madman
Super Moderator
Nonpharmacological Interventions for the Management of Testosterone and Sperm Parameters: A Scoping Review (2022)
Heitor O. Santos, MHS, RD, LDN; Flávio A. Cadegiani, MD, PhD and Scott C. Forbes, PhD
ABSTRACT
Purpose: Testosterone replacement and associated pharmacologic agents are effective strategies to treat male hypogonadism; however, nutraceutical agents and lifestyle modification approaches have gained medical interest. The purpose of this scoping review is to highlight the evidence (or lack thereof) of nutraceuticals and lifestyle modification approaches in the management of testosterone levels and sperm parameters.
Methods: A scoping review of nonpharmacologic interventions (supplements, herbal medicines, diets, sleep, and exercise) with the potential to improve male health was undertaken to elucidate changes in testosterone levels and sperm parameters in men with hypogonadism or infertility compared with healthy patients.
Findings: A multitude of nutraceuticals and functional nutrients are purported to stimulate testosterone production; however, only a select few have had promising results, such as zinc, vitamin D (in case of hypovitaminosis D), l-arginine, mucuna, and ashwagandha, based on well-controlled randomized clinical trials of men with low testosterone levels and related problems. Except for l-arginine, these natural agents, as well as Tribulus and ω3 fatty acids, can improve some degree of sperm parameters in infertile men. Before implementing these nutraceutical agents, adequate sleep, exercise, and weight loss in patients with obesity are imperative. The effects of nonpharmacologic interventions on testosterone levels are modest and hence do not directly translate into clinical benefits. Correspondingly, androgen receptor content, but not endogenous androgens, has been regarded as the principal factor in muscle hypertrophy.
Implications: A limited number of supplements and herbal medicines can be considered adjunctive approaches in the management of testosterone levels and sperm parameters, primarily in men with low testosterone levels and infertility, whereas most nonpharmacologic supplements appear to lack evidence. Although proper physical exercise, sleep, and diet are indisputable approaches because of the general benefits to health, the use of nutraceuticals, if considered, must be personalized by physicians and/or registered dietitians.
INTRODUCTION
Male hypogonadism is an increasingly common condition that affects progressively younger males.1 The diagnosis of hypogonadism requires the combination of clinical manifestations unexplained by other diagnoses and biochemical characterization of reduced serum testosterone.2,3 Symptoms may include sexual-related dysfunctions, such as impaired libido, erectile dysfunction, decreased ejaculation volume, and infertility, as well as systemic and unspecific symptoms, such as impaired cognitive function, attention-deficit/hyperactivity disorder–like symptoms, depression, fatigue, weakness, normocytic normochromic anemia, obesity, and decreased bone density and muscle mass.4 Although sexual symptoms may seem more specific, those related to erectile function and libido are more commonly related to non-hormonal causes.5,6 Conversely, in the absence of other diseases, a decrease in overall quality of life encompassing decreased energy levels and cognitive function may be more specific to hypogonadism than sexual symptoms.7,8 As such, weaker correlations between sexual manifestations and hypogonadism have been identified than those related to general health.9
The prevalence of male hypogonadism ranges from 2% to 13% in middle-aged to older Europeans and Americans, with an estimated 12 new cases per 1000 person-years,10 and appears to be increasing across all ages.11–13 Although the major concern of hypogonadism is among middle-aged and older men (≥45 years of age),4 younger males may also present with hypogonadism, particularly in those with metabolic and inflammatory dysfunctions, such as obesity, diabetes, abuse of anabolic steroids for aesthetic purposes, and prolonged exposure to endocrine disruptors.14–17 The first-line therapy for male hypogonadism is testosterone replacement; however, testosterone replacement may lead to a decrease in fertility and further inhibition of the gonadotropic axis.18 When fertility is desired and inhibition of endogenous testosterone production is unwanted, other therapy modalities may be considered, including drug enhancers of the endogenous production of testosterone that may act on different levels of the gonadotropic axis, including clomiphene (the most used drug for this purpose), human chorionic gonadotropin, tamoxifen, and anastrozole.19,20
Alternatives strategies, including nutraceuticals alone or in combination with allopathic pharmacotherapy, have been hypothesized as adjunct strategies to treat male hypogonadism by improving testosterone levels and sperm parameters.21–23 Despite the widespread use of nutraceuticals in this regard, to date, no guidelines from various endocrine societies have included them as a treatment modality for male hypogonadism.13,24,25
*In this scoping review, we address the effects of nutraceutical agents (herbal medicines and supplements) that have become popular as testosterone boosters and provide further underpinnings of potential dosages that could be proposed as adjunct strategies to improve both testosterone levels and sperm parameters. In addition, we highlight the importance of lifestyle modification, dietary strategies, sleep quality, physical exercise, and body composition on testosterone production.
MALE HYPOGONADISM
Primary and Secondary Hypogonadism
The origin of hypogonadism is multifactorial, typically related to metabolic or inflammatory dysfunctions, senescence, or genetic, anatomical, or organic causes, as well as by abnormalities in the testicles (primary, peripheral, or hypogonadotropic hypogonadism) or in the hypothalamic-pituitary axis (secondary, central, or hypergonadotropic hypogonadism).2,26 It can be present before puberty, when the development of secondary sexual characteristics does not occur, during or after adolescence, as well as in adulthood.27
Primary hypogonadism can be differentiated from secondary hypogonadism by the gonadotropic hormones, luteinizing hormone (LH), and follicle-stimulating hormone (FSH).28 Because the site of abnormality of primary hypogonadism is the testicles, increased LH and FSH are usually detected, accompanied by increased levels of sex hormone-binding globulin (SHBG) because SHBG is produced in the liver in response to LH and FSH.29,30 Conversely, secondary hypogonadism is caused by abnormalities in the pituitary or hypothalamus or by factors that stimulate or inhibit gonadotropin-releasing hormone in the hypothalamus, and LH and FSH levels are usually in the low or abnormally normal range (within the reference range).31,32 Both LH and FSH are considered to be abnormally normal because under low testosterone levels LH and FSH levels are expected to be high to stimulate testosterone production, as per normal homeostasis of the gonadotropic axis.33,34 Once a dysregulation of these hormones is detected, a semen analysis can also be performed for an initial laboratory screening for infertile men because endogenous testosterone is required for the maturation and production of sperm cells.35–37 The testosterone range is discussed below.
Clinical Measurement of Serum Testosterone
Low testosterone levels accompanied by related clinical symptoms constitute hypogonadism.38 However, the reference range for testosterone is still debated, particularly in the lower limit. In general, studies with a large number of males indicate that normal total testosterone (TT) levels ranged from 220 to 260 ng/dL to 900 to 915 ng/dL, with mean levels of 500 ng/dL, whereas males with obesity presented with slightly lower testosterone levels.39 No differences in terms of risk or benefits are usually found when males in the lowest quartile are compared with males in the highest quartile.39 Hence, except for select cases, it is not reasonable to try to reach the upper limits of testosterone levels. Of importance, testosterone secretion follows a circadian cycle, with higher levels during sleep40 and peaks between 5 am and 10 am, 41 when blood collection for determining serum testosterone is preferred.41–43 The testosterone peak in the early morning may partially justify the occurrence of the awakening erection,44 which is used to evaluate clinical signs of testosterone.
NUTRIENTS AND NUTRACEUTICAL STRATEGIES
Vitamins and Minerals
Vitamins and minerals are essential elements for humans.45,46 Screening of their status by serum levels and amount ingested may be useful in the management of male hypogonadism, in particular those that have roles in testosterone production and in antioxidant status of testes, including zinc, magnesium, and vitamin D. Their physiologic roles are described below.
*Zinc
*Magnesium
*Vitamin D
LIPIDS AND RELATED COMPOUNDS
*ω3 Polyunsaturated Fatty Acids
*Cholesterol
DHEA
AMINO ACIDS AND DERIVATE COMPOUNDS
*l-Arginine
*d-Aspartic Acid
*Creatine
HERBAL MEDICINES
*Mucuna
*ashwagandha
*Tribulus
NUTS
RELATIONSHIP BETWEEN SLEEP AND TESTOSTERONE
Adequate sleep is critical for health, mainly because of extensive metabolic regulation, including testosterone status.127 In an American cohort study of 1312 elderly men, those with lower TT levels (<250 ng/dL) had lower sleep efficiency, with increased nocturnal awakenings and less time in slow-wave sleep as well as a higher apnea-hypopnea index and more sleep time with oxygen saturation levels <90%.128 Among 2295 American men 16 to 80 years of age from the National Health and Nutrition Examination Survey (NHANES) dataset, with a mean serum TT level of 377 ng/dL and 7 hours of sleep, the serum TT level decreased by 5.85 ng/dL per hour of sleep loss (P < 0.01).129 In addition, a 1-week intervention of sleep restriction is capable of reducing serum TT concentrations by 10% to 15% in the morning, as found in a study in which 10 healthy men were included—they slept approximately 8 to 9 h/d and underwent approximately 5 h/d of sleep in the week of restriction.40 As discussed in the aforementioned sections, many nutraceutical agents proposed to increase testosterone do not cause a 10% to 15% change in TT levels.21,106 Therefore, adjusting sleep may be more important before considering the use of nutraceutical and even pharmacologic agents.
WEIGHT LOSS AND CALORIC DEFICIT ON TESTOSTERONE LEVELS: PROS AND CONS
Not only is adequate sleep important, but it is also important to consider body composition before considering the use of any nutraceutical or even drug treatment to increase testosterone concentrations, particularly in obesity-associated hypotestosteronemia, which is a nonpermanent state that may be reversible by adopting a weight loss plan.14 Cohort studies confirm an association between low testosterone levels and excess body fat.128,129 In the NHANES dataset, serum TT levels decreased by 6.18 ng/dL per unit of body mass index increase (P < 0.01).129
A recent meta-analysis of RCTs found that calorie restriction in patients with overweight or obesity leads to increased serum TT levels.130 Accordingly, in the case of obesity, the “simple” process of losing weight can be sufficient to improve plasma testosterone concentrations, apart from the countless benefits.131 Remarkably, weight loss achieved by adhering to physical exercise and diet plans, as well as bariatric surgery, are also associated with increased levels of TT.132
Young healthy adults with normal levels of testosterone may present with a reduction in testosterone levels with the abusive practice of physical exercise and under high caloric deficit, reaching hormone insufficiency. For instance, in the study by Longland et al,133 which was composed of young men undergoing a low-calorie diet (−40% of daily caloric requirement) plus combined training (resistance training and high-intensity interval training) for 4 weeks, the TT levels of the groups were approximately 500 to 600 ng/dL at baseline and reached approximately 100 ng/dL after the intervention.133 In addition, individuals increased lean body mass while losing body fat regardless of the decrease in serum testosterone concentrations, but researchers found greater benefits in body composition under a high-protein diet (2.4 g/kg of protein daily) compared with lower protein intake (1.2 g/kg of protein daily).133 Nonetheless, given that <300 ng/dL is a sign of impaired testosterone production,134 these data may be important clinically, especially if maintained for several months. Moreover, such a protocol is not viable in the long term, and most people are unable to follow it.135 Thus, normalization of serum testosterone concentrations can be expected naturally after an escalated increase in caloric intake and a reduction in training volume.
PHYSICAL EXERCISE AND TESTOSTERONE: THE YIN AND YANG
Research in the early 2000s speculated about the importance of training-induced short-term increases in testosterone secretion as a means of stimulating gains in muscle mass and enhancing strength.136 A few years later, however, a cohort had no significant correlations between the exercise-induced elevations in free testosterone levels and gains in lean body mass as well as leg press strength.137
There is a negative association between serum testosterone and cortisol in the recovery from physical exercise, whose event is manifested particularly on abundant physical stress.138 At the molecular level, androgen, and glucocorticoid receptors form heterodimers and have mutually inhibitory effects on each other’s hormone-dependent transcription activity, hence leading to decreased testosterone levels when hypercortisolism is present.139
Men performing excessive physical exercise may have lower serum testosterone levels compared with those who do not exercise. For example, in men, (mean [SD] age, 36.3 [9.2] years) who ran a mean of 81 km/wk, approximately265 ng/dL of TT was detected, whereas in men who did not exercise the level was approximately 467 ng/dL.140 Of interest, there was no change in serum cortisol concentrations between the groups. Therefore, excessive physical exercise may be associated with lower levels of serum testosterone regardless of the increase in serum cortisol.
Despite the massive prevalence of administration of testosterone and its derivatives in bodybuilding,141 natural bodybuilding is an attractive way to discuss the physiologic testosterone levels under the best aesthetic performance. In a prospective case study142 of a high-level, amateur natural bodybuilder, baseline TT levels of approximately 543 ng/dL decreased significantly to approximately 197 ng/dL immediately before the competition but returned to normal levels afterward (TT levels of approximately 595 and 702 ng/dL on the 30th and 60th days after the competition, respectively). Baseline SHBG levels (the higher the SHBG level, the lower the testosterone bioavailability because it is a protein that binds to testosterone) significantly increased from approximately 43.1 nmol/L to approximately 56.3 nmol/L immediately before the competition but, like the testosterone status, levels returned to normal afterward. Throughout the preparation period, the bodybuilder used a high-volume, high-frequency, full-body training program alongside a low-calorie, high-protein diet, altering his weight of 99.5 kg and his 8% to 9% body fat to approximately 89 kg and approximately 5% on the day of the competition day, respectively.
ANDROGEN RECEPTOR: THE CORNERSTONE
The prostate, adrenal gland, epididymis, and skeletal muscle are some examples of androgen target tissues in which the androgen receptor (AR) is largely expressed as modulating many intracellular processes.143,144 The actions of testosterone and dihydrotestosterone (DHT) are orchestrated via the AR, with the interplay between AR and androgens being responsible for maintaining libido, spermatogenesis, erythropoiesis, bone mineral density, muscle mass, and strength.143 Importantly, DHT is more biologically active than testosterone, binding to AR with a 2-fold higher affinity and a 5-fold decreased dissociation rate compared with testosterone.144
Instead of circulating hormones, AR has been regarded to be the key potential therapeutic target for the treatment of clinical conditions, such as cancer.145 Because of its crucial role in altering cellular function, AR has been proposed as a determinant in hypertrophy as well.142 A decisive study found that, despite circulating and even intramuscular testosterone and DHT concentrations, intramuscular AR content was the determinant for a greater hypertrophic response of the human skeletal muscle after a resistance-training intervention in previously trained men.142 This finding helps to support clinical situations in which a better aesthetic and physical response are noted in individuals with lower hormone levels than those with higher levels.
Furthermore, short-term AR signaling response to mechanical loading on skeletal muscle seems to be mediated by the equated volume and intensity of resistance training irrespective of the intramuscular testosterone and DHT content.146 More recently, Cardaci et al146 observed significantly greater increases in sarcoplasmic β-catenin content—an activator of AR—by approximately 94% and AR-DNA binding activity by approximately 74% but without elevations in serum or muscle androgen concentrations or AR protein content for high-load resistance exercise when compared with low load.
DECISION-MAKING PRACTICE AND PERSONALIZED STRATEGIES
Before any adjunct agent or functional nutrient is sought to boost testosterone levels, it is pivotal to manage lifestyle factors, such as avoiding sleep deprivation, a balanced routine of physical exercise, and reducing weight mainly in patients with obesity. In addition to obesity-associated hypotestosteronemia, other obesity-related diseases, such as diabetes and hypertension, should also be considered; therefore, controlling blood pressure and blood glucose is of paramount importance in this context. For instance, approximately one-third of men with type 2 diabetes mellitus have low testosterone levels, which may be generated by vascular complications of diabetes in itself as well as by increased status of low-grade inflammation resulting from visceral adiposity.147, 148
Moreover, although smoking is intriguingly associated with higher serum testosterone levels,149,150 this is also strongly associated with erectile dysfunction,151 a common problem among patients seeking medical care to increase testosterone levels. Thus, quitting smoking is a point that ought to be included in lifestyle changes as well. Equally important, ethanol directly inhibits testicular testosterone synthesis,152,153 affecting semen quality as well.154 Higher doses of ethanol can partially suppress testosterone production, as found in pioneering studies of ethanol-induced intoxication performed by Välimäki et al.155,156
The summary of mechanisms and studied dosage from RCTs regarding the efficacy (or the lack thereof) of the nutraceutical agents discussed in this review are given in Table I. Furthermore, those agents with a potential level of evidence can be seen in Table II
*Zinc, vitamin D (in case of hypovitaminosis D), L-Arginine, mucuna, and ashwagandha could be designed in personalized dosages alone or in combined treatment to increase TT levels into a physiologic range when embarking on a decision-making strategy in which pharmacologic drugs are not urgent. Except for L-Arginine, these natural agents, as well as Tribulus and n-3 PUFAs, can improve sperm parameters to some degree in infertile men. Viewed collectively, a proposed nutraceutical approach to the management of testosterone levels and sperm parameters can be seen in Figure 1.
It may be reasonable to prioritize zinc and vitamin D primarily over circulating deficiency of both because they are essential nutrients. Likewise, EPA and DHA are essential nutrients for which their supplementation must be prioritized mainly when their dietary intake is low; however, orders for circulating status are not common in clinical practice. Supplementing l-arginine should be considered regardless of dietary intake.
Because herbal medicines are nonessential products, they ought to be considered after controlling for the mentioned essential nutrients.
Particular food items, such as whole eggs and nuts, are not included in Figure 1 because the evidence remains more limited than the nutraceuticals discussed; they should only be considered as part of the dietary plan if the individual likes the taste and, preferably, through calculations made by a nutritionist. We did not discuss the effects of B vitamins, particularly folate, because there is great heterogeneity among RCTs and the effects are often in combination therapies.172
Indeed, proposed nonpharmacologic-based interventions are geared toward nonsevere male hypogonadism (ie, a condition for which pharmacologic therapy is not urgently needed, and thus alternative strategies can be tested first without the risk of serious consequences caused by treatment delay). Erectile dysfunction, low libido, low seminal volume, and infertility are some untoward effects of nonsevere male hypogonadism (although this is part of severe hypogonadism as well), whereas severe hypogonadism can be related to conditions that represent a high risk of mortality, such as muscle-wasting disorders (cachexia and sarcopenia)173 and loss of bone mass (osteoporosis),174 in which the effects of pharmacologic agents cannot be postponed.
CONCLUSIONS
Several nutraceutical agents and functional nutrients have putative actions in increasing testosterone levels, but only a few have potential based on the available evidence. Although most clinical research using eugonadal and healthy individuals has found null effects, in individuals with low testosterone levels and related problems, well-controlled RCTs corroborate a potential to increase testosterone levels mainly from zinc, vitamin D (in case of hypovitaminosis D), l-arginine, mucuna, and ashwagandha (at proper dosages). Except for l-arginine, these natural agents, as well as Tribulus and n-PUFAs, can improve sperm parameters to some degree in infertile men. Personalized dosing regimens must be made by physicians and/or registered dietitians based on the best existing evidence and patient conditions.
Taking into account that testosterone is often associated with body composition and health, before considering supplementing with these potential testosterone boosters, it is imperative to verify whether the patient is of normal weight and achieves adequate sleep and physical exercise because these lifestyle factors have a much more robust and effective response than any nutraceutical. Furthermore, a modest increase in circulating testosterone levels does not necessarily translate into clinical benefits. Therefore, the total AR content, but not endogenous androgens such as testosterone, has been considered the leading factor of hypertrophy.
Heitor O. Santos, MHS, RD, LDN; Flávio A. Cadegiani, MD, PhD and Scott C. Forbes, PhD
ABSTRACT
Purpose: Testosterone replacement and associated pharmacologic agents are effective strategies to treat male hypogonadism; however, nutraceutical agents and lifestyle modification approaches have gained medical interest. The purpose of this scoping review is to highlight the evidence (or lack thereof) of nutraceuticals and lifestyle modification approaches in the management of testosterone levels and sperm parameters.
Methods: A scoping review of nonpharmacologic interventions (supplements, herbal medicines, diets, sleep, and exercise) with the potential to improve male health was undertaken to elucidate changes in testosterone levels and sperm parameters in men with hypogonadism or infertility compared with healthy patients.
Findings: A multitude of nutraceuticals and functional nutrients are purported to stimulate testosterone production; however, only a select few have had promising results, such as zinc, vitamin D (in case of hypovitaminosis D), l-arginine, mucuna, and ashwagandha, based on well-controlled randomized clinical trials of men with low testosterone levels and related problems. Except for l-arginine, these natural agents, as well as Tribulus and ω3 fatty acids, can improve some degree of sperm parameters in infertile men. Before implementing these nutraceutical agents, adequate sleep, exercise, and weight loss in patients with obesity are imperative. The effects of nonpharmacologic interventions on testosterone levels are modest and hence do not directly translate into clinical benefits. Correspondingly, androgen receptor content, but not endogenous androgens, has been regarded as the principal factor in muscle hypertrophy.
Implications: A limited number of supplements and herbal medicines can be considered adjunctive approaches in the management of testosterone levels and sperm parameters, primarily in men with low testosterone levels and infertility, whereas most nonpharmacologic supplements appear to lack evidence. Although proper physical exercise, sleep, and diet are indisputable approaches because of the general benefits to health, the use of nutraceuticals, if considered, must be personalized by physicians and/or registered dietitians.
INTRODUCTION
Male hypogonadism is an increasingly common condition that affects progressively younger males.1 The diagnosis of hypogonadism requires the combination of clinical manifestations unexplained by other diagnoses and biochemical characterization of reduced serum testosterone.2,3 Symptoms may include sexual-related dysfunctions, such as impaired libido, erectile dysfunction, decreased ejaculation volume, and infertility, as well as systemic and unspecific symptoms, such as impaired cognitive function, attention-deficit/hyperactivity disorder–like symptoms, depression, fatigue, weakness, normocytic normochromic anemia, obesity, and decreased bone density and muscle mass.4 Although sexual symptoms may seem more specific, those related to erectile function and libido are more commonly related to non-hormonal causes.5,6 Conversely, in the absence of other diseases, a decrease in overall quality of life encompassing decreased energy levels and cognitive function may be more specific to hypogonadism than sexual symptoms.7,8 As such, weaker correlations between sexual manifestations and hypogonadism have been identified than those related to general health.9
The prevalence of male hypogonadism ranges from 2% to 13% in middle-aged to older Europeans and Americans, with an estimated 12 new cases per 1000 person-years,10 and appears to be increasing across all ages.11–13 Although the major concern of hypogonadism is among middle-aged and older men (≥45 years of age),4 younger males may also present with hypogonadism, particularly in those with metabolic and inflammatory dysfunctions, such as obesity, diabetes, abuse of anabolic steroids for aesthetic purposes, and prolonged exposure to endocrine disruptors.14–17 The first-line therapy for male hypogonadism is testosterone replacement; however, testosterone replacement may lead to a decrease in fertility and further inhibition of the gonadotropic axis.18 When fertility is desired and inhibition of endogenous testosterone production is unwanted, other therapy modalities may be considered, including drug enhancers of the endogenous production of testosterone that may act on different levels of the gonadotropic axis, including clomiphene (the most used drug for this purpose), human chorionic gonadotropin, tamoxifen, and anastrozole.19,20
Alternatives strategies, including nutraceuticals alone or in combination with allopathic pharmacotherapy, have been hypothesized as adjunct strategies to treat male hypogonadism by improving testosterone levels and sperm parameters.21–23 Despite the widespread use of nutraceuticals in this regard, to date, no guidelines from various endocrine societies have included them as a treatment modality for male hypogonadism.13,24,25
*In this scoping review, we address the effects of nutraceutical agents (herbal medicines and supplements) that have become popular as testosterone boosters and provide further underpinnings of potential dosages that could be proposed as adjunct strategies to improve both testosterone levels and sperm parameters. In addition, we highlight the importance of lifestyle modification, dietary strategies, sleep quality, physical exercise, and body composition on testosterone production.
MALE HYPOGONADISM
Primary and Secondary Hypogonadism
The origin of hypogonadism is multifactorial, typically related to metabolic or inflammatory dysfunctions, senescence, or genetic, anatomical, or organic causes, as well as by abnormalities in the testicles (primary, peripheral, or hypogonadotropic hypogonadism) or in the hypothalamic-pituitary axis (secondary, central, or hypergonadotropic hypogonadism).2,26 It can be present before puberty, when the development of secondary sexual characteristics does not occur, during or after adolescence, as well as in adulthood.27
Primary hypogonadism can be differentiated from secondary hypogonadism by the gonadotropic hormones, luteinizing hormone (LH), and follicle-stimulating hormone (FSH).28 Because the site of abnormality of primary hypogonadism is the testicles, increased LH and FSH are usually detected, accompanied by increased levels of sex hormone-binding globulin (SHBG) because SHBG is produced in the liver in response to LH and FSH.29,30 Conversely, secondary hypogonadism is caused by abnormalities in the pituitary or hypothalamus or by factors that stimulate or inhibit gonadotropin-releasing hormone in the hypothalamus, and LH and FSH levels are usually in the low or abnormally normal range (within the reference range).31,32 Both LH and FSH are considered to be abnormally normal because under low testosterone levels LH and FSH levels are expected to be high to stimulate testosterone production, as per normal homeostasis of the gonadotropic axis.33,34 Once a dysregulation of these hormones is detected, a semen analysis can also be performed for an initial laboratory screening for infertile men because endogenous testosterone is required for the maturation and production of sperm cells.35–37 The testosterone range is discussed below.
Clinical Measurement of Serum Testosterone
Low testosterone levels accompanied by related clinical symptoms constitute hypogonadism.38 However, the reference range for testosterone is still debated, particularly in the lower limit. In general, studies with a large number of males indicate that normal total testosterone (TT) levels ranged from 220 to 260 ng/dL to 900 to 915 ng/dL, with mean levels of 500 ng/dL, whereas males with obesity presented with slightly lower testosterone levels.39 No differences in terms of risk or benefits are usually found when males in the lowest quartile are compared with males in the highest quartile.39 Hence, except for select cases, it is not reasonable to try to reach the upper limits of testosterone levels. Of importance, testosterone secretion follows a circadian cycle, with higher levels during sleep40 and peaks between 5 am and 10 am, 41 when blood collection for determining serum testosterone is preferred.41–43 The testosterone peak in the early morning may partially justify the occurrence of the awakening erection,44 which is used to evaluate clinical signs of testosterone.
NUTRIENTS AND NUTRACEUTICAL STRATEGIES
Vitamins and Minerals
Vitamins and minerals are essential elements for humans.45,46 Screening of their status by serum levels and amount ingested may be useful in the management of male hypogonadism, in particular those that have roles in testosterone production and in antioxidant status of testes, including zinc, magnesium, and vitamin D. Their physiologic roles are described below.
*Zinc
*Magnesium
*Vitamin D
LIPIDS AND RELATED COMPOUNDS
*ω3 Polyunsaturated Fatty Acids
*Cholesterol
DHEA
AMINO ACIDS AND DERIVATE COMPOUNDS
*l-Arginine
*d-Aspartic Acid
*Creatine
HERBAL MEDICINES
*Mucuna
*ashwagandha
*Tribulus
NUTS
RELATIONSHIP BETWEEN SLEEP AND TESTOSTERONE
Adequate sleep is critical for health, mainly because of extensive metabolic regulation, including testosterone status.127 In an American cohort study of 1312 elderly men, those with lower TT levels (<250 ng/dL) had lower sleep efficiency, with increased nocturnal awakenings and less time in slow-wave sleep as well as a higher apnea-hypopnea index and more sleep time with oxygen saturation levels <90%.128 Among 2295 American men 16 to 80 years of age from the National Health and Nutrition Examination Survey (NHANES) dataset, with a mean serum TT level of 377 ng/dL and 7 hours of sleep, the serum TT level decreased by 5.85 ng/dL per hour of sleep loss (P < 0.01).129 In addition, a 1-week intervention of sleep restriction is capable of reducing serum TT concentrations by 10% to 15% in the morning, as found in a study in which 10 healthy men were included—they slept approximately 8 to 9 h/d and underwent approximately 5 h/d of sleep in the week of restriction.40 As discussed in the aforementioned sections, many nutraceutical agents proposed to increase testosterone do not cause a 10% to 15% change in TT levels.21,106 Therefore, adjusting sleep may be more important before considering the use of nutraceutical and even pharmacologic agents.
WEIGHT LOSS AND CALORIC DEFICIT ON TESTOSTERONE LEVELS: PROS AND CONS
Not only is adequate sleep important, but it is also important to consider body composition before considering the use of any nutraceutical or even drug treatment to increase testosterone concentrations, particularly in obesity-associated hypotestosteronemia, which is a nonpermanent state that may be reversible by adopting a weight loss plan.14 Cohort studies confirm an association between low testosterone levels and excess body fat.128,129 In the NHANES dataset, serum TT levels decreased by 6.18 ng/dL per unit of body mass index increase (P < 0.01).129
A recent meta-analysis of RCTs found that calorie restriction in patients with overweight or obesity leads to increased serum TT levels.130 Accordingly, in the case of obesity, the “simple” process of losing weight can be sufficient to improve plasma testosterone concentrations, apart from the countless benefits.131 Remarkably, weight loss achieved by adhering to physical exercise and diet plans, as well as bariatric surgery, are also associated with increased levels of TT.132
Young healthy adults with normal levels of testosterone may present with a reduction in testosterone levels with the abusive practice of physical exercise and under high caloric deficit, reaching hormone insufficiency. For instance, in the study by Longland et al,133 which was composed of young men undergoing a low-calorie diet (−40% of daily caloric requirement) plus combined training (resistance training and high-intensity interval training) for 4 weeks, the TT levels of the groups were approximately 500 to 600 ng/dL at baseline and reached approximately 100 ng/dL after the intervention.133 In addition, individuals increased lean body mass while losing body fat regardless of the decrease in serum testosterone concentrations, but researchers found greater benefits in body composition under a high-protein diet (2.4 g/kg of protein daily) compared with lower protein intake (1.2 g/kg of protein daily).133 Nonetheless, given that <300 ng/dL is a sign of impaired testosterone production,134 these data may be important clinically, especially if maintained for several months. Moreover, such a protocol is not viable in the long term, and most people are unable to follow it.135 Thus, normalization of serum testosterone concentrations can be expected naturally after an escalated increase in caloric intake and a reduction in training volume.
PHYSICAL EXERCISE AND TESTOSTERONE: THE YIN AND YANG
Research in the early 2000s speculated about the importance of training-induced short-term increases in testosterone secretion as a means of stimulating gains in muscle mass and enhancing strength.136 A few years later, however, a cohort had no significant correlations between the exercise-induced elevations in free testosterone levels and gains in lean body mass as well as leg press strength.137
There is a negative association between serum testosterone and cortisol in the recovery from physical exercise, whose event is manifested particularly on abundant physical stress.138 At the molecular level, androgen, and glucocorticoid receptors form heterodimers and have mutually inhibitory effects on each other’s hormone-dependent transcription activity, hence leading to decreased testosterone levels when hypercortisolism is present.139
Men performing excessive physical exercise may have lower serum testosterone levels compared with those who do not exercise. For example, in men, (mean [SD] age, 36.3 [9.2] years) who ran a mean of 81 km/wk, approximately265 ng/dL of TT was detected, whereas in men who did not exercise the level was approximately 467 ng/dL.140 Of interest, there was no change in serum cortisol concentrations between the groups. Therefore, excessive physical exercise may be associated with lower levels of serum testosterone regardless of the increase in serum cortisol.
Despite the massive prevalence of administration of testosterone and its derivatives in bodybuilding,141 natural bodybuilding is an attractive way to discuss the physiologic testosterone levels under the best aesthetic performance. In a prospective case study142 of a high-level, amateur natural bodybuilder, baseline TT levels of approximately 543 ng/dL decreased significantly to approximately 197 ng/dL immediately before the competition but returned to normal levels afterward (TT levels of approximately 595 and 702 ng/dL on the 30th and 60th days after the competition, respectively). Baseline SHBG levels (the higher the SHBG level, the lower the testosterone bioavailability because it is a protein that binds to testosterone) significantly increased from approximately 43.1 nmol/L to approximately 56.3 nmol/L immediately before the competition but, like the testosterone status, levels returned to normal afterward. Throughout the preparation period, the bodybuilder used a high-volume, high-frequency, full-body training program alongside a low-calorie, high-protein diet, altering his weight of 99.5 kg and his 8% to 9% body fat to approximately 89 kg and approximately 5% on the day of the competition day, respectively.
ANDROGEN RECEPTOR: THE CORNERSTONE
The prostate, adrenal gland, epididymis, and skeletal muscle are some examples of androgen target tissues in which the androgen receptor (AR) is largely expressed as modulating many intracellular processes.143,144 The actions of testosterone and dihydrotestosterone (DHT) are orchestrated via the AR, with the interplay between AR and androgens being responsible for maintaining libido, spermatogenesis, erythropoiesis, bone mineral density, muscle mass, and strength.143 Importantly, DHT is more biologically active than testosterone, binding to AR with a 2-fold higher affinity and a 5-fold decreased dissociation rate compared with testosterone.144
Instead of circulating hormones, AR has been regarded to be the key potential therapeutic target for the treatment of clinical conditions, such as cancer.145 Because of its crucial role in altering cellular function, AR has been proposed as a determinant in hypertrophy as well.142 A decisive study found that, despite circulating and even intramuscular testosterone and DHT concentrations, intramuscular AR content was the determinant for a greater hypertrophic response of the human skeletal muscle after a resistance-training intervention in previously trained men.142 This finding helps to support clinical situations in which a better aesthetic and physical response are noted in individuals with lower hormone levels than those with higher levels.
Furthermore, short-term AR signaling response to mechanical loading on skeletal muscle seems to be mediated by the equated volume and intensity of resistance training irrespective of the intramuscular testosterone and DHT content.146 More recently, Cardaci et al146 observed significantly greater increases in sarcoplasmic β-catenin content—an activator of AR—by approximately 94% and AR-DNA binding activity by approximately 74% but without elevations in serum or muscle androgen concentrations or AR protein content for high-load resistance exercise when compared with low load.
DECISION-MAKING PRACTICE AND PERSONALIZED STRATEGIES
Before any adjunct agent or functional nutrient is sought to boost testosterone levels, it is pivotal to manage lifestyle factors, such as avoiding sleep deprivation, a balanced routine of physical exercise, and reducing weight mainly in patients with obesity. In addition to obesity-associated hypotestosteronemia, other obesity-related diseases, such as diabetes and hypertension, should also be considered; therefore, controlling blood pressure and blood glucose is of paramount importance in this context. For instance, approximately one-third of men with type 2 diabetes mellitus have low testosterone levels, which may be generated by vascular complications of diabetes in itself as well as by increased status of low-grade inflammation resulting from visceral adiposity.147, 148
Moreover, although smoking is intriguingly associated with higher serum testosterone levels,149,150 this is also strongly associated with erectile dysfunction,151 a common problem among patients seeking medical care to increase testosterone levels. Thus, quitting smoking is a point that ought to be included in lifestyle changes as well. Equally important, ethanol directly inhibits testicular testosterone synthesis,152,153 affecting semen quality as well.154 Higher doses of ethanol can partially suppress testosterone production, as found in pioneering studies of ethanol-induced intoxication performed by Välimäki et al.155,156
The summary of mechanisms and studied dosage from RCTs regarding the efficacy (or the lack thereof) of the nutraceutical agents discussed in this review are given in Table I. Furthermore, those agents with a potential level of evidence can be seen in Table II
*Zinc, vitamin D (in case of hypovitaminosis D), L-Arginine, mucuna, and ashwagandha could be designed in personalized dosages alone or in combined treatment to increase TT levels into a physiologic range when embarking on a decision-making strategy in which pharmacologic drugs are not urgent. Except for L-Arginine, these natural agents, as well as Tribulus and n-3 PUFAs, can improve sperm parameters to some degree in infertile men. Viewed collectively, a proposed nutraceutical approach to the management of testosterone levels and sperm parameters can be seen in Figure 1.
It may be reasonable to prioritize zinc and vitamin D primarily over circulating deficiency of both because they are essential nutrients. Likewise, EPA and DHA are essential nutrients for which their supplementation must be prioritized mainly when their dietary intake is low; however, orders for circulating status are not common in clinical practice. Supplementing l-arginine should be considered regardless of dietary intake.
Because herbal medicines are nonessential products, they ought to be considered after controlling for the mentioned essential nutrients.
Particular food items, such as whole eggs and nuts, are not included in Figure 1 because the evidence remains more limited than the nutraceuticals discussed; they should only be considered as part of the dietary plan if the individual likes the taste and, preferably, through calculations made by a nutritionist. We did not discuss the effects of B vitamins, particularly folate, because there is great heterogeneity among RCTs and the effects are often in combination therapies.172
Indeed, proposed nonpharmacologic-based interventions are geared toward nonsevere male hypogonadism (ie, a condition for which pharmacologic therapy is not urgently needed, and thus alternative strategies can be tested first without the risk of serious consequences caused by treatment delay). Erectile dysfunction, low libido, low seminal volume, and infertility are some untoward effects of nonsevere male hypogonadism (although this is part of severe hypogonadism as well), whereas severe hypogonadism can be related to conditions that represent a high risk of mortality, such as muscle-wasting disorders (cachexia and sarcopenia)173 and loss of bone mass (osteoporosis),174 in which the effects of pharmacologic agents cannot be postponed.
CONCLUSIONS
Several nutraceutical agents and functional nutrients have putative actions in increasing testosterone levels, but only a few have potential based on the available evidence. Although most clinical research using eugonadal and healthy individuals has found null effects, in individuals with low testosterone levels and related problems, well-controlled RCTs corroborate a potential to increase testosterone levels mainly from zinc, vitamin D (in case of hypovitaminosis D), l-arginine, mucuna, and ashwagandha (at proper dosages). Except for l-arginine, these natural agents, as well as Tribulus and n-PUFAs, can improve sperm parameters to some degree in infertile men. Personalized dosing regimens must be made by physicians and/or registered dietitians based on the best existing evidence and patient conditions.
Taking into account that testosterone is often associated with body composition and health, before considering supplementing with these potential testosterone boosters, it is imperative to verify whether the patient is of normal weight and achieves adequate sleep and physical exercise because these lifestyle factors have a much more robust and effective response than any nutraceutical. Furthermore, a modest increase in circulating testosterone levels does not necessarily translate into clinical benefits. Therefore, the total AR content, but not endogenous androgens such as testosterone, has been considered the leading factor of hypertrophy.
