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The causes of adverse changes of testosterone levels in men
Abstract
Introduction: As men age, progressive testosterone deficiency syndrome becomes an increasingly common problem. However, the decreased testosterone levels are not only the result of advanced age.
Areas covered: PubMed search of published data on testosterone, nutritional deficiency, stress, sleep, and obesity. Many factors impact the male HPG axis (the hypothalamic-pituitary-adrenal), including body weight, calorific, and nutritional value of a diet, the amount and quality of sleep, as well as the level of stress. In the case of persons of healthy weight, a below-average calorific value of a diet may decrease the levels of testosterone in men. On the other hand, the same caloric deficiency in obese persons may result in a neutral or positive impact on testosterone levels.
Expert opinion: Many factors, including external, environmental, and internal factors, influence testosterone levels. Undoubtedly, nutritional deficiency, and particularly of such nutrients as zinc, magnesium, vitamin D, together with low polyphenols intake, affects the HPG axis. The levels of mental and oxidative stress can also adversely impact the axis. Hence, a diagnosis of the cause of disturbance in testosterone levels depends on many factors and requires a broad range of research, as well as a change of patients’ lifestyle.
Article highlights
• Most factors influencing testosterone levels in men are modifiable, such as diet, amount of sleep, or stress levels.
• Zinc is a cofactor of LH and FSH enzymes catalyzing the synthesis of trophic hormones of the pituitary. Zinc deficiency correlates with lower testosterone levels.
• The reduction of sleeping time to five hours per day during a single examination contributed to reducing testosterone levels by 10-15%. However, the evidence confirming the influence of sleep deprivation or circadian rhythm disorders on testosterone are inconclusive.
• In the case of people with a healthy weight, the too low calorific value of diet may result in the reduction of testosterone levels in men. This influence was not observed in obese persons.
• Excessive body mass may lead to higher levels of cortisol and affect androgens levels. Hair analysis of people of different body mass showed higher cortisol levels and lower testosterone levels in obese people.
• Long-term effects of treatment of hypogonadism are well-documented and are reported to decrease the risk of prostate cancer, cardiovascular diseases, type II diabetes, prediabetic state, nephropathy, or erection disorders.
1. Introduction
The popularity of a healthy lifestyle and rapid technological and medical progress have helped reduce mortality rates and increase life expectancy among both men and women over the past two decades in Poland. According to Statistics Poland (Pol. GUS), in 2018 the average life expectancy of an average 30-year-old man was 78 years [1], whereas in 1980 it was 66. As men age, the risk of late-life health problems increases. Apart from the most common afflictions, such as cardiovascular diseases or cancer, testosterone deficiency syndrome becomes an increasingly common problem for men [2]. However, testosterone secretion disorders are not characteristic only for older men. Many factors influence the male HPG axis, including environmental factors, such as excessive stress or low physical activity, as well as drug intake, diet, and body mass. Therefore, in order to prevent the risk of TDS during middle and older age, it is significant to determine which factors may adversely impact testosterone levels in men.
This study offers a brief outline of scientific articles on the subject of possible factors influencing testosterone level disorders in men. Although this article focuses primarily on nutritional factors, it also discusses the impact of mental stress, sleep duration, and age. We have critically reviewed available scientific literature on the impact of diet on testosterone levels, body mass, body mass change, mental stress, age, and sleep duration. We have typed the above keywords into the PubMed search engine in search of the relevant data on the subject. The bibliographical references consist of sources dated from 1980 to 2020.
2.Testosterone synthesis in the body
The function of male gonads, including secretion of testosterone, is regulated by pituitary hormones (hypothalamic-pituitary-gonadal axis). The luteinizing hormone (LH) activates steroidogenic enzymes by influencing Leydig cells, which enables a testosterone synthesis from cholesterol. The follicle-stimulating hormone (FSH) stimulates testicular growth, impacts Sertoli cells, and regulates spermatogenesis. Testosterone exerts negative feedback on gonadotropin secretion (GnRH) by affecting the hypothalamus, and LH, by impacting the anterior ACCEPTED MANUSCRIPT pituitary gland. The gonadal protein hormones, in turn, suppress (inhibin), or, alternatively, stimulate (activin) FSH secretion [3].
Testosterone, the principal male sex hormone, belongs to a group of steroid hormones. The group also includes 17β-estradiol, dihydrotestosterone (DHT), and adrenal androgen dehydroepiandrosterone. In a male body, steroid hormones are synthesized primarily by Leydig cells of the testis. Androgens are synthesized from cholesterol as a result of many enzymatic changes in the process of steroidogenesis [4-5]. The process starts when the receptors in the membrane of Leydig cells take up a cholesterol molecule and transport it inside the cell through endocytosis. Next, the luteinizing hormone stimulates the transport of cholesterol through StAR (steroidogenic acute regulatory protein) from the cytosol to the inner mitochondrial membrane in which multistage enzymatic conversion of cholesterol to testosterone occurs. As a result of the activity of cholesterol pregnenolone, the side-chain cleavage enzyme (P450scc cytochrome) is formed. Subsequently, the synthesis involves two pathways. The first is the dehydroepiandrosterone pathway, promoted in male gonads, in which pregnenolone, employing five enzymes, converts to 17-hydroxypregnenolone, and then to dehydroepiandrosterone (DHEA) and Δ5-androstenediol, and finally to testosterone. The second, a less active pathway of synthesis of the hormone, is the so-called progesterone pathway in which progesterone as well as 17-hydroxyprogesterone and androstenedione, respectively, are synthesized prior to the production of testosterone[6-7]. Physiological testosterone levels (80-280pg per cm3 of blood plasma) are regulated through the hypothalamus-pituitary-gonads axis[8]. The reduction of the testosterone levels stimulates the hypothalamus to release gonadoliberin (GnRH) which, while influencing the pituitary, precipitates the release of luteinizing (LH) and gametokinetic (FSH) hormones. The hormones, in turn, directly impact gonads (testicles) and stimulate testosterone synthesis [9]. The human body can synthesize up to 7 mg of testosterone in a day. Nevertheless, the healthy synthesis of the hormone results in the secretion of 4 to 6 mg of testosterone into the bloodstream per day. Free testosterone is transported into the cytoplasm of target tissue cells, where it can merge with the androgen receptor, or can be reduced to DHT by the cytoplasmic enzyme 5a-reductase. The T-receptor or DHT-receptor complex moves into the cell nucleus and activates specific genes. Protein products of the genes mediate numerous hormonal functions [9-10].
2.1 The importance of testosterone
3.The influence of energy intake and body mass
4. Nutritional deficiency
5. Stress and testosterone
6. Age and testosterone levels
7. Sleeping time and testosterone levels
8. Summary
Proper testosterone levels play a significant role in the regulation of male reproductive abilities, sexual functions, as well as the proper functioning of the skeletal system, metabolism, fatty acids, bone mass, and muscular strength [94]. Many factors, including external, environmental, and internal factors, influence testosterone levels. The impact of energy intake derived from a testosterone-boosting diet depends on a human body mass. In the case of people of healthy body mass, insufficient energy intake may result in a reduction in testosterone levels in men. The same energy deficit in obese people, may, in turn, result in a neutral or positive impact on the levels of the hormone. Undoubtedly, nutritional deficiency, and particularly of such nutrients as zinc, magnesium, vitamin D, together with low polyphenols intake, affects the HPG axis. The levels of mental and oxidative stress can also adversely impact the axis. The higher the cortisol levels in a human body, or the higher its daily fluctuation, the lower the testosterone levels. What is more, the effect seems to be strengthened by excessive body weight, which is related to the increased oxidative stress affecting the functions of the Leydig cells. Other factors that might disrupt testosterone synthesis may be the length and quality of sleep. Even though the issue is relatively unknown, it appears that both sleep deprivation (shorter than five hours) and low quality of sleep (sleeping with the light on, sleeping during the day, under the influence of alcohol) impact the testosterone levels negatively.
9. Expert opinion
Testosterone is a primary male hormone that performs many functions in a body, including the impact on primary and secondary gender-related characteristics such as muscle mass, facial features, as well as promoting athletic body and regulation of spermatogenesis. The available studies show a probable impact of diet composition and lifestyle on the testosterone level in men. However, the number of studies is limited.
The correlation between vitamin D level in a body and the hormonal balance, as well as the impact of the energy from carbohydrates and fats on the calorific value of a diet, seems to be one of the most exciting areas of research on the correlation of a diet and testosterone level. It appears that modification of a diet, regarding the number of carbohydrates and fats, may positively impact the hormonal parameters in men. More studies show that the role of cholecalciferol is not confined only to the skeletal system. It was proved that the active form of vitamin D (1,25 (OH) D) is a hormone of paracrine and autocrine signaling, which impacts cells through the vitamin D receptors (VDR). The presence of the receptors in almost all body cells (apart from erythrocytes and mature cells of skeletal muscle) suggests that vitamin D runs in different directions. Due to its properties, vitamin D is a subject of many studies, and undoubtedly, it is worth waiting for the newest research on the correlation between vitamin D and the level of male hormones.
Also, physical activity seems crucial as far as the proper functioning of male hormonal balance is concerned. The current research shows that any physical activity may positively influence the level of testosterone if it is adapted to the participant’s physical capabilities. The current research shows that the most effective is strength training which leads to hypertrophy and increased synthesis of testosterone shortly after the training session has been completed.
Another factor that may interfere with testosterone synthesis may be the length and quality of sleep. Although the matter has not been comprehensively examined, it seems that both sleep deprivation (lower than 5 hours), or reduced quality of sleep (sleeping when the light is on, sleeping during the day in a state of intoxication) negatively impact the testosterone level.
Hence, further research on the issue as well as on the impact of macronutrient intake on hormonal homeostasis in men is required. Undoubtedly, energy deficit, in the case of athletes with low body fat mass, may negatively impact the production of testosterone. However, as far as overweight persons are concerned, the low calorific value of a diet may lead to the reduction of excessive body fat, which, in turn, increases the level of testosterone. Moreover, too low or too high fat intake may negatively impact the level of testosterone. Nevertheless, the quality of fat is also crucial. It appears that monosaturated fatty acids should predominate over other nutrients in the athletes’ diet, especially if they eat a low-fat diet. Also, carbohydrates in a diet impact the optimization of the level of testosterone, since they reduce the deficit of glycogen and the level of cortisol after training.
Finally, it has to be noted that more detailed research on the correlation between the calorific value of a diet, as well as macronutrient intake and the level of steroid hormones, is required. These aspects need further explication.
Furthermore, the correlation between the level of cortisol and testosterone in the participants is a promising area of research. The factors impacting the level of a stress hormone also help reduce the level of testosterone. However, the exact processes and the size of the influence has not been fully explained so far.
Abstract
Introduction: As men age, progressive testosterone deficiency syndrome becomes an increasingly common problem. However, the decreased testosterone levels are not only the result of advanced age.
Areas covered: PubMed search of published data on testosterone, nutritional deficiency, stress, sleep, and obesity. Many factors impact the male HPG axis (the hypothalamic-pituitary-adrenal), including body weight, calorific, and nutritional value of a diet, the amount and quality of sleep, as well as the level of stress. In the case of persons of healthy weight, a below-average calorific value of a diet may decrease the levels of testosterone in men. On the other hand, the same caloric deficiency in obese persons may result in a neutral or positive impact on testosterone levels.
Expert opinion: Many factors, including external, environmental, and internal factors, influence testosterone levels. Undoubtedly, nutritional deficiency, and particularly of such nutrients as zinc, magnesium, vitamin D, together with low polyphenols intake, affects the HPG axis. The levels of mental and oxidative stress can also adversely impact the axis. Hence, a diagnosis of the cause of disturbance in testosterone levels depends on many factors and requires a broad range of research, as well as a change of patients’ lifestyle.
Article highlights
• Most factors influencing testosterone levels in men are modifiable, such as diet, amount of sleep, or stress levels.
• Zinc is a cofactor of LH and FSH enzymes catalyzing the synthesis of trophic hormones of the pituitary. Zinc deficiency correlates with lower testosterone levels.
• The reduction of sleeping time to five hours per day during a single examination contributed to reducing testosterone levels by 10-15%. However, the evidence confirming the influence of sleep deprivation or circadian rhythm disorders on testosterone are inconclusive.
• In the case of people with a healthy weight, the too low calorific value of diet may result in the reduction of testosterone levels in men. This influence was not observed in obese persons.
• Excessive body mass may lead to higher levels of cortisol and affect androgens levels. Hair analysis of people of different body mass showed higher cortisol levels and lower testosterone levels in obese people.
• Long-term effects of treatment of hypogonadism are well-documented and are reported to decrease the risk of prostate cancer, cardiovascular diseases, type II diabetes, prediabetic state, nephropathy, or erection disorders.
1. Introduction
The popularity of a healthy lifestyle and rapid technological and medical progress have helped reduce mortality rates and increase life expectancy among both men and women over the past two decades in Poland. According to Statistics Poland (Pol. GUS), in 2018 the average life expectancy of an average 30-year-old man was 78 years [1], whereas in 1980 it was 66. As men age, the risk of late-life health problems increases. Apart from the most common afflictions, such as cardiovascular diseases or cancer, testosterone deficiency syndrome becomes an increasingly common problem for men [2]. However, testosterone secretion disorders are not characteristic only for older men. Many factors influence the male HPG axis, including environmental factors, such as excessive stress or low physical activity, as well as drug intake, diet, and body mass. Therefore, in order to prevent the risk of TDS during middle and older age, it is significant to determine which factors may adversely impact testosterone levels in men.
This study offers a brief outline of scientific articles on the subject of possible factors influencing testosterone level disorders in men. Although this article focuses primarily on nutritional factors, it also discusses the impact of mental stress, sleep duration, and age. We have critically reviewed available scientific literature on the impact of diet on testosterone levels, body mass, body mass change, mental stress, age, and sleep duration. We have typed the above keywords into the PubMed search engine in search of the relevant data on the subject. The bibliographical references consist of sources dated from 1980 to 2020.
2.Testosterone synthesis in the body
The function of male gonads, including secretion of testosterone, is regulated by pituitary hormones (hypothalamic-pituitary-gonadal axis). The luteinizing hormone (LH) activates steroidogenic enzymes by influencing Leydig cells, which enables a testosterone synthesis from cholesterol. The follicle-stimulating hormone (FSH) stimulates testicular growth, impacts Sertoli cells, and regulates spermatogenesis. Testosterone exerts negative feedback on gonadotropin secretion (GnRH) by affecting the hypothalamus, and LH, by impacting the anterior ACCEPTED MANUSCRIPT pituitary gland. The gonadal protein hormones, in turn, suppress (inhibin), or, alternatively, stimulate (activin) FSH secretion [3].
Testosterone, the principal male sex hormone, belongs to a group of steroid hormones. The group also includes 17β-estradiol, dihydrotestosterone (DHT), and adrenal androgen dehydroepiandrosterone. In a male body, steroid hormones are synthesized primarily by Leydig cells of the testis. Androgens are synthesized from cholesterol as a result of many enzymatic changes in the process of steroidogenesis [4-5]. The process starts when the receptors in the membrane of Leydig cells take up a cholesterol molecule and transport it inside the cell through endocytosis. Next, the luteinizing hormone stimulates the transport of cholesterol through StAR (steroidogenic acute regulatory protein) from the cytosol to the inner mitochondrial membrane in which multistage enzymatic conversion of cholesterol to testosterone occurs. As a result of the activity of cholesterol pregnenolone, the side-chain cleavage enzyme (P450scc cytochrome) is formed. Subsequently, the synthesis involves two pathways. The first is the dehydroepiandrosterone pathway, promoted in male gonads, in which pregnenolone, employing five enzymes, converts to 17-hydroxypregnenolone, and then to dehydroepiandrosterone (DHEA) and Δ5-androstenediol, and finally to testosterone. The second, a less active pathway of synthesis of the hormone, is the so-called progesterone pathway in which progesterone as well as 17-hydroxyprogesterone and androstenedione, respectively, are synthesized prior to the production of testosterone[6-7]. Physiological testosterone levels (80-280pg per cm3 of blood plasma) are regulated through the hypothalamus-pituitary-gonads axis[8]. The reduction of the testosterone levels stimulates the hypothalamus to release gonadoliberin (GnRH) which, while influencing the pituitary, precipitates the release of luteinizing (LH) and gametokinetic (FSH) hormones. The hormones, in turn, directly impact gonads (testicles) and stimulate testosterone synthesis [9]. The human body can synthesize up to 7 mg of testosterone in a day. Nevertheless, the healthy synthesis of the hormone results in the secretion of 4 to 6 mg of testosterone into the bloodstream per day. Free testosterone is transported into the cytoplasm of target tissue cells, where it can merge with the androgen receptor, or can be reduced to DHT by the cytoplasmic enzyme 5a-reductase. The T-receptor or DHT-receptor complex moves into the cell nucleus and activates specific genes. Protein products of the genes mediate numerous hormonal functions [9-10].
2.1 The importance of testosterone
3.The influence of energy intake and body mass
4. Nutritional deficiency
5. Stress and testosterone
6. Age and testosterone levels
7. Sleeping time and testosterone levels
8. Summary
Proper testosterone levels play a significant role in the regulation of male reproductive abilities, sexual functions, as well as the proper functioning of the skeletal system, metabolism, fatty acids, bone mass, and muscular strength [94]. Many factors, including external, environmental, and internal factors, influence testosterone levels. The impact of energy intake derived from a testosterone-boosting diet depends on a human body mass. In the case of people of healthy body mass, insufficient energy intake may result in a reduction in testosterone levels in men. The same energy deficit in obese people, may, in turn, result in a neutral or positive impact on the levels of the hormone. Undoubtedly, nutritional deficiency, and particularly of such nutrients as zinc, magnesium, vitamin D, together with low polyphenols intake, affects the HPG axis. The levels of mental and oxidative stress can also adversely impact the axis. The higher the cortisol levels in a human body, or the higher its daily fluctuation, the lower the testosterone levels. What is more, the effect seems to be strengthened by excessive body weight, which is related to the increased oxidative stress affecting the functions of the Leydig cells. Other factors that might disrupt testosterone synthesis may be the length and quality of sleep. Even though the issue is relatively unknown, it appears that both sleep deprivation (shorter than five hours) and low quality of sleep (sleeping with the light on, sleeping during the day, under the influence of alcohol) impact the testosterone levels negatively.
9. Expert opinion
Testosterone is a primary male hormone that performs many functions in a body, including the impact on primary and secondary gender-related characteristics such as muscle mass, facial features, as well as promoting athletic body and regulation of spermatogenesis. The available studies show a probable impact of diet composition and lifestyle on the testosterone level in men. However, the number of studies is limited.
The correlation between vitamin D level in a body and the hormonal balance, as well as the impact of the energy from carbohydrates and fats on the calorific value of a diet, seems to be one of the most exciting areas of research on the correlation of a diet and testosterone level. It appears that modification of a diet, regarding the number of carbohydrates and fats, may positively impact the hormonal parameters in men. More studies show that the role of cholecalciferol is not confined only to the skeletal system. It was proved that the active form of vitamin D (1,25 (OH) D) is a hormone of paracrine and autocrine signaling, which impacts cells through the vitamin D receptors (VDR). The presence of the receptors in almost all body cells (apart from erythrocytes and mature cells of skeletal muscle) suggests that vitamin D runs in different directions. Due to its properties, vitamin D is a subject of many studies, and undoubtedly, it is worth waiting for the newest research on the correlation between vitamin D and the level of male hormones.
Also, physical activity seems crucial as far as the proper functioning of male hormonal balance is concerned. The current research shows that any physical activity may positively influence the level of testosterone if it is adapted to the participant’s physical capabilities. The current research shows that the most effective is strength training which leads to hypertrophy and increased synthesis of testosterone shortly after the training session has been completed.
Another factor that may interfere with testosterone synthesis may be the length and quality of sleep. Although the matter has not been comprehensively examined, it seems that both sleep deprivation (lower than 5 hours), or reduced quality of sleep (sleeping when the light is on, sleeping during the day in a state of intoxication) negatively impact the testosterone level.
Hence, further research on the issue as well as on the impact of macronutrient intake on hormonal homeostasis in men is required. Undoubtedly, energy deficit, in the case of athletes with low body fat mass, may negatively impact the production of testosterone. However, as far as overweight persons are concerned, the low calorific value of a diet may lead to the reduction of excessive body fat, which, in turn, increases the level of testosterone. Moreover, too low or too high fat intake may negatively impact the level of testosterone. Nevertheless, the quality of fat is also crucial. It appears that monosaturated fatty acids should predominate over other nutrients in the athletes’ diet, especially if they eat a low-fat diet. Also, carbohydrates in a diet impact the optimization of the level of testosterone, since they reduce the deficit of glycogen and the level of cortisol after training.
Finally, it has to be noted that more detailed research on the correlation between the calorific value of a diet, as well as macronutrient intake and the level of steroid hormones, is required. These aspects need further explication.
Furthermore, the correlation between the level of cortisol and testosterone in the participants is a promising area of research. The factors impacting the level of a stress hormone also help reduce the level of testosterone. However, the exact processes and the size of the influence has not been fully explained so far.
