onset of climacteric disorders, and a method for predicting the onset of climacteric disorders.

Brief Description of the Drawings

[0010]

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Mode for Carrying Out the Invention

[0011] <Menopausal disorder improver and menopausal disorder preventive agent> The menopausal disorder improver and menopausal disorder preventive agent of this embodiment contain a selenium compound as an active ingredient. The selenium compound used in this embodiment is not particularly limited as long as it is a compound containing selenium. For example, selenoneine, methylselenocysteine, selenocysteine, selenoglycose, sodium selenite, selenomethionine, sodium selenate, etc. can be mentioned. Further, the selenium compound used in this embodiment may be a protein containing selenium such as glutathione peroxidase, thioredoxin reductase, iodothyronine deiodinase, etc.

[0012] Selenium is contained in natural products such as raw fish such as liver and mackerel, selenium-containing microorganisms such as selenium-containing yeast (common name: mineral-containing yeast), and food and drink such as rice cakes, mustard, chicken eggs, tofu, and fried tofu. The selenium compound used in this embodiment may be contained as these selenium-containing natural products, microorganisms, or food and drink, extracts from these natural products, microorganisms, or food and drink, and these selenium-containing natural products, microorganisms, or food and drink themselves, or extracts from these natural products, microorganisms, or food and drink themselves may be used as the selenium compound. In particular, selenium is abundantly contained in liver, and as the selenium compound used in this embodiment, liver itself may be used, or processed products of liver such as liver paste may be used. The liver is not particularly limited, and for example, livers of chicken, pig, cow, sheep, etc. can be mentioned.

[0013] In addition, commercially available selenium compounds may be used in the present embodiment, or those purified and collected from natural products containing the above selenium, microorganisms such as yeast, foods and drinks, etc. by using ordinary purification means, for example, separation and purification methods such as precipitation methods, chromatography methods using ion exchange resins and activated carbon, etc. may also be used.

[0014] The menopausal disorder improver of the present embodiment can improve menopausal disorders or menopausal symptoms. Menopausal disorders refer to symptoms that do not result from organic changes among various symptoms that appear during menopause, and are called menopausal symptoms, and refer to pathological conditions that interfere with daily life among these symptoms. Menopausal symptoms include hot flashes, flushing, hot flushes, sweating, dizziness, palpitations, a feeling of tightness in the chest, headache, stiff shoulders, pain in the waist and back, joint pain, coldness, numbness, easy fatigue, mood swings, decreased motivation, irritability, or emotional instability, menopause, etc. The menopausal disorder improver of the present embodiment can improve menopausal disorders and / or menopausal symptoms.

[0015] The menopausal disorder preventive of the present embodiment can prevent the onset of menopausal disorders or the onset of menopausal symptoms. Menopausal symptoms include the above symptoms. The menopausal disorder preventive of the present embodiment can prevent the onset of menopausal disorders and / or the onset of menopausal symptoms.

[0016] The menopausal disorder improver and menopausal disorder preventive of the present embodiment may contain only a selenium compound, but various formulation components such as pharmaceutically acceptable ordinary carriers, antioxidants, binders, stabilizers, excipients, diluents, pH buffers, disintegrants, solubilizers, solubilizing aids, isotonic agents, etc. may be added. The dosage forms of the menopausal disorder improver and menopausal disorder preventive of the present embodiment may be solid preparations such as powders, granules, capsules, etc., or liquid preparations such as solutions, emulsions, suspensions, etc.

[0017] As a method of administering the agent for improving climacteric disorder and the agent for preventing climacteric disorder of the present embodiment, there is no particular limitation, and it may be administered orally or parenterally, but oral administration is preferred. As a method of parenteral administration, enteral administration and intravascular administration (preferably intravenous administration) can be preferably exemplified. The dosage of the agent for improving climacteric disorder and the agent for preventing climacteric disorder of the present embodiment may vary depending on symptoms, dosage form, body weight, etc., but in the case of oral administration, in terms of selenium conversion, it can be 5 μg to 250 μg, preferably 25 μg to 50 μg per day for an adult. Also, for patients with selenium deficiency, 50 μg to 500 μg, preferably 50 μg to 250 μg per day for an adult can be administered intravenously or orally in terms of selenium conversion.

[0018] The agent for improving climacteric disorder and the agent for preventing climacteric disorder of the present embodiment are not particularly limited and can be applied to any subject. The subjects to which the agent for improving climacteric disorder and the agent for preventing climacteric disorder of the present embodiment are applied include mammals such as humans, mice, rats, rabbits, cats, dogs, cows, horses, and monkeys, and female humans in menopause (40 to 60 years old) are preferred. The agent for improving climacteric disorder and the agent for preventing climacteric disorder of the present embodiment are also not particularly limited, but can be applied to subjects for whom improvement and prevention of climacteric disorder are desired, for example, subjects who feel discomfort related to menopause such as hot flashes, flushing, sweating, dizziness, palpitations, a feeling of tightness in the chest, headache, stiff shoulders, pain in the waist and back, joint pain, coldness, numbness, easy fatigue, mood depression, decreased motivation, irritability, emotional instability, or menopause.

[0019] <Food Composition for Improving Climacteric Disorder and Food Composition for Preventing Climacteric Disorder> Since selenium compounds have an effect of improving climacteric disorder and an effect of preventing climacteric disorder, they can be contained in various food compositions as an active ingredient of food compositions for improving and preventing climacteric disorder or various symptoms associated with climacteric disorder. In the present invention, food compositions include not only foods but also beverages.

[0020] Examples of the food composition for improving climacteric disorders and the food composition for preventing climacteric disorders in the present embodiment (hereinafter, collectively referred to as the food composition of the present embodiment unless otherwise specified) include not only general food and drink products, but also health foods, foods with function claims, foods for specified health uses, foods for patients, foods with nutrient function claims, dietary supplements, supplements, foods for specified health uses, enteral nutrition agents, therapeutic milk, and the like. General food and drink products include, for example, various beverages, various foods, processed foods, liquid foods (such as soups), seasonings, nutritional drinks, and confectioneries.

[0021] As used herein, the term "processed food" refers to a product obtained by processing and / or cooking natural food ingredients (such as animals and plants), and includes, for example, processed meat products, processed vegetable products, processed fruit products, frozen foods, retort foods, canned foods, bottled foods, and instant foods.

[0022] The food composition of the present embodiment may be a food with an indication of effects such as improvement and / or prevention of climacteric symptoms, hot flashes, flushes, hot flushes, sweating, dizziness, palpitations, a feeling of tightness in the chest, headache, stiff shoulders, pain in the waist and back, joint pain, coldness, numbness, easy fatigue, mood depression, decreased motivation, irritability, emotional instability, or menopause.

[0023] In addition, the food composition of the present embodiment may be provided in a form enclosed in a bag, a container, or the like. The bag and the container used in the present invention can be any bag and container commonly used for foods.

[0024] The blending amount of the selenium compound in the food composition of the present embodiment may be an amount that can exhibit the effect of improving and / or preventing climacteric disorders, and can be appropriately set according to the target, purpose, and intake method to be applied. For example, when orally ingested by humans, the intake amount per adult per day in terms of selenium can be formulated to be 5 μg to 250 μg, preferably 25 μg to 50 μg. In addition, for patients with selenium deficiency, the intake amount per adult per day in terms of selenium can be formulated to be 50 μg to 500 μg, preferably 50 μg to 250 μg.

[0025] <Method for determining onset of climacteric disorder> The method for determining the onset of climacteric disorder according to this embodiment includes a step of measuring the selenium concentration in a specimen of a subject, a step of comparing the selenium concentration with a reference value, and a step of evaluating that the subject is highly likely to have developed climacteric disorder when the selenium concentration is lower than the reference value. As is clear from the examples described later, it was confirmed that subjects with a low selenium concentration in the specimen had a significantly higher incidence of climacteric symptoms statistically compared to subjects with a high selenium concentration in the specimen. Therefore, when the selenium concentration in a subject's specimen is measured and is lower compared to the reference value, it can be evaluated that the subject is highly likely to have developed climacteric disorder, and when the selenium concentration in the subject's specimen is higher compared to the reference value, it can be evaluated that the subject is less likely to have developed climacteric disorder. For example, even if a subject does not perceive themselves to have climacteric disorder, if the selenium concentration in the subject's specimen is lower compared to the reference value, it can be evaluated that the subject is highly likely to have developed climacteric disorder. Therefore, the method for determining the onset of climacteric disorder according to this embodiment can be used for determining the onset of climacteric disorder.

[0026] Examples of the specimen include whole blood, plasma, serum, urine, cerebrospinal fluid, saliva, amniotic fluid, urine, sweat, pancreatic juice, etc., with whole blood, plasma, serum, urine, and hair being preferred, and serum being particularly preferred.

[0027] The selenium concentration in the sample can be measured by a known method. For example, it can be measured by Inductively Coupled Plasma Mass Spectrometry (ICP-MS) described in Journal of AOAC Int 94, 1240-1252 (2011). This method involves adding an internal standard to the sample, decomposing it in a sealed container microwave oven, and then measuring it by ICP-MS. It can also be measured by the method described in Anal.Chem. 144:569-576,198. This method involves wet-ashing the sample, reacting it with the fluorescent reagent 2,3-diaminonaphthlene (DAN) under hydrochloric acid acidity to induce the formation of piazselenol, extracting it with cyclohexane, and measuring the fluorescence intensity. The measurement of selenium concentration has been covered by insurance since April 2016, and it is also possible to measure it through insurance-based medical treatment.

[0028] As the reference value of the selenium concentration in the specimen, it can be appropriately set according to the type of the specimen, the age of the subject, etc. For example, the average value of the selenium concentration in the specimens of healthy people who have not developed menopausal disorders can be used as the reference value. Also, known reference values can be used depending on the specimen. For example, in the case of serum, the reference value can be set to 8.0 - 20.0 μg / dL, preferably 10.0 - 20.0 μg / dL, particularly preferably 14.0 - 20.0 μg / dL, and it can also be 9.0 - 18.0 μg / dL, 9.0 - 19.0 μg / dL, 9.0 - 20.0 μg / dL, 10.0 - 18.0 μg / dL, 10.0 - 19.0 μg / dL, 10.6 - 17.5 μg / dL, 11.0 - 18.0 μg / dL, 11.0 - 19.0 μg / dL, 11.0 - 20.0 μg / dL, 12.0 - 18.0 μg / dL, 12.0 - 19.0 μg / dL, 12.0 - 20.0 μg / dL, 13.0 - 18.0 μg / dL, 13.0 - 19.0 μg / dL, 13.0 - 20.0 μg / dL, 14.0 - 18.0 μg / dL, 14.0 - 19.0 μg / dL, 15.0 - 18.0 μg / dL, 15.0 - 19.0 μg / dL, 15.0 - 20.0 μg / dL, 16.0 - 18.0 μg / dL, 16.0 - 19.0 μg / dL, 16.0 - 20.0 μg / dL, 17.0 - 18.0 μg / dL, 17.0 - 19.0 μg / dL, 17.0 - 20.0 μg / dL, 18.0 - 19.0 μg / dL, 18.0 - 20.0 μg / dL, 19.0 - 20.0 μg / dL.

[0029] Next, the selenium concentration in the specimen is compared with the above reference value. When the selenium concentration in the specimen is lower compared to the reference value, it can be evaluated that the subject has a high possibility of developing menopausal disorders, and when the selenium concentration in the specimen of the subject is higher compared to the reference value, it can be evaluated that the subject has a low possibility of developing menopausal disorders. If it can be evaluated that the subject has a high possibility of developing menopausal disorders, this evaluation can be used to determine that the subject has a high possibility of developing menopausal disorders, and if it can be evaluated that the subject has a low possibility of developing menopausal disorders, this evaluation can be used to determine that the subject has a low possibility of developing menopausal disorders.

[0030] <Method for predicting onset of climacteric disorder> The method for predicting the onset of climacteric disorder according to the present embodiment includes a step of measuring the selenium concentration in a specimen of a subject, a step of comparing the selenium concentration with a reference value, and a step of evaluating that the subject is highly likely to develop climacteric disorder when the selenium concentration is lower than the reference value. As is clear from the examples described later, it was confirmed statistically significantly that subjects with a low selenium concentration in the specimen have more climacteric symptoms than subjects with a high selenium concentration in the specimen. Therefore, when the selenium concentration in the specimen of a subject is lower than the reference value, it can be evaluated that the subject is highly likely to develop climacteric disorder, and when the selenium concentration in the specimen of the subject is higher than the reference value, it can be evaluated that the subject is less likely to develop climacteric disorder. Therefore, the method for predicting the onset of climacteric disorder according to the present embodiment can be used for predicting the onset of climacteric disorder.

[0031] Examples of the specimen include whole blood, plasma, serum, urine, cerebrospinal fluid, saliva, amniotic fluid, urine, sweat, pancreatic juice, etc. Whole blood, plasma, serum, urine, and hair are preferred, and serum is particularly preferred.

[0032] The selenium concentration in the specimen can be measured by a known method. For example, it can be measured by Inductively Coupled Plasma Mass Spectrometry (ICP-MS) described in Journal of AOAC Int 94, 1240-1252 (2011). This method involves adding an internal standard to the sample, decomposing it in a sealed container microwave oven, and then measuring it by ICP-MS. It can also be measured by the method described in Anal.Chem. 144:569-576,198. This method involves wet-ashing the specimen, reacting it with the fluorescent reagent 2,3-diaminonaphthlene (DAN) under hydrochloric acid acidity to induce the piazselenol form, extracting it with cyclohexane, and measuring the fluorescence intensity. The measurement of selenium concentration has been covered by insurance since April 2016, and it is also possible to measure it through insurance-based medical treatment.

[0033] As a reference value for the selenium concentration in a specimen, it can be appropriately set according to the type of specimen, the age of the subject, etc. For example, the average value of the selenium concentration in a specimen of a healthy person without onset of climacteric disorder can be used as the reference value. Also, known reference values can be used depending on the specimen. For example, in the case of serum, the reference value can be set to 8.0 - 20.0 μg / dL, preferably 10.0 - 20.0 μg / dL, particularly preferably 14.0 - 20.0 μg / dL, and it can also be 9.0 - 18.0 μg / dL, 9.0 - 19.0 μg / dL, 9.0 - 20.0 μg / dL, 10.0 - 18.0 μg / dL, 10.0 - 19.0 μg / dL, 10.6 - 17.5 μg / dL, 11.0 - 18.0 μg / dL, 11.0 - 19.0 μg / dL, 11.0 - 20.0 μg / dL, 12.0 - 18.0 μg / dL, 12.0 - 19.0 μg / dL, 12.0 - 20.0 μg / dL, 13.0 - 18.0 μg / dL, 13.0 - 19.0 μg / dL, 13.0 - 20.0 μg / dL, 14.0 - 18.0 μg / dL, 14.0 - 19.0 μg / dL, 15.0 - 18.0 μg / dL, 15.0 - 19.0 μg / dL, 15.0 - 20.0 μg / dL, 16.0 - 18.0 μg / dL, 16.0 - 19.0 μg / dL, 16.0 - 20.0 μg / dL, 17.0 - 18.0 μg / dL, 17.0 - 19.0 μg / dL, 17.0 - 20.0 μg / dL, 18.0 - 19.0 μg / dL, 18.0 - 20.0 μg / dL, 19.0 - 20.0 μg / dL.

[0034] Next, the selenium concentration in the specimen is compared with the above reference value. When the selenium concentration in the specimen is lower compared to the reference value, it can be evaluated that the subject has a high possibility of developing climacteric disorder, and when the selenium concentration in the specimen of the subject is higher compared to the reference value, it can be evaluated that the subject has a low possibility of developing climacteric disorder. If it can be evaluated that the subject has a high possibility of developing climacteric disorder, this evaluation can be used to predict that the subject has a high possibility of developing climacteric disorder, and if it can be evaluated that the subject has a low possibility of developing climacteric disorder, this evaluation can be used to predict that the subject has a low possibility of developing climacteric disorder.

Example

[0035] The following are examples for specifically explaining the present invention, but the present invention is not limited to the following examples.

[0036] [Example 1] For the purpose of exploring the causes and related factors of discomfort in menopausal women, large-scale health data [n = 1056 (2018 data), n = 1065 (2019 data)] implemented in 2018 and 2019 were analyzed. From the physiological and biochemical changes of women before and after menopause, dietary survey BDHQ, and analysis of menopausal symptoms, the causes of discomfort and related factors for each symptom were extracted and examined. Here, BDHQ is a questionnaire designed to relatively simply investigate the amount of nutrients habitually ingested from normal diets (excluding supplements, etc.) for people living in Japan on an individual basis, and obtain information on the nutrient intake, food intake, and some other qualitative dietary behavior indicators for each individual. Its official name is the brief-type self-administered diet history questionnaire. There are three types of BDHQ in terms of structure (four types in terms of questionnaire type), and the questionnaire used varies depending on the age of the subject. In this study, the structure and questionnaire for adults (20 years old and above, including the elderly) were used.

[0037] As a result of data analysis in 2018, it was found that female subjects complaining of menopausal symptoms had low serum selenium concentrations. Figures 1 to 10 show the serum selenium concentrations of subjects complaining of various menopausal symptoms (any of the symptoms of hot flashes, sweating, irritability, depression, shoulder stiffness, headache, insomnia, and hand stiffness), hot flashes, sweating, irritability, depression, shoulder stiffness, headache, hand stiffness, and menopause for each age group. As shown in Figures 1 to 8, in the age range of 40 to 60 years old, subjects complaining of various menopausal symptoms, hot flashes, sweating, irritability, depression, shoulder stiffness, headache, and hand stiffness had low serum selenium concentrations. Also, as shown in Figure 9, menopausal subjects aged 35 to 50 years old had low serum selenium concentrations. Furthermore, as shown in Figure 10, menopausal subjects aged 20 to 50 years old also had low serum selenium concentrations. Table 1 shows the relationship between each menopausal symptom and serum selenium concentration for women aged 35 to 49 years old. Table 2 shows the relationship between menopausal symptoms and serum selenium concentration by age group. As shown in Table 1, subjects complaining of various menopausal symptoms, hot flashes, sweating, irritability, depression, shoulder stiffness, headache, and menopause had significantly low serum selenium concentrations. Also, as a result of data analysis in 2019, as shown in Table 2, subjects complaining of various menopausal symptoms had low serum selenium concentrations regardless of age group.

[0038] [Table 1]

[0039] [Table 2]

[0040] From the above results, it was found that each symptom due to menopause appears from the 30s with low serum selenium concentration, and there is also a tendency for early menopause. From this, it is considered that selenium is effective in improving and preventing menopausal symptoms.

[0041] [Example 2] The situation of complainants of menopausal symptoms and their nutrition and food intake were analyzed by BDHQ. In the complainants of menopausal symptoms (all items), the intakes of retinol equivalent, β-carotene equivalent, vitamin K, folic acid, daidzein, and genistein were significantly low, and the intakes of liver, green leafy vegetables, and root vegetables were significantly low. Next, regarding the liver that affects menopausal symptoms, the influence of the liver on menopausal symptoms was analyzed by binary logistic regression analysis. The results using the 2019 data (n = 210; women aged 40 - 59) and the 2018 data (n = 616; women) are shown in Table 3 and Table 4 respectively. Table 5 shows the results using the 2018 data (n = 98; women aged 40 - 59, menopause group).

[0042]

Table 3

[0043]

Table 4

[0044]

Table 5

[0045] As shown in Table 3, the odds ratio of the liver for the entire female population (n = 210) was 0.396 (p = 0.004), and it was confirmed that the fewer the intake of the liver, the more likely to have menopausal symptoms. Also, as shown in Table 4 and Table 5, in the analysis using the 2018 data for women (n = 616) and the analysis using the menopause group of women aged 40 - 59 (n = 98), the odds ratios were 0.818 (p = 0.029) and 0.623 (p = 0.029) respectively, and it was confirmed that the fewer the intake of the liver, the more likely to have menopausal symptoms.

[0046] [Example 3] Since it is known that the liver contains a large amount of selenium, regression analysis was performed using the 2018 data (n = 1042), with the selenium concentration in the serum as the dependent variable and various foods (chicken, pork / beef, tofu / fried tofu, liver, squid / octopus / shrimp / shellfish, raw fish) as the independent variables. The results are shown in Table 6.

[0047]

Table 6

[0048] As shown in Table 6, the selenium concentration in the serum was most affected by the liver (unstandardized coefficient: B = 0.149), followed by raw fish (B = 0.021) and tofu / fried tofu (B = 0.007) in that order.

[0049] From the above results, it was suggested that supplementing selenium is effective in improving climacteric disorders, preventing the early appearance of climacteric symptoms, and preventing premature menopause. In addition, it was found that measuring the selenium concentration in the serum can be used for the determination and prediction of the onset of climacteric disorders.

[0050] [Example 4] Selenium is known to be involved in the metabolism of thyroid hormones. On the other hand, symptoms of climacteric disorders such as being easily fatigued, having hot flashes, experiencing hot flushes, being irritable, and having palpitations are often similar to those of thyroid dysfunction, so it is possible that thyroid dysfunction is affecting. Therefore, since hyperthyroidism and hypothyroidism can be evaluated by the test value of thyroid-stimulating hormone (TSH) being lower and higher than the reference value, the relationship between the presence or absence of climacteric symptoms and the selenium concentration in the serum was examined as follows for subjects with TSH within the reference range. Using the large-scale health data (n = 1065) collected in 2019, for the female subjects (n = 207) aged 40 - 64 years with menopausal symptoms shown in Table 2 of Example 1, the subjects were divided into a group with TSH within the reference range (0.350 - 4.94 μIU / mL) and groups with TSH lower and higher than the reference range, and the menopausal symptoms were compared with the serum selenium concentration. The results are shown in Table 7.

[0051]

Table 7

[0052] As shown in Table 7, in the group with TSH within the reference range, the subjects complaining of menopausal symptoms had significantly lower serum selenium concentration. On the other hand, in the groups with TSH lower and higher than the reference range, although not significant, the subjects complaining of menopausal symptoms had lower selenium concentration. From the above, it was confirmed that even for the subjects complaining of menopausal symptoms without thyroid function abnormalities, the serum selenium concentration was low. As a result, it was found that measuring the serum selenium concentration can be used for the determination and prediction of the onset of menopausal disorders regardless of thyroid function abnormalities.

[0053] [Example 5] It is known that the onset of menopausal disorders is related to the balance between the sympathetic and parasympathetic nerves of the autonomic nervous system and the hormone balance of the endocrine system. Therefore, for the purpose of examining the influence of serum selenium on the onset of menopausal symptoms, regarding the influence on the onset of menopausal symptoms, several factors (items) of the autonomic nervous system and the endocrine system were compared with the serum selenium concentration, and whether the change in the serum selenium concentration alone causes the onset of menopausal symptoms was analyzed by a machine learning model. In the machine learning model, for the purpose of prediction and determination (here, prediction and determination of the onset of menopause), a large amount of data considered as factors was loaded, and an algorithm with high prediction accuracy was selected. An algorithm is a collection of procedures and rules for solving problems. Using AUC (Area Under the Roc Curve) as the evaluation criterion, a machine learning model with high accuracy was selected. This machine learning model enables simulation of the importance of serum selenium concentration for the onset of menopausal symptoms and the probability of onset of menopausal symptoms and serum selenium concentration. Specifically, among the large-scale health data collected from 2010 to 2022, data of women aged 40 - 59 years (n = 2613) were used to create a machine learning model grouped by subject ID, and an analysis was conducted on how serum selenium concentration affects the prediction of the onset of menopausal symptoms. In the machine learning model, a total of 17 items were used for analysis, including all menopausal symptoms, hot flashes, sweating, irritability, depression, shoulder stiffness, headache, insomnia, hand stiffness (9 items) as symptom items, and LF / HF (power value ratio of low-frequency region and high-frequency region by frequency analysis: balance of autonomic nerves), CVRR (coefficient of variation of heart rate), CCVTP (activity level of autonomic nerves) (3 items), age, serum selenium, serum sodium, C-peptide, ACTH (adrenocorticotropic hormone), TSH (thyroid-stimulating hormone), FSH (follicle-stimulating hormone), vasopressin, cortisol, aldosterone, leptin, adiponectin, DHEAs (dehydroepiandrosterone sulfate), testosterone (14 items) as feature quantities. From the obtained machine learning model, a model with high accuracy was extracted using AUC as the evaluation index, and the impact of the change in serum selenium concentration alone on the onset of menopausal symptoms was analyzed using the created machine learning model in terms of the relationship between menopausal symptoms and serum selenium concentration. In addition, regarding the created model, which items are strongly related to the onset of menopausal symptoms was evaluated by calculating the impact. For the calculation of the impact, the Permutation method was applied, and the importance of a certain item for the model is calculated by interpreting it as "how much a certain item contributes to improving the prediction accuracy of the model". The results are shown in FIGS. 11 and 12.

[0054] As shown in FIG. 11, in the model (Light Gradient Boosted Trees Classifier (4 leaves) model) that targeted all menopausal symptoms and input each item of serum selenium concentration, autonomic nerve indexes, and endocrine hormones, for the onset of menopausal symptoms, the importance of serum selenium concentration was high after age. Also, as shown in FIG. 12, as a result of simulating the impact of the change in serum selenium concentration alone on the onset of menopausal symptoms, when the serum selenium concentration was 18 - 19 μg / dL or less, menopausal symptoms increased significantly, and it was found that maintaining the serum concentration of selenium at about 18 μg / dL or more was preferable for preventing the onset of menopausal symptoms.

[0055] Next, a model (Random Forest Classifier (Gini) model) that targeted headache among menopausal symptoms and input each item of serum selenium, autonomic nerve indexes, and endocrine hormones was examined. The results are shown in FIGS. 13 and 14. As shown in FIG. 13, for the onset of headache, the importance of serum selenium concentration was the highest. Also, as shown in FIG. 14, as a result of simulating the impact of the change in serum selenium concentration alone on the onset of menopausal symptoms, when the serum selenium concentration was 18 - 19 μg / dL or less, headache symptoms increased significantly, and it was found that maintaining the serum concentration of selenium at about 18 μg / dL or more was preferable for preventing the onset of headache, which is a menopausal symptom.

Industrial Applicability

[0056] According to the present invention, it is possible to provide an agent for improving climacteric disorder, an agent for preventing climacteric disorder, a food composition for improving climacteric disorder, a food composition for preventing climacteric disorder, a method for determining the onset of climacteric disorder, and a method for predicting the onset of climacteric disorder.

Claims

1. An agent for improving menopausal disorders, which contains a selenium compound as an active ingredient.

2. The agent for improving menopausal disorders according to claim 1 , wherein the selenium compound is contained as a natural product, microorganism, or food or drink containing selenium, or an extract of such a natural product, microorganism, or food or drink.

3. A preventive agent for menopausal disorders containing a selenium compound as an active ingredient.

4. The agent for preventing menopausal disorders according to claim 3 , wherein the selenium compound is contained as a natural product, microorganism, or food or drink containing selenium, or an extract of such a natural product, microorganism, or food or drink.

5. A food composition for improving menopausal disorders, comprising a selenium compound as an active ingredient.

6. 6. The food composition for improving menopausal disorders according to claim 5, wherein the selenium compound is contained as a natural product, microorganism, or food or drink containing selenium, or an extract of such a natural product, microorganism, or food or drink.

7. The food composition for improving menopausal disorders according to claim 5 or 6, which is a health food, a functional food, a special purpose food, a food for sick people, a nutritionally functional food, a nutritional supplement, a supplement, a food for specified health uses, therapeutic milk or an enteral nutrient.

8. A food composition for preventing menopausal disorders, comprising a selenium compound as an active ingredient.

9. 9. The food composition for preventing menopausal disorders according to claim 8, wherein the selenium compound is contained as a natural product, microorganism, or food or drink containing selenium, or an extract of such a natural product, microorganism, or food or drink.

10. The food composition for preventing menopausal disorders according to claim 8 or 9, which is a health food, a functional food, a food for special uses, a food for the sick, a nutritionally functional food, a nutritional supplement, a supplement, a food for specified health uses, therapeutic milk or an enteral nutrient.

11. Measuring the selenium concentration in a sample from a subject; comparing the selenium concentration with a reference value; and evaluating whether the selenium concentration is lower than a standard value as indicating that the subject is highly likely to develop menopausal disorder.

12. Measuring the selenium concentration in a sample from a subject; comparing the selenium concentration with a reference value; and evaluating whether the selenium concentration is lower than a standard value indicates that the subject is likely to develop menopausal disorders.

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