Composition for the prevention, improvement, or treatment of infertility

Abstract

To provide a technique capable of preventing, ameliorating or treating infertility or reproductive dysfunction, or a technique capable of preventing, ameliorating, treating or suppressing testis dysfunction, sperm hypofunction or ovulation disorder.SOLUTION: Provided is a composition containing trigonelline for preventing, ameliorating or treating infertility or reproductive dysfunction. Also provided is a composition containing trigonelline for preventing, ameliorating or treating testis dysfunction, sperm hypofunction or ovulation disorder. Disorder may be infertility or reproductive dysfunction caused by men-side or women-side or male side or female side. Disorder may be caused by systemic heat stress or topical heat stress. The composition may be used for men / women or male / female. Disorder may be caused by summer heat stress.SELECTED DRAWING: None

Description

【Technical Field】 【0001】 The present invention relates to a composition for preventing, improving or treating infertility, etc. 【Background Art】 【0002】 In recent years, due to the aging of the childbirth plan, the decrease in sperm count, stress, etc., it is said that one in five or six couples in Japan has infertility. Infertility refers to "the situation where healthy men and women who desire pregnancy have sexual intercourse without contraception but do not become pregnant for a certain period of time". The Japan Society of Obstetrics and Gynecology states that this "certain period" is generally "one year". For those who desire pregnancy, infertility treatments such as reproductive assisted medicine are carried out, and the number of infertility treatments is increasing year by year. As infertility treatments, artificial insemination, in vitro fertilization-embryo transfer, micro-insemination (intracytoplasmic sperm injection, ICSI), frozen embryo-thawed embryo transfer, etc. are carried out. 【0003】 The causes of infertility originate equally from both men and women. Infertility treatment rarely succeeds in one attempt, places a large economic burden on the household, and particularly places a large physical and mental burden on women. 【0004】 The main factors on the female side are: (1) ovulation disorder or endocrine abnormality, (2) organic abnormalities such as fallopian tube disorder and endometriosis, and (3) chromosomal abnormality. Among these, treatment with ovulation-inducing agents targets (1) ovulation disorder or endocrine abnormality. In recent years, due to physical and mental stress such as excessive dieting and mental stress at work and home, the number of women who fall into amenorrhea, oligomenorrhea, and irregular menstruation has been increasing, and infertility caused by ovulation disorder is on the rise. 【0005】 On the other hand, the main factors on the male side include (1) impaired spermatogenesis (spermatogenic dysfunction) such as azoospermia, (2) obstruction of the sperm tract such as congenital abnormalities of the epididymis, and (3) sperm dysfunction such as immune abnormalities of anti-sperm antibodies. Approximately 90% of male infertility is due to impaired spermatogenesis. The causes are said to be elevated testicular temperature due to varicocele or prolonged sitting, the onset of orchitis, and impaired blood flow, and many are related to heat stress and inflammation. Heat stress is thought to include systemic heat stress and localized heat stress. 【0006】 Thus, for both men and women, it is important to provide technologies that can prevent, improve, or treat stress-related reproductive dysfunction as a measure against infertility. 【0007】 Furthermore, infertility is not only a problem for humans, but also occurs in animals such as livestock and pets. Infertility in livestock and pets is caused by factors such as rising summer temperatures (global warming), eutrophication due to overfeeding, and stress. In particular, summer heat stress reduces the reproductive capacity of livestock and pets, a condition known as summer infertility, and affects both males and females. In females, summer infertility causes delayed estrus and decreased conception rates after insemination, while in males (mainly pigs and broiler chickens), it leads to a decrease in both the quantity and quality of sperm, resulting in reduced reproductive capacity. This summer infertility, coupled with ongoing global warming, is considered a serious problem for the livestock industry, making it difficult to ensure a stable and planned supply of livestock products such as meat, eggs, and milk. Furthermore, the stress-induced decline in reproductive capacity due to heat stress is also a concern because it affects pets' ability to reproduce. Stress on the male side, or heat stress, can cause increased testicular temperature (heat stress), testicular dysfunction such as decreased sperm count and motility, or decreased sperm function. On the other hand, stress on the female side, or heat stress, can cause delayed estrus cycles, reduced mating and breeding opportunities due to anestrus, a decrease in the number of ovulated eggs, and a decrease in conception rates after mating and breeding. For these reasons, reduced reproductive capacity due to stress such as heat stress is a problem in livestock and pet animals. 【0008】 Thus, for both males and females, it is important to provide technologies that can prevent, improve, or treat stress-induced decreased reproductive capacity or stress-induced reproductive disorders as a measure against infertility. 【0009】 Furthermore, the present inventors have proposed an infertility treatment agent and an agent for preventing and / or improving testicular dysfunction, which contains one or more selected from oleuropein, oleuropein derivatives, or hydroxytyrosol as an active ingredient (Patent Documents 1 and 2). [Prior art documents] [Patent Documents] 【0010】 [Patent Document 1] Japanese Patent Publication No. 2009-191012 [Patent Document 2] Japanese Patent Publication No. 2018-193313 [Non-patent literature] 【0011】 [Non-Patent Document 1] Miki Sakatani, "The Effects of Heat Stress on the Productivity of Farm Animals," Journal of Industrial Animal Clinical Medicine, 2015, Vol. 5, Supple, pp. 238-246. [Non-Patent Document 2] Samina Salim, “Oxidative stress: a potential link between emotional wellbeing and immune response” (2016) Current Opinion in Pharmacology, Vol. 29, 70-76. [Overview of the Initiative] [Problems that the invention aims to solve] 【0012】 However, further technologies are needed for the prevention, improvement, or treatment of infertility and other related conditions. Therefore, the primary objective of the present invention is to provide a technology that can prevent, improve, or treat infertility or reproductive dysfunction. [Means for solving the problem] 【0013】 As a result of diligent research to solve the above problems, the inventors of the present invention have found that trigonelline is effective in preventing, improving, or treating infertility or reproductive dysfunction in both men and women. Based on this, the inventors of the present invention have completed the present invention. 【0014】 The present invention can provide a composition containing trigonelline for the prevention, improvement, or treatment of infertility or reproductive dysfunction. The present invention can provide a composition containing trigonelline for the prevention, improvement, or treatment of testicular dysfunction, decreased sperm function, or ovulation disorders. The present invention can provide a composition containing trigonelline for the prevention, improvement, or treatment of reduced reproductive capacity. The present invention can provide a method for preventing, improving, or treating a decline in reproductive capacity by feeding trigonelline or a composition containing trigonelline. 【0015】 The infertility or reproductive dysfunction, the symptoms or diseases mentioned above may be caused by the male or female, or by the male or female side. The infertility or reproductive dysfunction, the symptoms or diseases mentioned above may be caused by systemic heat stress or localized heat stress. It may be used for males and females or for both sexes. The infertility or reproductive dysfunction, the symptoms or diseases mentioned above may be caused by heat stress. The composition may take the form of food or beverage, pharmaceuticals, animal feed, or additives. The aforementioned composition may also be an oral composition. [Effects of the Invention] 【0016】 The present invention can provide a technology that can prevent, improve, or treat infertility or reproductive dysfunction. However, the present invention is not necessarily limited to the effects described herein, and may also provide any of the effects described herein. 【Brief Description of the Drawings】 【0017】 [Figure 1] It is a diagram showing an overview of a male mouse model test for examining the effect of trigonelline on heat stress-dependent mature sperm dysfunction using ICR male mice in Test Example 1. [Figure 2] It is a diagram showing the results of sperm motility rate (%) and progressive ratio (%) in each test group in Test Example 1. ※Progressive ratio: The ratio of sperm with a straight-line velocity of 25 μm / s or more and a straightness of 0.7 or more. [Figure 3] It is a diagram showing an overview of a male mouse model test for examining the effect of trigonelline on heat stress-dependent spermatogenesis disorder using ICR male mice in Test Example 2. [Figure 4] It is a diagram showing an overview of a male mouse model test for examining the effect of trigonelline on heat stress-dependent sperm dysfunction using ICR male mice in Test Example 3. [Figure 5] It is a diagram showing the results of sperm motility rate (%) and progressive ratio (%) in each test group in Test Example 3. [Figure 6] It is a diagram showing the results of the inhibitory effect of trigonelline on heat stress-dependent testicular weight loss in each test group in Test Example 4. [Figure 7] It is a diagram showing the results of the inhibitory effect of trigonelline on heat stress-dependent apoptosis of testicular germ cells in each test group in Test Example 4. [Figure 8] It is a diagram showing an overview of a female mouse model test for examining the effect of trigonelline on heat stress-induced reduction in the number of ovulated eggs in each test group in Test Example 5. [Figure 9] It is a diagram showing the results of the inhibitory effect of trigonelline on heat stress-induced reduction in the number of ovulated eggs in each test group in Test Example 5. 【Modes for Carrying Out the Invention】 【0018】 The following describes preferred embodiments for carrying out the present invention. The embodiments described below are merely examples of representative embodiments of the present invention, and this should not be interpreted as narrowing the scope of the invention. In this specification, percentages are expressed in mass unless otherwise specified (mass / mass%). Furthermore, the upper limit (below) and lower limit (above) of each numerical range (~) can be arbitrarily combined as desired. 【0019】 1. Outline of this embodiment In recent years, infertility and its treatment have become a major concern. However, the causes of infertility are not related to gender, but are equally divided between male and female factors. So-called stress-induced reproductive disorders, which are not caused by genetic factors, not only exacerbate the declining birthrate but also hinder women's participation in society through the physical, mental, and time burdens placed on women by in vitro fertilization. Furthermore, reproductive dysfunction such as amenorrhea caused by various stresses is linked to an increased risk of osteoporosis in young women, as well as in postmenopausal women. 【0020】 Stress is known to be a major contributing factor to infertility or reproductive dysfunction. Examples of stress include mental stress, excessive exercise, excessive dieting (such as dietary restrictions), obesity, heat stress (systemic, localized, or due to heat), and inflammatory stress (such as obesity, chronic inflammation, or mastitis in dairy cows). One or more of these can be used. In this embodiment, the device can be used to alleviate each of these stresses, and is preferably used to alleviate heat stress. 【0021】 This embodiment provides a technology that enables the prevention, improvement, or treatment of reproductive dysfunction and / or infertility by using trigonelline or a composition containing trigonelline, and a more preferred embodiment is the prevention, improvement, or treatment of reproductive dysfunction and / or infertility caused by heat stress (preferably hot stress). The composition containing trigonelline may be obtained by using a material containing trigonelline or a processed product of said material (residue, extract, isolate, purified product, and highly concentrated product, etc.) as is, or by using a material containing trigonelline or a processed product of said material as a raw material for the composition or by incorporating it into the composition as a raw material to obtain a composition containing trigonelline. 【0022】 In men, excluding erectile dysfunction, reproductive dysfunction can be primarily described as testicular dysfunction, which involves some abnormality in the testes, i.e., testicular dysfunction (damage to germ cells or parenchymal cells). Examples of testicular dysfunction include decreased sperm function and / or decreased spermatogenesis. For example, a decrease in spermatogenesis for some reason leads to a decrease in the number and / or quality of sperm formed; or, for some reason, a decrease in the number of mature sperm or a decline in sperm motility. This testicular dysfunction ultimately manifests in the final sperm count and motility, and more specifically, in sperm function parameters such as head amplitude, head frequency, linear velocity, and curvilinear velocity. Infertility is an extension of this reproductive dysfunction. 【0023】 Sperm are normally formed from spermatogonia (spermatogonia) in the following order: spermatogonia → spermatocyte → spermatid → mature sperm, taking 5 weeks in mice and 2.5 months in humans. This formation process and the development of mature sperm are sensitive to heat, and for this reason, testicular temperature in mammals is maintained 2°C to 5°C lower than body temperature. The inventors constructed a model system for two disorders caused by heat stress: impaired spermatogenesis and impaired mature sperm. Using this model system, they investigated substances that can be used for the prevention, improvement, or treatment of stress-related reproductive dysfunction. 【0024】 In this embodiment, it is more preferable to use it for reproductive dysfunction caused by or dependent on heat stress, and the heat stress is preferably systemic heat stress and / or local heat stress, of which local heat stress is more preferably scrotal local heat stress, and of which heat stress is more preferably summer heat stress. 【0025】 In this embodiment, it is preferable to apply it to male infertility patients due to reproductive dysfunction, and it may be used, for example, to improve the conception rate. In this embodiment, it is preferable to apply it to male farm animals and pets, and it may be used, for example, to improve the decreased conception rate and the decrease in the number of offspring and eggs laid due to reproductive dysfunction, and to improve the conception rate and production efficiency. Furthermore, in this embodiment, it is preferable to apply it to healthy individuals and healthy animals, and it can be used to prevent or improve infertility or reproductive dysfunction. In the case of healthy individuals, for example, it may be used for cases where, although it has not reached the stage of reproductive dysfunction (e.g., testicular dysfunction), when considering the criteria for determining dysfunction, reproductive function (e.g., testicular function such as sperm function and spermatogenesis) is reduced. In this embodiment, when applied to males, testicular dysfunction is preferred among reproductive disorders, and more preferably, it is used to suppress, prevent, improve, or treat one or more symptoms or diseases selected from mature sperm or decreased sperm motility, decreased spermatogenesis, decreased testicular weight, and apoptosis of testicular germ cells. 【0026】 Testicular dysfunction includes, but is not limited to, decreased sperm function and / or decreased spermatogenesis. More specifically, it includes disorders in which the number of mature sperm decreases or sperm motility decreases for some reason. 【0027】 Furthermore, sperm function and / or spermatogenesis can be evaluated using a Sperm Motility Analysis System (SMAS) (Detect, Tokyo, Japan) with one or more evaluation items (parameters) selected from, for example, sperm concentration, sperm motility rate, motile sperm concentration, linear velocity, curved velocity, mean velocity, head amplitude, progressive sperm ratio (progressive sperm: linear velocity ≥ 50 μm / s and straight-line movement ≥ 70%), and progressive sperm concentration (progressive sperm: linear velocity ≥ 50 μm / s and straight-line movement ≥ 70%). Note that straight-line movement refers to linear velocity / curved velocity. By using this sperm motility analysis system, the effects of the sample substance on each evaluation item, sperm function and / or spermatogenesis (such as the inhibitory effect on functional decline) can be evaluated. 【0028】 In females, reproductive dysfunction manifests as menstrual cycle abnormalities, including amenorrhea (in livestock and pets, this includes delayed estrus cycles, anestrus, and a decrease in the number of ovulated eggs), and failure to conceive or miscarriage (in livestock and pets, failure to conceive even after mating or insemination). As with males, infertility is a consequence of these reproductive dysfunctions. Furthermore, amenorrhea, a type of reproductive dysfunction unique to women, leads to low estrogen levels, and this decrease in estrogen can lead to osteoporosis. For example, osteoporosis model mice have been created by removing the ovaries, which produce estrogen. 【0029】 (1) Techniques for the prevention and improvement of male-caused infertility and male reproductive disorders. Currently, one in five to six couples experiences infertility, and in half of these cases, the male partner is at fault. Many infertile couples undergo in vitro fertilization (including intracytoplasmic sperm injection), and in 2019, one in 14 babies born was conceived through in vitro fertilization. Recently, the decline in sperm count in men has become a concern. Previously, endocrine disruptors were thought to be the cause, but now the prevailing view is that it is caused by elevated testicular temperature due to lifestyle diseases and various stresses. For example, prolonged sitting and varicocele can lead to elevated testicular temperature (heat stress, specifically localized heat stress), which can cause heat stress or testicular dysfunction. 【0030】 Male reproductive dysfunction (preferably stress-related reproductive dysfunction) can be defined as, but is not limited to, one or more types of stress, such as heat stress (preferably heat stress), obesity, and mental stress. Heat stress (preferably heat stress): Examples include heat stress as a lifestyle habit (heat stress from sitting for long periods of time, e.g., more than one hour), heat stress due to morphological abnormalities, and heat stress due to increased testicular temperature in high-temperature environments (e.g., above 30°C). Heat stress as a lifestyle habit: desk work, prolonged sitting during travel in cars or trains, wearing tight briefs (underwear that compresses or constricts the scrotum, etc.) which can increase testicular temperature. Heat stress due to morphological abnormalities: poor blood flow due to varicocele, which can lead to increased temperature. Obesity: People with a high BMI have lower sperm count and motility. Obesity is considered a form of chronic inflammation, and inflammation is linked to oxidative stress. At least some of various stresses, including heat stress, are converted into oxidative stress. Mental stress: Mental stress is converted into oxidative stress, at least partially, within the body, which may lead to reproductive disorders. 【0031】 In this embodiment, as described above, it is possible to prevent, improve, or treat reproductive dysfunction caused by stress (such as a decrease in sperm count and motility in men) and infertility caused by reproductive dysfunction. 【0032】 (2) Techniques for the prevention and improvement of stress-induced reproductive disorders in non-human animals such as male livestock and pets. In high-temperature environments during the summer, the reproductive capacity of both male and female livestock decreases. Normally, mature sperm and spermatogenesis are sensitive to high temperatures, so testicular temperature is kept lower than body temperature. However, rising external temperatures cause a decrease in semen volume, sperm count, and sperm motility. Furthermore, the stresses that cause stress-induced reproductive dysfunction in males can be the various stresses described above in the section on stress-induced reproductive dysfunction in men. In this embodiment, it is possible to prevent, improve, or treat summer infertility, stress-induced reproductive disorders in males due to heat stress, reduced reproductive capacity due to stress, and infertility in non-human animals such as livestock and pets. 【0033】 (3) Techniques for the prevention and improvement of stress-induced reproductive disorders in non-human animals such as female livestock and pets. Summer infertility, or infertility due to heat stress, occurs in both males and females. In females, heat stress during the summer can lead to delayed estrus cycles, reduced mating and breeding opportunities due to anestrus, a decrease in the number of ovulated eggs, and a decline in conception rates after mating and breeding. Female reproductive dysfunction (preferably stress-induced reproductive dysfunction) can be selected from, but is not particularly limited, one or more types from, for example, heat stress, inflammatory stress, etc. Heat stress (preferably heat stress) caused by rising summer temperatures: Heat stress can lead to reproductive problems such as delayed estrus cycles (making estrus less likely), decreased number of ovulated eggs (occurring in polyovulatory livestock and pets, but in animals with only one ovulation, such as humans and cattle, it means anovulation = amenorrhea), and failure to conceive even after mating or insemination. In this example, the decrease in the number of ovulated eggs is observed as an indicator of heat stress caused by rising summer temperatures. Inflammation: Mastitis in dairy cows, etc.: Dairy cows are prone to mastitis because they are milked daily. Dairy cows infected with mastitis may also experience effects on their ovaries. Female mice in which inflammation is induced by administering lipopolysaccharide show a decrease in the number of ovulated eggs. In this embodiment, it is possible to prevent, improve, or treat summer infertility, stress-induced reproductive disorders in females due to heat stress, stress-induced decreased reproductive capacity, and infertility in non-human animals such as livestock and pets. 【0034】 (4) Techniques for the prevention and improvement of infertility caused by female factors and stress-related reproductive disorders in women. The increasing infertility among women is attributed primarily to factors such as the advanced age of childbearing planning and various forms of stress. Recently, issues such as menstrual irregularities and amenorrhea caused by stress in working women, as well as reproductive dysfunction caused by excessive dieting or excessive exercise, have been gaining attention. Amenorrhea not only leads to infertility, but also results in a decrease in estrogen, a female hormone important for bone formation, and this decrease in estrogen can induce osteoporosis. Stress-induced reproductive disorders in women include, but are not limited to, stress-induced reproductive disorders caused by one or more factors selected from, for example, advanced maternal age, excessive exercise, excessive dieting, and heat stress. Later age at childbirth: Due to factors such as later marriages and women's increased participation in the workforce, the average age at which women plan to have children is increasing. This aging is linked to aging itself, which at the very least generates oxidative stress in the body and leads to a decline in reproductive function, such as the deterioration of eggs. Excessive exercise: Reproductive dysfunction such as amenorrhea caused by excessive exercise, particularly among athletes (especially aesthetic athletes), is a problem. The decrease in estrogen due to reproductive dysfunction such as amenorrhea is also a problem because it can induce osteoporosis in women. In fact, amenorrhea is 6 to 9 times more common among aesthetic athletes than among the general female population, and one in four of them has experienced a stress fracture. Excessive dieting (dietary restrictions): Excessive dieting in women can lead to nutritional deficiencies and a reduced ability to cope with various stresses, resulting in reproductive dysfunction such as amenorrhea. Mental stress: At least some of mental stress is converted into oxidative stress, which impairs ovarian function, such as causing amenorrhea. Obesity: Obesity is classified as chronic inflammation, and at least part of this inflammation is linked to oxidative stress, which can lead to ovarian damage. Osteoporosis: In women who engage in excessive exercise or extreme dieting (athletes, dieters, thin female models, etc.), reproductive dysfunction such as amenorrhea or menstrual irregularities can lead to a low estrogen state, which can result in osteoporosis. In this embodiment, it is possible to prevent, improve, or treat female reproductive dysfunction caused by stress, as well as associated osteoporosis and infertility. 【0035】 Furthermore, this embodiment is preferably used for purposes such as reducing heat stress, preventing, improving, and treating reproductive disorders (e.g., testicular dysfunction, female menstrual cycle abnormalities, etc.), preventing, improving, and treating a decline in spermatogenesis or sperm function, and preventing, improving, and treating a decline in conception rates, or for providing a composition for such purposes. 【0036】 Here, "for reducing heat stress" has the same meaning as it is generally understood by those skilled in the art. Specifically, for example, when humans or animals are exposed to hot and humid environments such as the Japanese summer, it can cause symptoms like loss of appetite and insomnia, similar to summer fatigue, as well as a decrease in the reproductive capacity of livestock animals, and in some cases, harm the health of humans or animals. Therefore, it includes the purpose of improving the biological functions in such conditions and reducing heat stress. 【0037】 Furthermore, the phrase "for the prevention, improvement, and treatment of reproductive dysfunction" is synonymous with the meaning commonly understood by those skilled in the art. Specifically, for example, since various stresses now cause a decline in reproductive function in humans and animals, it includes the purpose of preventing or improving the biological functions related to reproductive function. 【0038】 Furthermore, the phrase "for the prevention, improvement, and treatment of a decline in spermatogenesis or sperm function" is synonymous with the meaning commonly understood by those skilled in the art. Specifically, for example, the decline in male sperm count has become a global concern recently, and the rate of infertility due to a decrease in sperm count, decreased fertilization ability, and other declines in sperm function is increasing. This phrase includes the purpose of improving the biological functions related to sperm function and resolving infertility. In this case, it includes not only sperm function related to fertilization within the body, but also the prevention and improvement of a decline in sperm function related to fertilization outside the body. 【0039】 Furthermore, "for improving conception rates" has the same meaning as commonly understood by those skilled in the art, and specifically includes, for example, improving the conception rate after sexual intercourse or mating of humans or non-human animals. In particular, it also includes the purpose of improving the reproductive capacity of livestock animals such as pigs, cattle, and chickens, and non-human animals such as pets, thereby increasing the number of individuals produced and the weight per individual produced. 【0040】 Furthermore, this embodiment is preferably used for purposes such as preventing, improving, and treating infertility or reproductive dysfunction caused by females, preventing, improving, and treating menstrual abnormalities in women, preventing, improving, and treating abnormalities in the estrous cycle of females, and other forms of biological function decline, or is preferably provided as a composition for such purposes. 【0041】 Here, "for the prevention, improvement, and treatment of infertility or reproductive dysfunction caused by female factors" is synonymous with the meaning as normally understood by those skilled in the art. Specifically, for example, resolving infertility caused by various stresses is a challenge for modern people, and this includes improving conditions such as inhibited follicular development, excessive follicular atresia, and deterioration of the eggs themselves, thereby reducing fertilization and developmental capacity, and resolving infertility caused by mental and physical stress and aging. 【0042】 Furthermore, "menstrual abnormalities in women" refers to a state of menstrual disorder that includes not only abnormalities in the cycle, such as frequent menstruation (less than 25 days), infrequent menstruation (more than 39 days), and amenorrhea (no menstruation for more than 3 months), but also abnormalities in the duration of menstruation. 【0043】 Furthermore, the phrase "for the prevention, improvement, and treatment of female infertility or reproductive dysfunction" is synonymous with the meaning commonly understood by those skilled in the art. Generally, infertility caused by stress such as overcrowding and high temperatures is a major issue in the livestock industry. For example, "summer infertility" is a well-known example of stress-induced infertility. In hot and humid environments such as the Japanese summer, the reproductive capacity of both male and female livestock decreases, making it difficult to ensure a stable supply of meat, eggs, and milk—a serious problem. Normally, the estrous cycle of female livestock is constant depending on the species, such as 20-21 days for cattle, pigs, and goats, 16-17 days for sheep, and 20-24 days for horses. However, rising external temperatures can cause delays in the estrous cycle or anestrus in females. Human infertility and menstrual abnormalities caused by mental and physical stress, as well as livestock infertility caused by overcrowding and high temperatures, are all thought to manifest as external stress being converted into oxidative stress within the body. (Non-patent literature 1: Miki Sakatani, "The Effects of Heat Stress on the Productivity of Farm Animals," Journal of Industrial Animal Clinical Medicine, 2015, Vol. 5, Supple, pp. 238-246.; Non-patent literature 2: Samina Salim, "Oxidative stress: a potential link between emotional wellbeing and immune response," (2016) Current Opinion in Pharmacology, Vol. 29, 70-76. See references.) 【0044】 2. Composition relating to the prevention of infertility, etc., according to this embodiment This embodiment preferably provides a composition containing trigonelline for the prevention, improvement, or treatment of infertility or reproductive dysfunction. Furthermore, this embodiment is preferable to provide a composition containing trigonelline for the prevention, improvement, or treatment of testicular dysfunction, decreased sperm function, or ovulation disorders. 【0045】 2-1. Trigonelline The trigonelline used in this embodiment is a type of alkaloid containing a pyridine ring found in many plants, and is 1-methylpyridine-1-ium-3-carboxylate, also known as N-methylnicotinic acid or caffearine. Trigonelline is a betaine-type molecule with both charged groups in a single molecule. Trigonelline is known to decompose upon heat and change into nicotinic acid. 【0046】 The trigonelline or trigonelline-containing composition used in this embodiment (hereinafter also referred to as "trigonelline composition") can be obtained, for example, from a material containing trigonelline by processing (extraction, separation and purification, etc.). The material is not particularly limited, and one or more types selected from, for example, plant-derived, animal-derived, or microbial-derived materials can be used. Furthermore, the trigonelline or trigonelline-containing composition used in this embodiment can be obtained using known manufacturing methods (for example, organic synthesis methods, microbial production methods, etc.), and precursors or intermediates of trigonelline that can be synthesized into trigonelline may also be used. 【0047】 In this embodiment, one or more selected from the raw materials, or from extracts, processed products, residues, or separated and purified products obtained by drying, freezing, heating, grinding, pressing, extraction, etc., or from these, can be used as raw materials or as is for the trigonelline or trigonelline composition according to this embodiment. 【0048】 Furthermore, in this embodiment, a processed product containing trigonelline (hereinafter also referred to as "trigonelline processed product") obtained by a processing step to obtain trigonelline and / or other components or target products from the material can be used as is or as a composition containing trigonelline. The trigonelline processed product is not particularly limited and examples include residue, extract, isolate, purified product, and highly concentrated product, and one or more selected from these can be used. In this embodiment, a highly concentrated trigonelline composition (e.g., highly concentrated trigonelline, isolated and purified trigonelline, etc.) with a higher trigonelline concentration than the trigonelline concentration generally contained in trigonelline processed products (e.g., trigonelline extract, trigonelline-containing residue, etc.) and trigonelline compositions such as food and beverages is more preferable. For example, a high-concentration trigonelline composition can be obtained by using one or more raw materials selected from materials, material extracts, material residues, food and beverages, and food and beverage compositions as raw materials, and separating and purifying these raw materials to increase the trigonelline content, or by adding an additive containing trigonelline to these raw materials. 【0049】 In this embodiment, an extract containing the desired compound described above can be obtained from a material containing trigonelline (preferably a plant, more preferably coffee or Sakurajima radish) using one or more solvents selected from organic solvents (e.g., water, alcohol, etc.) and oils. 【0050】 The aforementioned material, preferably a part of a plant, is not particularly limited, but may include any part such as fruit, leaves, flowers, stems, or roots, or one or more selected from these. These may be used in their fresh state, or as dried or crushed material. 【0051】 The processing method (e.g., extraction, separation, purification) used in this embodiment is not particularly limited. The processing (e.g., extraction, separation, or purification) can be carried out using a solvent by immersion or the like at a constant temperature (low temperature, room temperature, or heated) for a predetermined period of time. 【0052】 Examples of processing methods (preferably extraction methods) include, for example, processing a material such as coffee with a solvent (for example, water, alcohols, or a water-alcohol mixture) at room temperature (for example, around 5-40°C) or heated (around 40-100°C) for 5 minutes to 1 month. In this embodiment, processing using a solvent containing water (preferably hot water processing) is preferred, and in the case of extraction, hot water extraction is more preferred. The processing temperature (preferably the extraction temperature) is preferably 60°C or higher, more preferably 60 to 100°C, even more preferably 70 to 100°C, and even more preferably 80 to 100°C. The processing period (preferably the extraction period) may be, for example, 5 minutes to about 1 week, or in the case of heating, 10 minutes to about 3 hours (preferably 2 to 3 hours). 【0053】 Examples of solvents used in the aforementioned treatment (preferably extraction) include water, alcohols, glycols, ketones, esters, ethers, and halogenated carbon compounds. One or more selected from these can be used, with water, alcohols, and glycols being preferred. Examples of alcohols (preferably with 1 to 3 carbon atoms) include ethanol, methanol, and propanol. Examples of glycols include ethylene glycol, diethylene glycol, butylene glycol, propylene glycol, and glycerin. Examples of ketones include acetone and methyl ethyl ketone. Examples of esters include ethyl acetate, propyl acetate, and ethyl formate. Examples of ketones include acetone and methyl ethyl ketone. Examples of esters include ethyl acetate, propyl acetate, and ethyl formate. Examples of ethers include diethyl ether. Examples of halogenated carbon compounds include chloroform and dichloromethane. Alternatively, aqueous organic solvents obtained by mixing these organic solvents with water may also be used. One or more selected from these can be used. 【0054】 Of these, from the viewpoint of oral administration to humans or animals and from the viewpoint of improving trigonelline extraction efficiency, a solvent containing water is more preferable, for example, water and / or alcohols are more preferable, water and / or aqueous alcohols are even more preferable, and water is even more preferable. The water concentration in the water-containing solvent is preferably 50% by mass or more, more preferably 70% by mass or more, more preferably 80 or 90% by mass or more, and even more preferably 95% by mass or more. Furthermore, because trigonelline is highly hydrophilic, from the viewpoint of improving extraction efficiency, such as extracting trigonelline from raw materials or further separating, purifying, or concentrating trigonelline from trigonelline-treated products containing trigonelline crude extract, it is preferable to use hot water extraction (for example, preferably 70-100°C, more preferably 80-100°C), and trigonelline can be recovered more effectively by using water as the extraction solvent. Furthermore, these solvents and their extraction methods may also be used in microbial production, separation, or purification processes for the extraction, separation, or purification of trigonelline, or for the treatment of increasing the concentration of trigonelline. 【0055】 As the material containing trigonelline, one or more selected from coffee and Sakurajima radish can be used, and coffee and / or Sakurajima radish are preferred from the viewpoint of recovery efficiency, and using their residues is preferred from the viewpoint of cost and other factors. 【0056】 When trigonelline is obtained from natural products, materials, plants, or extracts thereof, a suitable material is coffee material, and the coffee is more preferably a plant belonging to the genus Coffea (hereinafter also referred to as "coffee tree"), and may be a plant belonging to the Arabica, Canephora, Congensis, Liberica, etc., which are generally known as coffee bean varieties, or a plant belonging to other genera. 【0057】 As the plant part used as the source or extraction of the aforementioned coffee material, coffee fruit is preferred, more preferably immature or mature coffee fruit, and even more preferably mature coffee fruit. The more preferred part of the coffee fruit to be used may be the whole fruit, the seed portion used for coffee beans, or one or more partial components of the whole fruit excluding the seeds. Unroasted seeds are preferred. Even more preferred parts may be one or more partial components of the whole fruit, such as the peel, pulp, pectin layer, parchment, silverskin, center cut, or stem. For example, in the production of typical roasted coffee beans, there is a step to remove the seeds from unroasted fruit, and the parts of the fruit from which the seeds have been removed (pulp, peel, etc.) are produced as a by-product. This is usually discarded as coffee residue (preferably coffee cherry residue), so it is relatively inexpensive to obtain and also reduces the amount of waste. The coffee material used in this embodiment (preferably coffee cherry material) may be used as a residue source or as an extractant. 【0058】 The material or extract containing trigonelline used in this embodiment may be used as is as an active ingredient, or it may be treated with known separation and purification methods as appropriate to remove impurities such as contaminants or to enhance its efficacy without impairing its effectiveness. For example, if necessary, it may be used after further purification treatment such as distillation of the treatment solvent, filtration, or deodorization and decolorization using ion exchange resins. Alternatively, only the highly active fraction may be used using separation means such as liquid chromatography. Furthermore, in this embodiment, the material or processed product or extract containing trigonelline may be used as is, either as a treatment solution alone or mixed with treatment solutions obtained by different treatment methods, or the processed product may be diluted, concentrated or dried to prepare it in liquid, powder, or paste form before use. 【0059】 The trigonelline-treated material or extract used in this embodiment may be in any form, such as solid, liquid (juice), paste, gel, oil, or emulsion. Furthermore, in an embodiment not limited to this one, drying aids such as dextrin and emulsifiers such as sucrose fatty acid esters may be added during or at the time of preparation of the trigonelline composition. In another embodiment not limited to this one, the trigonelline composition may be subjected to heat treatment such as roasting so that the trigonelline concentration in the trigonelline composition reaches a desired concentration. 【0060】 Furthermore, this embodiment may be for therapeutic or non-therapeutic purposes. In this embodiment, "use" may be administration or ingestion to a human, and may be for therapeutic or non-therapeutic purposes. "Non-therapeutic" is a concept that does not include medical procedures, that is, methods that do not include surgery, treatment, or diagnosis of a human being, and more specifically, methods that do not include surgery, treatment, or diagnosis performed on a human being by a physician or a person under the direction of a physician. Examples of non-therapeutic purposes include treatment of non-human animals other than humans, such as pets, livestock, and poultry, and oral ingestion in food, beverages, or feed. 【0061】 Furthermore, in this embodiment, "prevention" means preventing or delaying the onset of symptoms or diseases in the subject area, or reducing the risk of developing symptoms or diseases in the subject area. In this embodiment, "improvement" means improving or maintaining the condition of a disease, symptoms, or state in the subject area; preventing or delaying deterioration; reversing, preventing, or delaying progression. Furthermore, "treatment" includes not only complete cure of the disease but also improvement of symptoms. 【0062】 2-2. Uses and methods of use related to this embodiment 【0063】 The trigonelline or trigonelline-containing composition used in this embodiment has effects such as the prevention, improvement, and treatment of infertility, the prevention, improvement, and treatment of reproductive dysfunction, the prevention, improvement, and treatment of testicular dysfunction, the prevention, improvement, treatment, or suppression of decreased sperm function, the prevention, improvement, treatment, or suppression of decreased spermatogenesis, the prevention, improvement, and treatment of ovulation disorders, the prevention, improvement, and treatment of menstrual abnormalities, the prevention, improvement, and treatment of decreased reproductive capacity, and the prevention, improvement, treatment, or suppression of osteoporosis or osteoporosis due to female reproductive dysfunction, and one or more selected from this group may be used for any purpose. In this embodiment, the above-mentioned symptoms and diseases are preferably caused by the male or female side, or by the male or female side. Furthermore, in this embodiment, the above-mentioned symptoms and diseases are preferably caused by stress (preferably heat stress), more preferably by heat stress, or even more preferably by systemic heat stress or local (preferably local scrotal) heat stress. 【0064】 Furthermore, the trigonelline or trigonelline composition used in this embodiment can be used to prevent, improve, or treat the above-mentioned reproductive dysfunction and infertility, and the trigonelline or trigonelline composition can be included as an active ingredient in compositions for specific uses such as prevention, improvement, or treatment of the above-mentioned reproductive dysfunction and infertility, or for suppressing functional decline or capacity decline. In addition, in this embodiment, the trigonelline or trigonelline composition can be used in methods or methods of use such as methods for preventing, improving, or treating various symptoms or diseases such as the above-mentioned reproductive dysfunction and infertility. Thus, in this embodiment, it is also possible to perform prevention, improvement, or treatment on target animals that have or are likely to have one or more symptoms or diseases selected from the group consisting of infertility, reproductive dysfunction, testicular dysfunction, decreased sperm function, decreased spermatogenesis, ovulation disorders, menstrual abnormalities, and decreased reproductive capacity. Furthermore, symptoms of infertility or reproductive dysfunction include, for example, one or more selected from testicular dysfunction, decreased sperm function, decreased sperm formation, ovulation disorders, menstrual abnormalities, decreased reproductive capacity, and osteoporosis (preferably osteoporosis due to female reproductive dysfunction). 【0065】 Furthermore, in this embodiment, trigonelline or a trigonelline composition can be used as is in the target area in the expectation of the effects described above, or the preventive effects described above. In addition, trigonelline or a composition containing trigonelline can be included in various formulations or compositions or compositions for specific uses in the expectation of the effects described above, or the preventive effects described above, and compositions for specific uses containing trigonelline or a trigonelline composition, etc., and can be used in such compositions. 【0066】 Furthermore, trigonelline or trigonelline compositions may also be used as a substance or active ingredient for preventing, improving, or treating one or more conditions selected from the above-mentioned infertility, reproductive dysfunction, testicular dysfunction, decreased sperm function, decreased sperm formation ability, ovulation disorders, menstrual abnormalities, decreased reproductive capacity, and osteoporosis (preferably osteoporosis due to female reproductive dysfunction), with the expectation of the aforementioned preventive effects. 【0067】 Furthermore, the compositions according to this embodiment are preferably provided as one or more selected from foods and beverages, pharmaceuticals, animal feed, and additives, and may be provided as food and beverage compositions, pharmaceutical compositions, or animal feed compositions. Furthermore, the trigonelline composition used in this embodiment may be a composition obtained by blending one or more trigonelline-treated products (e.g., extracts, residues, high-concentration products, etc.) obtained from materials containing trigonelline, and additives containing trigonelline, or any other optional components, with pharmaceuticals, food and beverages, or animal feed, or a composition obtained by blending them to a trigonelline concentration equal to or greater than that normally present, and is not particularly limited. 【0068】 The animals to which this embodiment can be applied are not particularly limited, but animals are preferred, and more preferably vertebrates. Examples of vertebrates include fish, amphibians, reptiles, birds, and mammals, from which one or more species can be selected. More specifically, examples of the animals to which this embodiment can be applied include humans, pets (e.g., birds, dogs, cats, rabbits, rodents (order Rodentia; e.g., squirrels (suborder Sciuriformes), mice (suborder Mucilionae; e.g., rats, mice, hamsters, etc.)), ornamental or domesticated fish (e.g., freshwater fish such as medaka, carp, and goldfish, and saltwater fish), and livestock (e.g., cattle, pigs, chickens, ducks, etc.), from which one or more species can be selected. 【0069】 Furthermore, this embodiment may be applied to healthy animals, or to healthy animals with reduced stress tolerance, reproductive function, or reproductive capacity. It is also preferable to use this embodiment on one or more species selected from animals undergoing sterilization treatment, breeding animals, etc. 【0070】 The composition for specific uses according to this embodiment is not particularly limited, but is preferably one or more selected from, for example, pharmaceuticals (including quasi-drugs, designated quasi-drugs, veterinary pharmaceuticals, etc.), food and beverages (including supplements, foods for specified health uses, functional foods, etc.), and animal feed (including supplements, etc.). The composition according to this embodiment may be administered or ingested to the target in a desired dosage or intake. The additive according to this embodiment may also be incorporated into the manufacturing process of pharmaceuticals, food and beverages, or animal feed as a composition or additive for pharmaceuticals, food and beverages, or animal feed. The additive according to this embodiment may be added to food and beverages or animal feed, and then the food and beverages or feed with the additive added may be administered or ingested to the target. The composition according to this embodiment is preferably for oral use. 【0071】 Examples of administration forms for pharmaceuticals (including quasi-drugs and veterinary drugs) include oral administration forms such as tablets, capsules, granules, powders, and syrups, or parenteral administration forms such as injections, suppositories, inhalants, skin absorbents, and topical preparations, but oral administration forms are preferred. 【0072】 Furthermore, food, beverages, or animal feed may include foods, beverages, or supplements that are based on the concept of prevention, improvement, or treatment of infertility or reproductive dysfunction, or related symptoms or diseases, and may be labeled accordingly as needed. Oral use or oral ingestion is preferred. 【0073】 Depending on the target patient, the state of symptoms, and the stage of the disease, the duration of administration should ideally be, for example, one week to several years, or even longer, from the viewpoint of preventing and improving infertility, and from the viewpoint of safety, continuous administration is preferable. Furthermore, in this embodiment, since it can exert a good effect against heat stress such as that of summer, it is preferable to administer or take it orally during the summer or when the environment becomes hot. It is also advisable to administer or take other components (e.g., antioxidants), review dietary habits, and review lifestyle habits such as smoking and exercise while administering or having patients ingest trigonelline or a trigonelline composition. 【0074】 The amount of trigonelline used when using trigonelline or a trigonelline composition in this embodiment may vary depending on the condition, weight, sex, age, or other factors of the animal being studied. For example, for an adult, a suitable lower limit is preferably 0.1 mg / 60 kg body weight or more, more preferably 0.5 mg / 60 kg body weight or more, and a suitable upper limit is preferably 500 mg / 60 kg body weight or less, more preferably 100 mg / 60 kg body weight or less. Furthermore, in the case of pets such as dogs and cats, the amount of trigonelline used per animal is preferably 0.1 mg / 3 kg of body weight or more, more preferably 0.5 mg / 3 kg of body weight or more, as a suitable lower limit, and preferably 500 mg / 3 kg of body weight or less, more preferably 100 mg / 3 kg of body weight or less, as a suitable upper limit. 【0075】 Furthermore, the trigonelline or trigonelline composition in this embodiment can be used according to any usage plan, and can be used once or multiple times a day (approximately 2-3 or 5 times) for several weeks to several months. However, as mentioned above, based on empirical rules in food and beverages, the usage period is not particularly limited and can be used for long periods such as several years or even decades. 【0076】 The compositions according to this embodiment may contain or incorporate components commonly used in various compositions such as food and beverages, pharmaceuticals (including quasi-drugs), animal feed, and additives, as necessary or within the limits that do not impair the effects of this technology. Examples of such components include preservatives, cell activators, antioxidants, solvents (water, alcohols, etc.), oils, surfactants, thickeners, powders, chelating agents, pH adjusters, emulsifiers, stabilizers, colorants, flavoring agents, odor masking agents, excipients, binders, disintegrants, lubricants, diluents, osmotic pressure adjusters, and fragrances. One or more of these may be appropriately selected and used. Furthermore, the composition or form of the composition according to this embodiment is not particularly limited and may be in any form, such as liquid, paste, gel, solid, or powder. 【0077】 2-2-1. Pharmaceutical Compositions The pharmaceutical product of this embodiment can be used orally, for example, as a sugar-coated tablet, capsule, elixir, microcapsule, or granule, or parenterally as an injectable preparation such as a sterile solution or suspension with water or other pharmaceutically acceptable liquid. The dosage form of the pharmaceutical product of the present invention is not particularly limited, but an oral preparation is preferred from the viewpoint of ease of administration. 【0078】 The pharmaceutical product of this embodiment is manufactured by mixing trigonelline used in this embodiment or a composition containing it with physiologically recognized carriers, flavoring agents, excipients, vehicles, preservatives, stabilizers, binders, etc., in a unit dose form generally required for formulation. Examples of additives that can be mixed into tablets, capsules, etc. include binders such as gelatin, corn starch, tragacanth, and gum arabic; excipients such as crystalline cellulose; leavening agents such as corn starch, gelatin, and alginic acid; lubricants such as magnesium stearate; sweeteners such as sucrose, lactose, or saccharin; and flavoring agents such as peppermint, red ginger oil, or cherry. 【0079】 The pharmaceutical product of this embodiment may contain, in addition to the trigonelline used in this embodiment or a composition containing the same, other components that are effective in some way for animals (including humans), such as polyphenols, proteins, amino acids, steroids, vitamins, carbohydrates, lipids, minerals, hormones, antibiotics, dyes, etc. Specifically, examples include astaxanthin, coenzyme Q10, vitamin E, vitamin C, vitamin A, potassium chloride, calcium gluconate, sodium saccharin, etc. 【0080】 The amount of trigonelline used in this embodiment or a composition containing it incorporated into the pharmaceutical product of this embodiment is not particularly limited as long as it does not impair the effects of the present invention. Furthermore, the amount may vary depending on the dosage form. The amount of the compound used in the pharmaceutical product is preferably, for example, 1 to 95% by mass, more preferably 5 to 90% by mass, and particularly preferably 10 to 50% by mass, of the compound used in this embodiment. 【0081】 Furthermore, the dosage of the pharmaceutical product in this embodiment is not particularly limited as long as it does not impair the effects of the present invention, and can be appropriately changed considering the type of dosage form, the method of administration, the age and weight of the recipient (human, non-human animal, pet), symptoms, etc. The daily dose required for the target to obtain the desired effect is preferably 1 to 3000 mg / 60 kg body weight per day, more preferably 2 to 1000 mg / 60 kg body weight, particularly preferably 3 to 500 mg / 60 kg body weight, and most preferably 4 to 200 mg / 60 kg body weight. 【0082】 2-2-2.Food and beverages The food and beverages of this embodiment can be in the form of, for example, a beverage, powder, powdered beverage, tablet, supplement, jelly, hard capsule or soft capsule, and the form is preferably one that is suitable for oral intake or oral administration. 【0083】 The food and beverages of this embodiment can be manufactured by appropriately blending trigonelline used in this embodiment or a composition containing it with glucose, fructose, sucrose, maltose, sorbitol, stevioside, rubusoside, corn syrup, lactose, citric acid, tartaric acid, malic acid, succinic acid, lactic acid, L-ascorbic acid, dl-α-tocopherol, sodium erythorbate, glycerin, propylene glycol, glycerin fatty acid ester, polyglycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, gum arabic, carrageenan, casein, gelatin, pectin, agar, B vitamins, nicotinamide, calcium pantothenate, amino acids, minerals such as calcium salts, and various other nutrients, pigments, flavorings, preservatives, and other ingredients commonly used in food and beverages. Furthermore, it may be mixed with rice, wheat, corn, potatoes, sweet potatoes, soybeans, kelp, wakame seaweed, tengusa seaweed, etc., which are commonly used as food and beverage ingredients. 【0084】 The amount of trigonelline used in this embodiment to be incorporated into the food and beverage of this embodiment is not particularly limited, but it is preferably 0.001 to 10% by mass, more preferably 0.01 to 5% by mass, and particularly preferably 0.1 to 1% by mass in the composition. For example, in the case of a beverage, it is preferable that the amount of trigonelline used in this embodiment in the beverage be 0.001 to 0.5% by mass, more preferably 0.005 to 0.25% by mass, and particularly preferably 0.02 to 0.15% by mass. When the composition is a supplement such as a capsule or tablet, it is preferable that the trigonelline used in this embodiment is contained in an amount of 1 to 95% by mass, more preferably 5 to 90% by mass, and particularly preferably 10 to 50% by mass. 【0085】 Examples of food and beverage forms include health foods, functional foods, foods for specified health uses, nutritional supplements, enteral nutrition foods, etc. Furthermore, if necessary, food and beverages may also display information indicating that they are for use in the specific purposes mentioned above, or that they are intended for specific purposes, or that they are intended for people concerned about stress, reproductive function decline, etc., or that they have a specific concept. In addition, food and beverages that display such functionality or concepts can also be fed to non-human animals (e.g., pets, livestock, etc.). Examples of food and beverage forms include health foods, functional foods, foods for specified health uses, nutritional supplements, enteral nutrition foods, etc., and they can also be applied to feed for non-human animals (e.g., pets, livestock, etc.). 【0086】 2-2-3. Feed The feed of this embodiment can be obtained by mixing trigonelline used in this embodiment or a composition containing it with fresh grass, hay, green-cut forage crops (such as green-cut corn), straw, etc. The feed may also be in the form of feed used for the specific purposes described above, or feed that is labeled with a specific purpose or concept. 【0087】 Generally, livestock feed is broadly classified into three types: roughage, concentrate, and special feed. Of these, roughage refers to feed that is relatively high in crude fiber and has a large volume but low digestible nutrients. Roughage includes fresh grass, hay, green-cut forage crops (such as green-cut corn), root vegetables, and straw. Concentrate, on the other hand, refers to feed that is relatively high in nutrients and low in moisture and crude fiber. Concentrate includes grains such as corn, milo, barley, oats, rice, millet, foxtail millet, proso millet, and sorghum, as well as grain by-products (bran) such as rice bran and wheat bran, and oilseed meal such as peanut meal, cottonseed meal, sunflower meal, rapeseed meal, sesame meal, and flaxseed meal. Furthermore, pet feed, ornamental fish feed, and other similar products can be manufactured using the same concept as livestock feed. They can also be manufactured by mixing the trigonelline used in this embodiment or a composition containing it with commonly used pet food ingredients. 【0088】 The feed of this embodiment can also be manufactured by adding coffee cherry fruits, flowers, stems, roots, and preferably leaves, either fresh or dried, to these feeds. Coffee cherry fruits, seeds, or the pulp and peel (excluding the seeds) can be added as is or crushed into a powder. Coffee cherry residue generated during the harvesting of green coffee beans can also be added. The food and beverage products of this embodiment can also be manufactured using this method. 【0089】 The amount of trigonelline or a composition containing it used in this embodiment to be added to the feed in this embodiment, as well as the dosage, can be determined in accordance with the above-mentioned pharmaceuticals and food products. 【0090】 3. This technology can employ the following configurations. [1] A composition comprising trigonelline for (a) the prevention, improvement, or treatment of infertility or reproductive dysfunction; (b) the prevention, improvement, or treatment of testicular dysfunction, decreased sperm function, decreased spermatogenesis, menstrual disorders, or ovulation disorders; (c) the prevention, improvement, or treatment of decreased reproductive capacity; or (d) the prevention, improvement, or treatment of osteoporosis. 【0091】 [2] A component or a composition containing such component, or a use thereof, for the manufacture or use in the manufacture of a composition for the prevention, improvement or treatment of infertility or reproductive dysfunction, or for the manufacture or use in the manufacture of the composition described in [1] above, wherein the component is trigonelline. The composition may also be a formulation. 【0092】 • [3] For use in the prevention, improvement, treatment, or suppression of infertility or reproductive dysfunction, testicular dysfunction, decreased sperm function, decreased spermatogenesis, menstrual disorders or ovulation disorders, osteoporosis, osteoporosis due to reproductive dysfunction in women (females), or for the prevention, improvement, treatment, or suppression of one or more symptoms selected from these, wherein the component is trigonelline. 【0093】 [4] A method for preventing, improving, treating, or suppressing one or more conditions selected from infertility, reproductive disorders, testicular disorders, decreased sperm function, decreased spermatogenesis, ovulation disorders, menstrual abnormalities, decreased reproductive capacity, osteoporosis, and osteoporosis due to reproductive disorders in women (females), using trigonelline or a trigonelline composition. 【0094】 • [5] The symptoms or diseases described above are caused by a composition or component or a composition containing such component, or a method thereof, as described in any one of [1] to [4] above, which are caused by a male or female side, or by a male or female side. • [6] A composition, component, or composition containing such component, or a method of use thereof, according to any one of [1] to [5] above, in which the symptoms or disease, etc., are caused by the male or female side, or by the male or female side. • [7] A composition, component, or composition containing such component, or a method of using the same, according to any one of [1] to [6] above, wherein the symptoms or disease, etc., are caused by systemic heat stress or localized heat stress. • [8] A composition, or component, or a composition containing such component, or a method of using the same, as described in any one of [1] to [7] above, for use by males and females or male and female. • [9] The target animal using the composition is a vertebrate, preferably one or more vertebrates selected from fish, amphibians, reptiles, birds, and mammals, and the composition, component, or composition containing such component, or the use or method thereof, as described in any one of [1] to [8] above. Of these, one or more selected from pets (dogs, cats, birds, rabbits, rodents, etc.), fish (ornamental fish, etc.), humans, livestock, etc. are preferred. •

[10] A composition or component or a composition containing such component, or a method of using the same, according to any one of [1] to [9] above, wherein the symptoms or disease are caused by heat stress. •

[11] A composition or component or a composition containing such component, or a method of using the same, for use against heat stress or for use in summer, as described in any one of [1] to

[10] above. 【0095】 •

[12] A composition, or component, or a composition containing such component, or a method of using the same, according to any one of [1] to

[11] above, wherein the form of the composition is one or more selected from food and beverages (tablets, etc.), pharmaceuticals (for non-human animals, quasi-drugs, designated quasi-drugs, etc.), animal feed (tablets, etc.), or additives (for food and beverages, for pharmaceuticals, for animal feed, etc.). •

[13] A composition or component or a composition containing such component, or a method of using the same, according to any one of [1] to

[12] above, wherein the trigonelline is a composition containing trigonelline. The trigonelline-containing composition is preferably one or more selected from coffee processed products, coffee fruit or its residue, Sakurajima radish or its residue, and extracts thereof, and a high-concentration trigonelline composition. •

[14] The trigonelline is a substance contained in one or more selected from coffee fruit or its residue, Sakurajima radish or its residue, and their extracts, and a trigonelline high-concentration composition, as described in any one of [1] to

[13] above, a composition or component or a composition containing said component, or a method of using the same. The coffee fruit is preferably the seeds, peel and / or pulp. The coffee fruit is preferably a mature fruit, and more preferably a coffee cherry. •

[15] The trigonelline is derived from coffee fruit and / or Sakurajima radish, and is a composition or component or a composition containing such component, or a method of using the same.

[16] A composition, or component, or a composition containing such component, or a method of using the same, according to any one of [1] to

[15] above, wherein the composition is for oral use, oral ingestion, oral administration, or feeding. 【0096】

[17] The trigonelline or a composition containing the same, or the use of the same, or a method according to any one of [1] to

[16] , wherein the trigonelline or a composition containing the same is for oral use, or is used for oral ingestion, oral administration or feeding, or the method is an oral ingestion method, an oral administration method or a feeding method.

[18] A method of orally ingesting, orally administering, or feeding a human or non-human animal a composition or food or feed obtained by incorporating any one of the compositions described in [1] to

[17] above, or trigonelline or a trigonelline composition. 【0097】 •

[19] A method for extracting trigonelline, a method for separating and purifying trigonelline, or a method for producing a trigonelline composition, or a method for producing the composition or trigonelline according to any one of [1] to

[18] above, for obtaining a trigonelline composition (e.g., an extract, a high-concentration trigonelline product, etc.) from a trigonelline material (more preferably a material selected from coffee fruit or its residue, Sakurajima radish or its residue). •

[20] A method for producing a trigonelline-containing composition or a composition for a specific use according to any one of [1] to

[19] above, comprising using trigonelline or a trigonelline or trigonelline composition obtained by the method of

[19] above as a raw material. It is preferable that the trigonelline-containing composition is one or more selected from pharmaceuticals, food and beverages, animal feed and additives. [Examples] 【0098】 The present invention will be described in more detail below based on the following examples. The examples described below are merely representative examples of the present invention and should not be interpreted as narrowing the scope of the invention. 【0099】 <1. Materials> <Animal> ICR mice purchased from Charles River Japan Co., Ltd. were bred in-house using the standard diet "MF Powder" (Charles River Japan Co., Ltd.) and used in various tests. <Test substance> Trigonelline (Tokyo Chemical Industries Co., Ltd.) 【0100】 Furthermore, while the seeds are removed from coffee cherries as a pretreatment during the coffee bean roasting process, the coffee cherry residue from which the seeds have been removed contains approximately 1% trigonelline, and this can also be used as a trigonelline-treated product. In addition, by further grinding the coffee cherry residue and extracting the ground material with hot water at 80-100°C for 2-3 hours, an extract with a higher concentration of trigonelline can be obtained as a trigonelline-treated product. Moreover, by utilizing the fact that trigonelline is poorly soluble in ethanol, the dried trigonelline hot water extract can be stirred with ethanol at room temperature (around 10°C), then filtered, and the filtrate collected to further remove ethanol-soluble impurities from the trigonelline-treated product, thereby obtaining a trigonelline-high-concentration product with even higher trigonelline purity. Furthermore, trigonelline can be recovered from the trigonelline-treated product using HPLC to obtain a trigonelline-high-concentration product. 【0101】 <2. Animal Experiments> <Breeding conditions> Eight-week-old male ICR mice were divided into a treatment group receiving the test substance and a control group not receiving the test substance. In the treatment group, trigonelline (5 mg / kg or 15 mg / kg) was mixed into standard diet powder and administered using a powder feeder. The mice in each group were housed at room temperature of 23-25°C with a photoperiod of 12 L:12 D (lights turned on at 7 AM). <Heat stress load> Seven days after the start of administration of the test substance, mice were subjected to heat stress. Specifically, after anesthesia, the lower half of their bodies were exposed to 41°C or 42°C water for 15-20 minutes. In the untreated group, mice were left at room temperature after anesthesia. 【0102】 In the figures and tables, the trigonelline-administered group subjected to heat stress is labeled "TRG Heat," "HEAT TRG," and "Trigonelline Heat," the control group that was not administered the test substance and was not subjected to heat stress is labeled "Control RT," "CONT -," and "- Control," and the heat stress group that was subjected to heat stress without being administered the test substance is labeled "Control Heat," "HEAT -," and "- Heat." 【0103】 <Evaluation of sperm function> When evaluating sperm function in mice from each test group, the following procedure should be followed. Specifically, during dissection, the cervical vertebrae of the mouse are dislocated to remove the epididymal tail, and the epididymal tail is placed in sperm culture buffer [2.2 mM HEPES (pH 7.4), 1.2 mM MgCl2, 100 mM NaCl, 4.7 mM KCl, 4.8 mM Lactic acid Ca, 5.5 mM D-Glucose, 20 mM Sodium bicarbonate, and 88 mM Pyruvic acid]. An incision is made in one place in the epididymal tail with an 18G needle, and the stored sperm are scraped out. After culturing at 37°C for 15 minutes, the sample is centrifuged at 500 rpm for 1 minute, and the supernatant spermate is collected. 【0104】 For sperm evaluation, we use the Sperm Motility Analysis System (SMAS) (Detect, Tokyo, Japan). This system can evaluate the following parameters: sperm concentration, sperm motility, motile sperm concentration, straight-line velocity, curvilinear velocity, average path velocity, amplitude of lateral head displacement, progressive sperm ratio (progressive sperm: straight-line velocity ≥ 50 μm / s and straight-line progression ≥ 70%), and progressive sperm concentration (progressive sperm: straight-line velocity ≥ 50 μm / s and straight-line progression ≥ 70%). Note that straight-line progression refers to the ratio of straight-line velocity to curvilinear velocity. 【0105】 <3. Statistical Processing> Experimental results are shown as mean ± SE (Standard error). Significant difference testing was performed using a t-test for data between two groups. Significant difference testing was performed using Holm's test for data between three or more groups, and a p-value of <0.05 was considered statistically significant. 【0106】 <Test Example 1> In an animal experiment using 8-week-old male ICR mice, three test groups were established: a treatment group in which trigonelline powder was orally administered as the test substance and subjected to heat stress; a control group in which the test substance was not administered and heat stress was not applied; and a heat stress group in which heat stress was applied without the test substance being administered. Mice were assigned to each test group (n=10-11). An overview of this animal experiment is shown in Figure 1. In the trigonelline administration group, trigonelline was mixed into standard feed powder at a daily intake of approximately 5 mg / kg body weight and administered for 7 days. After applying heat stress, administration was continued for another 24 hours. The heat stress in this case was localized to the testes by immersing the lower half of the mice in a hot water bath (42°C, 20 minutes). This simulates the rise in testicular temperature in humans while seated. This experimental system focused on the effect on damage to mature sperm. 【0107】 Sperm motility parameters were measured for mice in each test group. Specifically, 24 hours after heat exposure, the mice were subjected to cervical dislocation and the epididymal tail was removed. Then, according to the <Sperm Function Evaluation> described above, the stored mature sperm were scraped out, the supernatant semen was collected, and sperm motility parameters were measured using a sperm motility analysis system. The results for sperm motility rate (%) and progressive ratio (%) are shown in Figure 2. *Progressive ratio: The percentage of sperm with a linear velocity of 25 μm / s or higher and a straight-line movement of 0.7 or higher. Based on these results, trigonelline was able to suppress the decrease in motility of mature sperm caused by heat stress. 【0108】 <Test Example 2> In an animal experiment using 8-week-old male ICR mice, three test groups were established: a treatment group in which trigonelline powder was orally administered as the test substance and subjected to heat stress; a control group in which the test substance was not administered and heat stress was not applied; and a heat stress group in which heat stress was applied without the test substance being administered. Mice were assigned to each test group (n=5-6). An overview of this animal experiment is shown in Figure 3. In the trigonelline administration group, trigonelline was mixed into standard feed powder at a daily intake of approximately 15 mg / kg body weight and administered for 7 days. After applying heat stress, administration was continued for another 28 days. The heat stress in this study involved localized stress on the testes by placing the lower half of the mice in a hot water bath (41°C, 15 minutes). This simulated the rise in testicular temperature in humans while seated. This experimental system focused on the effect on spermatogenesis disorders. 【0109】 For each group of mice, the supernatant sperm solution was collected in the same manner as in <Test Example 1> above, and sperm motility parameters were measured using a sperm motility analysis system. The results for each group are shown in Table 1. Based on these results, while trigonelline was ineffective in reducing sperm concentration, which is a heat stress-dependent decline in spermatogenesis, it was able to improve a wide range of spermatogenesis-related declines, including motility, velocity, and head oscillation amplitude. 【0110】 [Table 1] 【0111】 <Test Example 3> In an animal experiment using 8-week-old male ICR mice, three test groups were established: a treatment group in which trigonelline powder was orally administered as the test substance and subjected to heat stress; a control group in which the test substance was not administered and heat stress was not applied; and a heat stress group in which heat stress was applied without the test substance being administered. Mice were assigned to each test group (n=3). An overview of this animal experiment is shown in Figure 4. In the trigonelline administration group, trigonelline was mixed into standard feed powder at a daily intake of approximately 5 mg / kg body weight and administered for 7 days. After applying heat stress, administration was continued for another 4 days. Heat stress (systemic heat stress) was induced by placing the mice in a heat chamber (35°C). This was intended to simulate the reproductive disorders caused by high summer temperatures in livestock, or the various chronic stresses in humans, as heat stress is converted into oxidative stress in the body. 【0112】 For each group of mice, the supernatant spermatum was collected in the same manner as in <Test Example 1> above, and sperm motility parameters were measured using a sperm motility analysis system. The results for sperm motility rate (%) and progressive ratio (%) are shown in Figure 5. Based on these results, trigonelline was able to improve the decreased sperm motility caused by heat stress. 【0113】 <Test Example 4> In animal experiments using 8-week-old male ICR mice, three test groups were established: a treatment group in which trigonelline powder was orally administered as the test substance and subjected to heat stress; a control group in which the test substance was not administered and heat stress was not subjected; and a heat stress group in which heat stress was subjected without the test substance being administered. Mice were then assigned to each test group (n=3). The heat stress loading conditions for each of these test groups were the same as those in <Test Example 3>, except that the trigonelline administration group was administered 15 mg / kg of trigonelline (compared to 5 mg / kg in Test Example 3). 【0114】 In each test group of mice, testicular DNA fragmentation was examined. Specifically, four days after heat exposure, the mice were subjected to cervical dislocation and the testes were removed. Testicular weight was measured to confirm the effect of trigonelline on heat stress-dependent testicular weight loss (Figure 6). Subsequently, total DNA was extracted from the testes using a standard method, and 2 μg of DNA was mixed with Orange G. This was then subjected to a 2% agarose gel [2 g Agarose, 100 ml TBE buffer (89 mM Tris, 89 mM Boric acid, 2 mM EDTA-2Na)] and electrophoresis was performed at 50 V. After electrophoresis, the gel was stained with Gelred™ nucleic acid gel stain (Biotium), and DNA detection was performed using a gel imaging device ("Printgraph," ATTO Corporation) (Figure 7). This confirmed the effect of trigonelline on heat stress-dependent apoptosis of testicular germ cells. 【0115】 Based on these results, trigonelline can suppress the decrease in testicular weight caused by heat stress. The testes contain numerous seminiferous tubules, and many germ cells are present within these tubules. The decrease in testicular weight is thought to be a result of apoptosis in germ cells. Furthermore, trigonelline can suppress heat stress-dependent testicular DNA fragmentation. 【0116】 <Test Example 5> In animal experiments using 8-week-old female ICR mice, three test groups were established: a treatment group in which trigonelline powder was orally administered as the test substance and subjected to heat stress; a control group in which the test substance was not administered and heat stress was not subjected; and a heat stress group in which heat stress was subjected without the test substance being administered. Mice were then assigned to each test group (n=4,3,4). Female mice were subjected to high-temperature rearing at 35°C for 16 hours from 1 day after initiation of oral administration of trigonelline (mixed into their diet) to 11 days (9 days + 48 hours) (Figure 8). Nine days after the start of high-temperature rearing, female mice were subcutaneously injected with pregnant mare serum-derived gonadotropin (PMSG), and two days later, with human chorionic gonadotropin (hCG) to induce ovulation. As a result, the number of ovulated oocytes decreased significantly in the control group subjected to heat stress, but this decrease was greatly suppressed in the trigonelline-administered group subjected to heat stress (Figure 9). These results suggest that trigonelline can improve the decrease in the number of ovulated oocytes caused by heat stress.

Claims

[Claim 1] A composition containing trigonelline as an active ingredient, for use in women or females, for the prevention, improvement, or treatment of female infertility or reproductive dysfunction caused by systemic heat stress (excluding coffee cherry residue). [Claim 2] A composition containing trigonelline as an active ingredient, for use in women or females, for the prevention, improvement, or treatment of ovulation disorders caused by systemic heat stress (excluding coffee cherry residue). [Claim 3] The composition according to claim 1 or 2, for use in conditions caused by heat stress. [Claim 4] The composition according to claim 1 or 2, wherein the form of the composition is a food or beverage, a pharmaceutical, animal feed, or an additive. [Claim 5] The composition according to claim 1 or 2, wherein the composition is an oral composition. [Claim 6] A composition containing trigonelline as an active ingredient for the prevention, improvement, or treatment of reduced reproductive capacity in female non-human animals caused by systemic heat stress (excluding coffee cherry residue). [Claim 7] A method for preventing, improving, or treating a decline in the reproductive capacity of female non-human animals caused by systemic heat stress, comprising feeding female non-human animals a composition containing trigonelline as an active ingredient, or a composition containing trigonelline as an active ingredient (excluding coffee cherry residue).

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