madman
Super Moderator
Abstract
Progressive deterioration of male reproductive function is occurring in Western countries. Environmental factors and unhealthy lifestyles have been implicated in the decline of testosterone levels and sperm production observed in the last fifty years. Among unhealthy lifestyles, substance and drug abuse is a recognized cause of possible alterations of steroidogenesis and spermatogenesis. Alcohol, opioids, and anabolic-androgenic steroids are capable to reduce testosterone production in males interfering with testicular and/or hypothalamic-pituitary function. Other substances such as nicotine, cannabis, and amphetamines alter spermatogenesis inducing oxidative stress and subsequent apoptosis in testicular tissue. Substance and drug abuse is a potentially reversible cause of hypogonadism, defined as the failure of the testis to produce physiological concentrations of testosterone and/or a normal number of spermatozoa. The identification of the abuse is important because the withdrawal of substance intake can reverse the clinical syndrome. This review summarizes the most important clinical and experimental evidence on the effect of substance abuse on testosterone and sperm production.
1. Introduction
According to the most recent definition, hypogonadism is a clinical syndrome resulting from the failure of the testis to produce physiological concentrations of testosterone and/or a normal number of spermatozoa due to pathologies of the hypothalamic-pituitary-testicular axis [1].
Testosterone concentrations, impairment of spermatogenesis, and elevated gonadotropin levels, defined as primary hypogonadism. Otherwise, secondary hypogonadism is caused by a dysfunction of the hypothalamus-pituitary unit, resulting in low testosterone concentrations, impairment of spermatogenesis, and low or inappropriately normal gonadotropin levels [1]. Hypogonadism is defined as organic when a congenital, structural, or destructive disorder results in a permanent dysfunction, and functional when potentially reversible conditions suppress temporarily gonadotropin and/or testosterone production [1].
*Symptoms and signs suggestive of testosterone deficiency include reduced libido and sexual activity, decreased spontaneous erections, erectile dysfunction, gynecomastia, infertility, osteopenia/osteoporosis, hot flushes, and sweats. Other non-specific symptoms, such as fatigue, depressed mood, poor concentration, and memory, sleep disturbance, reduced muscle mass and strength, increased body fat and body mass index [1], although not decisive for defining the diagnosis, are important from a clinical point of view because they have a great impact on the quality of life of hypogonadal patients.
Factors that could contribute to the worsening of testicular function in Western countries include the progressive increase in visceral adiposity among the population, changes in lifestyle and behaviors, environmental pollution, and exposure to endocrine-disrupting compounds (i.e., phthalates) [5]. Among unhealthy behaviors, alcohol abuse, cigarette smoking, excessive caffeine intake, illicit drug intake, opioid consumption and inappropriate use of anabolic steroids have been studied as a possible cause of reduced sperm production and/or reduced testosterone levels in hypogonadal men [6].
In our review, we summarized the most important clinical and experimental evidence on the effect of substance abuse on testosterone and sperm production For many of the substances examined most of the evidence comes from in vivo and in vitro animal studies or from retrospective human studies. Indeed, for ethical reasons, no intervention studies on humans can be performed. Unfortunately, data obtained in animals are not always reproducible in humans; so some aspects regarding the mechanisms of action of several substances on the reproductive function must be further clarified.
2. Alcohol
Since ancient times the consumption of alcoholic beverages has been part of the socio-cultural heritage of most populations. However, chronic and acute alcohol abuse is involved in the pathogenesis of many diseases, including liver diseases, cancers, cardiovascular disease, and neuropsychiatric disorders. The effects of alcohol intake on male reproductive function have also been evaluated, in vitro and in vivo. Both testosterone production and spermatogenesis seem to be affected by alcohol abuse.
2.1. Effects on Testosterone Production
2.2. Effects on Spermatogenesis
3. Cigarette Smoking
Even more than alcohol, cigarette smoking is recognized as a risk factor for many diseases: cardiovascular diseases, lung diseases, malignant neoplasms, etc. Since the 1980s, scientific literature has been interested in evaluating the effects of cigarette smoking on reproductive function. Tobacco smoke is a complex mixture of over 8,700 substances. Harmful cigarette smoke constituents include carbon monoxide, nitrogen oxide, ammonia, heavy metals, various polycyclic aromatic hydrocarbons, and aldehydes, such as hydroquinone, catechol, acrolein, crotonaldehyde, and formaldehyde [30]. Recently, even nicotine, the major psychoactive substance in cigarette smoke, has been called into question in the pathogenesis of smoker's sperm alterations with a possible neuroendocrine mechanism [31]. Indeed, it has been demonstrated that nicotine and its metabolites are capable to cross the blood-testis barrier [32].
2.1. Effects on Testosterone Production
2.2. Effects on Spermatogenesis
4. Caffeine
Caffeine is a methylated xanthine, structurally similar to purine and uric acid, present in coffee, tea, soft drinks, and chocolate. One cup of coffee contains about 137 mg of caffeine, a cup of tea 47 mg, a bottle or can of caffeinated soft drinks (i.e., cola) about 46 mg, a serving of chocolate about 7 mg [59]. Caffeine stimulates heart contraction and rate, dilates blood vessels by relaxing smooth muscles, increases the secretion of catecholamine, increases diuresis, enhances alertness, and decreases drowsiness and fatigue. It is able to cross the blood-testicular barrier and it is found in the same concentrations in blood and semen [60]. For these reasons, its effects on reproductive function have been investigated.
2.1. Effects on Testosterone Production
2.2. Effects on Spermatogenesis
5. Cannabis
Extract from Cannabis sativa, commonly referred to as marijuana, is the most widely used illegal drug in many countries. The major psychoactive substance contained in cannabis, ∆9-tetrahydrocannabinol (THC), is able to interact with cannabinoid receptors CB1 and CB2, belonging to the superfamily of G-protein coupled receptors. In humans, CB1 is localized in the nervous system and other tissues, including the reproductive system (ovary, uterine endometrium in women, testis, and vas deferens in men), while CB2 is found predominantly in immune cells but also in Sertoli cells [70]. The endogenous ligands for cannabinoid receptors are the endocannabinoids produced and released on-demand by neurons and peripheral cells. The main endocannabinoids are anandamide and 2-arachidonoylglycerol [71]. The endocannabinoid system is involved in the regulation of reproductive function [72]. For these reasons, the effects of cannabis on male reproductive function have been investigated for almost 50 years, leading to contrasting results.
2.1. Effects on Testosterone Production
2.2. Effects on Spermatogenesis
6. Cocaine
Cocaine is an alkaloid obtained from the leaves of many species of the Erythroxylaceae family. It is a powerful local anesthetic, it alters thermoregulation and exerts stimulating effects on the cardiovascular system, central and peripheral nervous system [91]. Cocaine abuse and dependence are very frequent, especially in Western countries. However, the relationship between cocaine intake and male reproductive function has not been extensively studied. In the infertile male population, a low prevalence of cocaine use (<1%) has been reported, but men consuming cocaine are more likely to use other illicit drugs and substances (e.g., alcohol, tobacco) which may negatively impact their reproductive function [92].
2.1. Effects on Testosterone Production
2.2. Effects on Spermatogenesis
7. Amphetamine, Methamphetamine, and MDMA (Ecstasy)
Amphetamine is a drug derived from phenethylamine with the addition of an α-methyl group that protects it against metabolism by monoamine oxidase. It stimulates the release of monoamines (i.e., dopamine and noradrenaline) in the central nervous system and it has been used since the 1930s in the treatment of psychiatric disorders [104]. It is still employed in the U.S. and in some European countries in the management of Attention-Deficit/Hyperactivity Disorder (ADHD); however, for its euphoric and stimulant effects, it is also taken for recreational purposes. Methamphetamine is obtained from the methylation of amphetamine which confers it greater psychostimulant activity. It is also known with the street names Speed and Meth Crystal and it is often abused for recreational purposes. 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as Ecstasy, is a synthetic amphetamine, with serotonin and dopamine-releasing properties. It has several stimulating and inhibiting effects on the central and peripheral nervous systems (i.e., euphoria, increased energy, insomnia, enhanced sensory perception; attention and memory deficit, reduction of psychomotor speed and executive cognitive function); furthermore, it alters circadian rhythms and thermoregulation, causing hyperthermia. It is the entactogen molecule par excellence since it is able to produce feelings of empathy [105]. Amphetamines have demonstrated, in experimental settings, several effects on testicular function, as summarized below. However, studies on humans are not available.
2.1. Effects on Testosterone Production
2.2. Effects on Spermatogenesis
8. Opioids
Opioids are derived from opium, extracted from the seed pod of the opium poppy (Papaver somniferum). They include opium alkaloids, such as morphine, and synthetic derivatives, such as codeine and heroin. They have the ability to bind with three main classes of receptors - mu (µ), delta (δ), and kappa (κ) - belonging to the superfamily of G-protein coupled receptors, which usually interact with three major classes of endogenous opioid peptides (endorphins, enkephalins, and dynorphins) [120]. The endogenous opioids are physiologically implicated in the regulation of several functions: motor, immune, gastrointestinal, cardiovascular, neuroendocrine, cognitive, and, more notoriously, nociceptive function. Opioid analgesics, such as oxycodone, hydrocodone, propoxyphene, fentanyl, and methadone are frequently prescribed in muscular-skeletal and rheumatological conditions because they are effective in reducing pain, inexpensive and long-lasting. However, their potential risk for addiction is well known [120]. Opioid receptor antagonists, such as naloxone and naltrexone, are clinically used to reverse the effects of opioid overdose. The inhibitory effects of opioids on testosterone production are widely known; while effects on spermatogenesis are still controversial.
2.1. Effects on Testosterone Production
2.2. Effects on Spermatogenesis
9. Anabolic-Androgenic Steroids
Anabolic-androgenic steroids (AAS) are the most used drugs by athletes, amateur sportsmen, and bodybuilders all over the world to improve sports performance and/or physical appearance. The global lifetime prevalence rate of their use is 6.4% for males [142]. At least 30 different AAS exist, including testosterone, its 17α-alkyl-derivates (e.g., oxandrolone, stanozolol), its 17β-ester-derivates (e.g., nandrolone, testosterone esters), and its precursors (androstenedione, dehydroepiandrosterone) [143]. The detrimental effect of AAS on endogenous androgens production and spermatogenesis is widely known and below summarized.
2.1. Effects on Testosterone Production
2.2. Effects on Spermatogenesis
10. Conclusions
Surely, substance abuse can contribute to the increased prevalence of hypogonadism observed in Western countries. However, not all abused drugs have a significant negative impact on testicular function.
A low-moderate alcohol intake would seem not to impair reproductive function [22]. Conversely, in heavy drinkers and alcoholic men, both testosterone production and spermatogenesis are altered with multiple mechanisms. Alcohol inhibits some stages of steroidogenesis, increases the conversion of testosterone in estradiol inducing the enzyme aromatase, suppresses β-LH gene expression and protein release from the pituitary gland, and inhibits hypothalamic GnRH secretion through the increase in β-endorphin-like peptides [9–11,14,15]. Furthermore, it has been demonstrated that alcohol induces testicular atrophy and histological regressive changes enhance the production of ROS and reduces the anti-oxidant testicular defenses [8,10,29].
Regarding tobacco, it has been demonstrated that both cigarette smoke extract and nicotine increase apoptotic markers in sperm [52,53]. Indeed, four meta-analyses have confirmed that smoking is a risk factor for oligozoospermia [44,49–51]. Testicular damage is probably due to smoke-induced oxidative stress, but also a neuroendocrine mechanism of nicotine has been hypothesized [31]. Conversely, tobacco does not decrease testosterone levels in men; rather, it would seem to increase androgen concentrations with mechanisms not entirely clear [43].
Caffeine would not seem to reduce testosterone production nor spermatogenesis in men, even if the pro-oxidant effect has been described for very elevated dosage [69].
Despite animal studies showed a decreased testosterone production after exposition to cannabis, a clear relationship between marijuana use and hypogonadism has not been found in men. However, marijuana users have worse sperm parameters, including sperm total count and concentration, compared to controls in most studies [80].
Data about cocaine are few and contrasting. Overall, cocaine abuse seems not to reduce testosterone levels. However, an odds ratio of 2.1 of having low sperm concentration has been found in cocaine abusers [101]. Some Authors found histological regressive changes and apoptotic markers in both germ and Sertoli cells in rats treated with cocaine [91].
Data about the effects of amphetamines on human testicular function are lacking and those on animals are contrasting. Amphetamine, methamphetamine, and MDMA caused variably positive, negative, and no effects on testosterone concentrations in rats [109,110,113]. Regarding spermatogenesis, amphetamines induce apoptosis in murine testicular germ cells [114]. Oxidative stress, overproduction of serotonin and GABA, thermic rise, and decreased expression of progesterone and estradiol receptors in testis have been called into question in the pathogenesis of testicular damage [111,116,119].
Opioids intake is a known cause of hypogonadotropic hypogonadism. Indeed, opioids are able to suppress the hypothalamic-pituitary-gonadal axis, with variable grade and intensity depending on the type of compound [120]. The effects on spermatogenesis are less clear. Only one study showed a higher prevalence of oligozoospermia in opium-addicted males [128]. In rats, histological changes increased apoptosis, and oxidative stress has been described [137].
The inhibitory effects of AAS on testosterone production and spermatogenesis are also widely known. Anabolic-androgenic steroids exert negative feedback on both the pituitary gland and hypothalamus, suppressing the release of gonadotropins and testosterone [143]. Testicular volume decreases and sperm production, no longer supported by adequate intratubular testosterone concentration, drop. These effects are usually reversible, even if a complete recovery of the axis can take more than one year. However, incomplete normalization of testosterone levels and sperm production following AAS withdrawal have also been described [148].
The main mechanisms by which substance abuse interferes with testosterone production and spermatogenesis are summarized in Figure 1 and in Table 1.
*The effect of the concomitant abuse of more than one of the substances is unpredictable but often additive. Substance withdrawal in most cases leads to the resolution of hypogonadism. Indeed, during the evaluation of the patient referring for hypogonadism, investigating the use of illicit drugs and legal substances such as tobacco and alcohol is mandatory. Especially in younger men, when no organic causes of hypogonadism are detectable, substance abuse must be suspected and, eventually, the withdrawal must be recommended.
Progressive deterioration of male reproductive function is occurring in Western countries. Environmental factors and unhealthy lifestyles have been implicated in the decline of testosterone levels and sperm production observed in the last fifty years. Among unhealthy lifestyles, substance and drug abuse is a recognized cause of possible alterations of steroidogenesis and spermatogenesis. Alcohol, opioids, and anabolic-androgenic steroids are capable to reduce testosterone production in males interfering with testicular and/or hypothalamic-pituitary function. Other substances such as nicotine, cannabis, and amphetamines alter spermatogenesis inducing oxidative stress and subsequent apoptosis in testicular tissue. Substance and drug abuse is a potentially reversible cause of hypogonadism, defined as the failure of the testis to produce physiological concentrations of testosterone and/or a normal number of spermatozoa. The identification of the abuse is important because the withdrawal of substance intake can reverse the clinical syndrome. This review summarizes the most important clinical and experimental evidence on the effect of substance abuse on testosterone and sperm production.
1. Introduction
According to the most recent definition, hypogonadism is a clinical syndrome resulting from the failure of the testis to produce physiological concentrations of testosterone and/or a normal number of spermatozoa due to pathologies of the hypothalamic-pituitary-testicular axis [1].
Testosterone concentrations, impairment of spermatogenesis, and elevated gonadotropin levels, defined as primary hypogonadism. Otherwise, secondary hypogonadism is caused by a dysfunction of the hypothalamus-pituitary unit, resulting in low testosterone concentrations, impairment of spermatogenesis, and low or inappropriately normal gonadotropin levels [1]. Hypogonadism is defined as organic when a congenital, structural, or destructive disorder results in a permanent dysfunction, and functional when potentially reversible conditions suppress temporarily gonadotropin and/or testosterone production [1].
*Symptoms and signs suggestive of testosterone deficiency include reduced libido and sexual activity, decreased spontaneous erections, erectile dysfunction, gynecomastia, infertility, osteopenia/osteoporosis, hot flushes, and sweats. Other non-specific symptoms, such as fatigue, depressed mood, poor concentration, and memory, sleep disturbance, reduced muscle mass and strength, increased body fat and body mass index [1], although not decisive for defining the diagnosis, are important from a clinical point of view because they have a great impact on the quality of life of hypogonadal patients.
Factors that could contribute to the worsening of testicular function in Western countries include the progressive increase in visceral adiposity among the population, changes in lifestyle and behaviors, environmental pollution, and exposure to endocrine-disrupting compounds (i.e., phthalates) [5]. Among unhealthy behaviors, alcohol abuse, cigarette smoking, excessive caffeine intake, illicit drug intake, opioid consumption and inappropriate use of anabolic steroids have been studied as a possible cause of reduced sperm production and/or reduced testosterone levels in hypogonadal men [6].
In our review, we summarized the most important clinical and experimental evidence on the effect of substance abuse on testosterone and sperm production For many of the substances examined most of the evidence comes from in vivo and in vitro animal studies or from retrospective human studies. Indeed, for ethical reasons, no intervention studies on humans can be performed. Unfortunately, data obtained in animals are not always reproducible in humans; so some aspects regarding the mechanisms of action of several substances on the reproductive function must be further clarified.
2. Alcohol
Since ancient times the consumption of alcoholic beverages has been part of the socio-cultural heritage of most populations. However, chronic and acute alcohol abuse is involved in the pathogenesis of many diseases, including liver diseases, cancers, cardiovascular disease, and neuropsychiatric disorders. The effects of alcohol intake on male reproductive function have also been evaluated, in vitro and in vivo. Both testosterone production and spermatogenesis seem to be affected by alcohol abuse.
2.1. Effects on Testosterone Production
2.2. Effects on Spermatogenesis
3. Cigarette Smoking
Even more than alcohol, cigarette smoking is recognized as a risk factor for many diseases: cardiovascular diseases, lung diseases, malignant neoplasms, etc. Since the 1980s, scientific literature has been interested in evaluating the effects of cigarette smoking on reproductive function. Tobacco smoke is a complex mixture of over 8,700 substances. Harmful cigarette smoke constituents include carbon monoxide, nitrogen oxide, ammonia, heavy metals, various polycyclic aromatic hydrocarbons, and aldehydes, such as hydroquinone, catechol, acrolein, crotonaldehyde, and formaldehyde [30]. Recently, even nicotine, the major psychoactive substance in cigarette smoke, has been called into question in the pathogenesis of smoker's sperm alterations with a possible neuroendocrine mechanism [31]. Indeed, it has been demonstrated that nicotine and its metabolites are capable to cross the blood-testis barrier [32].
2.1. Effects on Testosterone Production
2.2. Effects on Spermatogenesis
4. Caffeine
Caffeine is a methylated xanthine, structurally similar to purine and uric acid, present in coffee, tea, soft drinks, and chocolate. One cup of coffee contains about 137 mg of caffeine, a cup of tea 47 mg, a bottle or can of caffeinated soft drinks (i.e., cola) about 46 mg, a serving of chocolate about 7 mg [59]. Caffeine stimulates heart contraction and rate, dilates blood vessels by relaxing smooth muscles, increases the secretion of catecholamine, increases diuresis, enhances alertness, and decreases drowsiness and fatigue. It is able to cross the blood-testicular barrier and it is found in the same concentrations in blood and semen [60]. For these reasons, its effects on reproductive function have been investigated.
2.1. Effects on Testosterone Production
2.2. Effects on Spermatogenesis
5. Cannabis
Extract from Cannabis sativa, commonly referred to as marijuana, is the most widely used illegal drug in many countries. The major psychoactive substance contained in cannabis, ∆9-tetrahydrocannabinol (THC), is able to interact with cannabinoid receptors CB1 and CB2, belonging to the superfamily of G-protein coupled receptors. In humans, CB1 is localized in the nervous system and other tissues, including the reproductive system (ovary, uterine endometrium in women, testis, and vas deferens in men), while CB2 is found predominantly in immune cells but also in Sertoli cells [70]. The endogenous ligands for cannabinoid receptors are the endocannabinoids produced and released on-demand by neurons and peripheral cells. The main endocannabinoids are anandamide and 2-arachidonoylglycerol [71]. The endocannabinoid system is involved in the regulation of reproductive function [72]. For these reasons, the effects of cannabis on male reproductive function have been investigated for almost 50 years, leading to contrasting results.
2.1. Effects on Testosterone Production
2.2. Effects on Spermatogenesis
6. Cocaine
Cocaine is an alkaloid obtained from the leaves of many species of the Erythroxylaceae family. It is a powerful local anesthetic, it alters thermoregulation and exerts stimulating effects on the cardiovascular system, central and peripheral nervous system [91]. Cocaine abuse and dependence are very frequent, especially in Western countries. However, the relationship between cocaine intake and male reproductive function has not been extensively studied. In the infertile male population, a low prevalence of cocaine use (<1%) has been reported, but men consuming cocaine are more likely to use other illicit drugs and substances (e.g., alcohol, tobacco) which may negatively impact their reproductive function [92].
2.1. Effects on Testosterone Production
2.2. Effects on Spermatogenesis
7. Amphetamine, Methamphetamine, and MDMA (Ecstasy)
Amphetamine is a drug derived from phenethylamine with the addition of an α-methyl group that protects it against metabolism by monoamine oxidase. It stimulates the release of monoamines (i.e., dopamine and noradrenaline) in the central nervous system and it has been used since the 1930s in the treatment of psychiatric disorders [104]. It is still employed in the U.S. and in some European countries in the management of Attention-Deficit/Hyperactivity Disorder (ADHD); however, for its euphoric and stimulant effects, it is also taken for recreational purposes. Methamphetamine is obtained from the methylation of amphetamine which confers it greater psychostimulant activity. It is also known with the street names Speed and Meth Crystal and it is often abused for recreational purposes. 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as Ecstasy, is a synthetic amphetamine, with serotonin and dopamine-releasing properties. It has several stimulating and inhibiting effects on the central and peripheral nervous systems (i.e., euphoria, increased energy, insomnia, enhanced sensory perception; attention and memory deficit, reduction of psychomotor speed and executive cognitive function); furthermore, it alters circadian rhythms and thermoregulation, causing hyperthermia. It is the entactogen molecule par excellence since it is able to produce feelings of empathy [105]. Amphetamines have demonstrated, in experimental settings, several effects on testicular function, as summarized below. However, studies on humans are not available.
2.1. Effects on Testosterone Production
2.2. Effects on Spermatogenesis
8. Opioids
Opioids are derived from opium, extracted from the seed pod of the opium poppy (Papaver somniferum). They include opium alkaloids, such as morphine, and synthetic derivatives, such as codeine and heroin. They have the ability to bind with three main classes of receptors - mu (µ), delta (δ), and kappa (κ) - belonging to the superfamily of G-protein coupled receptors, which usually interact with three major classes of endogenous opioid peptides (endorphins, enkephalins, and dynorphins) [120]. The endogenous opioids are physiologically implicated in the regulation of several functions: motor, immune, gastrointestinal, cardiovascular, neuroendocrine, cognitive, and, more notoriously, nociceptive function. Opioid analgesics, such as oxycodone, hydrocodone, propoxyphene, fentanyl, and methadone are frequently prescribed in muscular-skeletal and rheumatological conditions because they are effective in reducing pain, inexpensive and long-lasting. However, their potential risk for addiction is well known [120]. Opioid receptor antagonists, such as naloxone and naltrexone, are clinically used to reverse the effects of opioid overdose. The inhibitory effects of opioids on testosterone production are widely known; while effects on spermatogenesis are still controversial.
2.1. Effects on Testosterone Production
2.2. Effects on Spermatogenesis
9. Anabolic-Androgenic Steroids
Anabolic-androgenic steroids (AAS) are the most used drugs by athletes, amateur sportsmen, and bodybuilders all over the world to improve sports performance and/or physical appearance. The global lifetime prevalence rate of their use is 6.4% for males [142]. At least 30 different AAS exist, including testosterone, its 17α-alkyl-derivates (e.g., oxandrolone, stanozolol), its 17β-ester-derivates (e.g., nandrolone, testosterone esters), and its precursors (androstenedione, dehydroepiandrosterone) [143]. The detrimental effect of AAS on endogenous androgens production and spermatogenesis is widely known and below summarized.
2.1. Effects on Testosterone Production
2.2. Effects on Spermatogenesis
10. Conclusions
Surely, substance abuse can contribute to the increased prevalence of hypogonadism observed in Western countries. However, not all abused drugs have a significant negative impact on testicular function.
A low-moderate alcohol intake would seem not to impair reproductive function [22]. Conversely, in heavy drinkers and alcoholic men, both testosterone production and spermatogenesis are altered with multiple mechanisms. Alcohol inhibits some stages of steroidogenesis, increases the conversion of testosterone in estradiol inducing the enzyme aromatase, suppresses β-LH gene expression and protein release from the pituitary gland, and inhibits hypothalamic GnRH secretion through the increase in β-endorphin-like peptides [9–11,14,15]. Furthermore, it has been demonstrated that alcohol induces testicular atrophy and histological regressive changes enhance the production of ROS and reduces the anti-oxidant testicular defenses [8,10,29].
Regarding tobacco, it has been demonstrated that both cigarette smoke extract and nicotine increase apoptotic markers in sperm [52,53]. Indeed, four meta-analyses have confirmed that smoking is a risk factor for oligozoospermia [44,49–51]. Testicular damage is probably due to smoke-induced oxidative stress, but also a neuroendocrine mechanism of nicotine has been hypothesized [31]. Conversely, tobacco does not decrease testosterone levels in men; rather, it would seem to increase androgen concentrations with mechanisms not entirely clear [43].
Caffeine would not seem to reduce testosterone production nor spermatogenesis in men, even if the pro-oxidant effect has been described for very elevated dosage [69].
Despite animal studies showed a decreased testosterone production after exposition to cannabis, a clear relationship between marijuana use and hypogonadism has not been found in men. However, marijuana users have worse sperm parameters, including sperm total count and concentration, compared to controls in most studies [80].
Data about cocaine are few and contrasting. Overall, cocaine abuse seems not to reduce testosterone levels. However, an odds ratio of 2.1 of having low sperm concentration has been found in cocaine abusers [101]. Some Authors found histological regressive changes and apoptotic markers in both germ and Sertoli cells in rats treated with cocaine [91].
Data about the effects of amphetamines on human testicular function are lacking and those on animals are contrasting. Amphetamine, methamphetamine, and MDMA caused variably positive, negative, and no effects on testosterone concentrations in rats [109,110,113]. Regarding spermatogenesis, amphetamines induce apoptosis in murine testicular germ cells [114]. Oxidative stress, overproduction of serotonin and GABA, thermic rise, and decreased expression of progesterone and estradiol receptors in testis have been called into question in the pathogenesis of testicular damage [111,116,119].
Opioids intake is a known cause of hypogonadotropic hypogonadism. Indeed, opioids are able to suppress the hypothalamic-pituitary-gonadal axis, with variable grade and intensity depending on the type of compound [120]. The effects on spermatogenesis are less clear. Only one study showed a higher prevalence of oligozoospermia in opium-addicted males [128]. In rats, histological changes increased apoptosis, and oxidative stress has been described [137].
The inhibitory effects of AAS on testosterone production and spermatogenesis are also widely known. Anabolic-androgenic steroids exert negative feedback on both the pituitary gland and hypothalamus, suppressing the release of gonadotropins and testosterone [143]. Testicular volume decreases and sperm production, no longer supported by adequate intratubular testosterone concentration, drop. These effects are usually reversible, even if a complete recovery of the axis can take more than one year. However, incomplete normalization of testosterone levels and sperm production following AAS withdrawal have also been described [148].
The main mechanisms by which substance abuse interferes with testosterone production and spermatogenesis are summarized in Figure 1 and in Table 1.
*The effect of the concomitant abuse of more than one of the substances is unpredictable but often additive. Substance withdrawal in most cases leads to the resolution of hypogonadism. Indeed, during the evaluation of the patient referring for hypogonadism, investigating the use of illicit drugs and legal substances such as tobacco and alcohol is mandatory. Especially in younger men, when no organic causes of hypogonadism are detectable, substance abuse must be suspected and, eventually, the withdrawal must be recommended.
