Psychological and Behavioural Effects of Endogenous Testosterone Levels and Anabolic-Androgenic Steroids Among Males: A Review


by Michael S. Bahrke, Charles E. Yesalis III, and James E. Wright

Taken from: mesomorphosis.com

Summary

1. History of Anabolic-Androgenic Steroid Use in Competitive Sports and Medicine
2. Potential Mechanisms for Some Anabolic-Androgenic Steroid Effects on the Nervous System
3. Plasma Testosterone Levels and Aggression

3.1 Testosterone and Aggression in Animals
3.2 Testosterone, Mood and Aggression in Humans

3.2.1 Testosterone Levels and Aggression in Adolescents and Young Athletes
3.2.2 Testosterone and Mood in Adult Males
3.2.3 Testosterone Levels and Aggression in Prisoners

3.3 Relationship of Testosterone to Moods Other Than Aggression
3.4 Testosterone Levels and Stress

4. Anabolic Steroid Therapy and Moods
5. Steroids and Mental Health
6. Anabolic Steroids, Athletes and Behaviour
7. Psychological Dependence and Withdrawal Effects of Anabolic Steroids
8. Prevention and Treatment of Anabolic-Androgenic Steroid Abuse
9. Discussion of Major Methodological Issues

9.1 Sample Selection and Size
9.2 Control Subjects
9.3 Steroids Investigated
9.4 Assessing Aggression and Aggressive Behaviour
9.5 Psychological Inventories
9.6 Self-Reported vs Observed Alterations in Behaviour

10. Conclusions

Summary

The psychological and behavioural effects of endogenous testosterone levels and anabolic-androgenic steroids in males have been investigated for over 50 years in both clinical and nonmedical uses, including the influence of anabolic-androgenic steroids on the nervous system and neuromuscular expression as a mechanism for behavioural and ergogenic effects. The relationship between moods, behaviour and endogenous plasma testosterone levels, as well as anabolic steroids and corticosteroid administration has been studied, including psychological dependence, withdrawal effects, and major methodological issues. While a relationship between endogeous testosterone levels and aggressive behaviour has been observed in various animal species, it is less consistent in humans. It can be concluded that, although the use of exogenous anabolic-androgenic steroids may have psychological and behavioural effects in some patients and athletes, the effects are variable, transient upon discontinuation of the drugs, and appear to be related to type (17a -alkalated rather than 17b -esterified), but not dose, of anabolic-androgenic steroids administered. The roles of genetic factors, medical history, environmental and peer influences, and individual expectations are likewise unclear. In general, the evidence at present is limited and much additional research will be necessary for a complete understanding of this relationship.

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More than 500 steroidal substances have been identified in human/mammalian/vertebrate tissues (Kochakian 1990). There are 5 major groups of steroids produced in mammals, which are generally recognised on the basis of their physiological actions: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestins. These classes of hormones are structurally similar and arise from a common series of pathways. They are distinguished by their actions on one or more specific steroid hormone receptors. The hormone-receptor complexes function as tissue-specific transcriptional regulators of distinct domains of genes and, consequently, exert their broad array of effects.

The most potent sex steroid produced in human males is testosterone. Testosterone has been chemically characterised (David et al. 1935; Ruzicka & Wettstein 1935) and more than 100 derivatives synthesized (Potts et al. 1976; Vida 1969), some of which have found uses in human and veterinary medicine, animal husbandry, and most recently, in athletics. Virtually all cells in the body are potential targets for these steroids. Furthermore, since all steroids exert their effects in the same above-mentioned manner, anabolism (tissue building) differs from androgenicity (masculinising) only in location (which differ in number of receptors and steroid metabolising enzymes) and not in essence (Kruskemper 1968). A purely anabolic steroid has not been found and, therefore, Kochakian (1976) suggests that the appropriate nomenclature should refer to anabolic-androgenic steroids, a recommendation that will be adhered to in this review.

Anabolic-androgenic steroids promote tissue growth by stimulating the synthesis and retarding catabolism of protein (Kochakian 1976; Kruskemper 1968; Overbeek & deVisser 1961). When administered to experienced athletes engaged in a vigorous training programme, therapeutic doses of anabolic-androgenic steroids promote small but significant increases in strength and lean body mass relative to those that would occur from training alone (American College of Sports Medicine 1984; Haupt & Rovere 1984; Wright 1980).

The psychological and behavioural aspects of maleness were noted by Aristotle prior to 300 BC and were studied in numerous uncontrolled experiments up through the 1800s, which sought to demonstrate that the testes contained substances which produced and maintained vitality, strength, energy and youthfulness (Brown-Sequard 1889). The effects of purified sex hormones, including those on mood and mental disorders, began to be experimentally and clinically explored more intensively a half century ago when commercial preparations became available (Miller et al. 1938; Salmon & Geist 1943; Samuels et al. 1942; Vest & Howard 1938). Since that time, a number of literature reviews have reported on these and other effects (Choi et al. 1989; Haupts & Rovere 1984; Hickson et al. 1989; Kochakian 1976; Kopera 1985; Kruskemper 1968; Lamb 1984; Taylor 1982; Wilson 1988; Wilson & Griffin 1980; Wright 1978, 1980; Wright & Stone 1985).

Testosterone preparations were rather widely and successfully used in the treatment of involutional psychoses, melancholia and depression for many years (Altschule & Tillotson 1948; Ault 1937; Beumont et al. 1972; Burnett 1963; Dnaziger & Blank 1942; Guirdham 1940; Hamilton 1937; Heller & Myers 1944; Itil 1976; MacMaster & Alamin 1963; Sansoy et al. 1971; Tec 1974; Thomas & Hill 1940; Vogel et al. 1985; Werner 1939, 1943; Werner et al. 1934; Wynn & Landon 1961). However, in contrast to these earlier findings, more recent focused clinical reports have suggested that affective and psychotic syndromes, some of violent proportions, may be associated with the use of anabolic-androgenic steroids in particular individuals (Annitto & Layman 1980; Choi et al. 1989; Conacher & Workman 1989; Freinhar & Alvarez 1985; Katz & Pope 1990; Pope & Katz 1987, 1988, 1990).

Several cases have recently been reported (Coacher & Workman 1989; Editorial 1988b,c,d,e; Lubell 1989; Maryland v. Michael D. Williams 1986; Moss 1988) wherein presumed psychological and behavioural effects of anabolic-androgenic steroids are alleged by defendants to have significantly influenced the commission of criminal acts. This legal strategy has been identified in the popular press as the ‘dumbbell defense’ (Editorial 1988c). The purported behavioural effects of anabolic-androgenic steroids, the consequent legislative impact and educational requirements, and the growing number of competitive and recreational athletes of both sexes and virtually all ages using anabolic-androgenic steroids (Anderson & McKeag 1985, 1989; Buckley et al. 1988; Burkett & Falduto 1984; Dezelsky et al. 1985; Frankle et al. 1984; Government Accounting Office 1989; Moore 1988; Newman 1986; Pope et al. 1988; Yesalis 1989; Yesalis & Friedl 1988; Yesalis et al. 1988, 1990a), dictate the need for a comprehensive and critical review of the relevant literature.

The purposes of this paper are to review: (a) selected aspects of the history and prevalence of anabolic-androgenic steroid use in competitive sports; (b) some effects of androgens on the central and peripheral nervous system; (c) the relationship between endogenous plasma testosterone levels and mood and behaviour in normal males and in prisoner populations; (d) the effects of the clinical use of anabolic-androgenic steroids on mood and behaviour in hypogonadal males and depressed patients; (e) the relationship of anabolic-androgenic steroid use to aggression and mental health in athletes, including issues of psychological dependence and withdrawal; and (f) the major relationship between anabolic-androgenic steroid administration, mood and behaviour.

1. History of Anabolic-Androgenic Steroid Use in Competitive Sports and Medicine

The primary use of anabolic-androgenic steroids is in replacement therapy for male hypogonadism; other medical uses of anabolic-androgenic steroids include growth promotion in various forms of stunted growth, osteoporosis, mammary carcinoma, anaemias and hereditary angioneurotic oedema. Observation and clinical trials indicate that adjuvant therapy with anabolic-androgenic steroids can be supportive in the treatment of conditions characterised by a negative nitrogen balance: major surgery, cachexia of various origins, burns, traumata, convalescence from illness, injuries and immobilisations, as well as during radiotherapy and therapy with cytotoxic drugs (Kochakian 1976; Kopera 1976, 1985; Kruskemper 1968). Unfortunately, research concerning additional legitimate applications of anabolic-androgenic steroids has most likely been impeded by the existing emotional polarisation of anabolic-androgenic steroid supporters and opponents. As Kochakian (1990) has pointed out, the frequent and often hysterical references in the popular press to unsubstantiated adverse effects of anabolic-androgenic steroids has often resulted in the loss of both media and medical/scientific credibility, deterring research on beneficial and legitimate medical uses, and as a stimulus and encouragement for litigation against physicians.

The use of various physical and chemical aids in performance enhancement is not a novel problem but has been a feature of athletic competition since the beginning of recorded history (Csaky 1972; Strauss & Curry 1987). Ancient Greeks ate sesame seeds, bufotenin was used by the legendary berserkers in Norwegian mythology, and the Andean Indians and the Australian aborigines chewed, respectively, coca leaves and the pituri plant for stimulating and antifatiguing effects (Csaky 1972; Williams 1974). Anabolic steroids have been used by athletes to enhance appearance and performance for many years. The first ergogenic use of anabolic-androgenic steroids was reported to have occurred in the 1950s among weightlifters and bodybuilders (Wright 1978). Since that time their use has permeated a myriad of sports (Anderson & McKeag 1985, 1989; Buckley et al. 1988; Gilbert 1969; Starr 1981; Todd 1987; Wade 1972; Yesalis et al. 1990a). Payne (1979) suggested that the use of anabolic-androgenic steroids was a significant problem at the 1964 Olympic Games. Ljungqvist (1975) reported that one-third of a sample of elite track and field athletes in Sweden; surveyed admitted to systematic anabolic-androgenic steroid use by 1972. Silvester (1973) reported that 68% of a sample interviewed at the 1972 Olympic Games from 7 countries, and who were competing in such diverse activities as throwing, jumping, vaulting, sprinting, and running up to 5000m, admitted having used anabolic-androgenic steroids. Although it was suggested as early as 1973 (Frazier 1973) and reiterated later (Wright 1978, 1980, 1982), it is now evident that the use of anabolic-androgenic steroids is not limited to elite amateur and professional athletes. It has trickled down from the professional and college levels to the high schools and junior high schools (Buckley et al. 1988; Yesalis et al. 1989a, 1990a). The estimated prevalence of nonmedical anabolic-androgenic steroid use and the implications for society and public health have also prompted several scientific meetings, including a technical review at the National Institute on Drug Abuse in 1989, and both federal and state investigations and efforts to reclassify anabolic-androgenic steroids as controlled substances (Government Accounting Office 1989; Halligan et al. 1989; Taylor 1987a,b; Yesalis 1989; Yesalis et al. 1990a) despite nonconcurrence from the American Medical Association (AMA 1989).

Patterns of anabolic-androgenic steroid use among athletes have been determined from several surveys. Burkett and Falduto (1984) interviewed 24 weight-training athletes at a gymnasium in a metropolitan area of the southwestern United States. Subjects surveyed took a combined steroid does of 4 to 8 times the recommended medical does, used more than one anabolic-androgenic steroid at a time (‘stacking’), combined use of injectable and oral anabolic-androgenic steroids, and used the drugs frequently, usually in cycles (an episode of use from 6 to 12 weeks or more). Although Burkett and Falduto questioned a very specific sample of anabolic-androgenic steroid users, they concluded that their subjects seemed to be representative of the type of athletes who used anabolic-androgenic steroids. Cohen et al. (1988), in a study of hypercholesterolaemia in 21 male powerlifters using various anabolic-androgenic steroids, reported significantly higher levels of anabolic-androgenic steroid use in their subjects than Burkett and Falduto (1984), with daily dosages ranging from 60 to 400mg. Pope and Katz (1988) have also reported daily dosages between 10 and 200mg (of various anabolic-androgenic steroids) for anabolic-androgenic steroid users in their investigation of affective and psychotic symptoms associated with anabolic-androgenic steroid use.

Frankle et al. (1984) found that 110 of 250 weightlifters they interviewed in several gymnasia in the metropolitan Chicago area, many of whom were noncompetitive lifters, also used a variety of anabolic-androgenic steroids. 50 weightlifters were interviewed in detail; a majority (56%) had no competitive intents in weightlifting, bodybuilding or any other athletic events, a proportion that substantially exceeds that found by Buckley et al. (1988) in a nation-wide survey of male high school seniors. Frankle et al. (1984) concluded that anabolic-androgenic steroid abuse had reached alarming proportions in noncompetitive athletes.

The Buckley et al. (1988) survey suggests that one-quarter to one-half million adolescents in the United States have used or are currently using anabolic-androgenic steroids. Anderson and McKeag (1985) reporting on a nation-wide survey of alcohol and drug use among college athletes indicated that anabolic-androgenic steroids were used in all men’s sports, one women’s sport, and that the sport with the greatest admitted use (9%) was football. The overall anabolic-androgenic steroid use rate in all sports nationally was 4%. Anderson and McKeag (1989) replicated their original study 4 years later and although they found that overall use rates for anabolic-androgenic steroids had remained stable, anabolic-androgenic steroids were now being used in 2 additional women’s sports. A survey and follow-up telephone interview by Yesalis et al. (1988) following the 1987 US Powerlifting Federations’ National Championship found 33% of the initial respondents and 55% in a follow-up subsurvey of the same group, admitting previous anabolic-androgenic steroid use. Since athletes may have a propensity to underreport of disguise their actual anabolic-androgenic steroid use for various reasons, caution must be used when interpreting values concerning the prevalence of anabolic-androgenic steroid use by athletes.

2. Potential Mechanisms for Some Anabolic-Androgenic Steroid Effects on the Nervous System

Anabolic-androgenic steroids have been shown to exert significant effects on both the development and functioning of the nervous system. Androgens were shown to act directly on the brain long ago (Phoenix et al. 1959). These authors suggested that during early development androgens acted to organise neural pathways involved in male behaviours, while during adulthood they acted on differentiated pathways to activate previously organised behaviours. Data from studies of sexual dimorphism in animals clearly demonstrate differences in brain areas in male rats including: a much larger nucleus of the preoptic area (Gorski et al. 1978), a larger mid-portion of the medial amygdaloid nucleus (Nishizuka & Arai 1981), a greater number of motor neurons innervating the bulbocavernosus muscle (Breedlove & Arnold 1980), and a larger superior cervical ganglion (McEwen 1980). This latter testosterone-induced increase in post-ganglionic neuron number has been attributed to the ability of testosterone to increase nerve growth factor (Ishii & Shooter 1975), which in turn enhances neuronal survival (Hendry & Campbell 1976; Levi-Montalcini 1964).

In both rodents and primates androgen receptors are concentrated in the pituitary, hypothalamus, preoptic area, septum, and amygdala (McEwen 1980; Tobet et al. 1985). Androgen receptors in the brain recognise both testosterone and its 5a -reduced metabolite, 5a -dihydrotestosterone (Christensen & Gorski 1978). Many central nervous system and behavioural effects are thought to be produced by aromatisation of androgens to estradiol, which varies from region to region in the brain but is most prominent in the hippocampus, amygdala and preoptic area (McEwen 1980). The roles of aromatisation and 5a -reduction in producing the effects of testosterone in adults are, however, not well studied, particularly with regard to behaviour. Inasmuch as aromatase blockers inhibit testosterone-induced sexual behaviour in male rats (Morali et al. 1977), it seems likely that aromatisation of testosterone to estrogen plays a key role in the facilitation of male sexual behaviour.

Adult male rats eat more and are less active than females (Wade 1976). Castration reduces both eating and activity (Hoskins 1925; Kakolewski et al. 1968; Wang et al. 1925). Low doses of testosterone restore food intake while pharmacological doses reduce it further, a decrease which is blocked by progesterone as is the inhibitory effect of estradiol on feeding, suggesting that the inhibitory effect of high doses is due to aromatisation. 5a -Dihydrotestosterone, which is not aromatisable, increases food intake (Wade 1976). Estradiol, but not 5a -dihydrotestosterone, stimulates locomotion in castrated male rats (Roy & Wade 1975). Antiestrogens attenuate testosterone-induced activity while antiandrogens do not, indicating that aromatisation to estrogen is necessary for enhancement of physical activity (Stern & Murphy 1971). Both testosterone and 5a -dihydrotestosterone thus appear to be responsible for increasing feeding behaviour while aromatisation of testosterone to estrogen is required to increase activity level. Testosterone is known to affect growth hormone secretion (Martin et al. 1968) and plasma somatomedin C (Rosenfield & Furlanetto 1985). In one study of adult athletes self-administrating anabolic-androgenic steroids, but not growth hormone, levels of growth hormone were reported to be 5 to 60 times higher than normal (Alen et al. 1987). Modulation of secretion of growth-promoting, and possibly other, hormones appears to occur via endogenous opiate peptide pathways (Rogol et al. 1990; Veldhuis et al. 1984), probably as a result of the action of the estrogen metabolites of testosterone (Ho et al. 1987). The effects of synthetic anabolic-androgenic steroids, with their prolonged half-lives, and of pharmacological doses are not known, but it is apparent that they or their metabolites can bind to glucocorticoid and progesterone, as well as estrogen, receptors and thus elicit other than purely androgenic effects (Janne 1990).

Data from animal studies indicate that both estrogens and androgens act on neural structures that are identical to or closely associated with sensory pathways and the ventricular recess organs (periventricular gland) of the hypothalamus (Stumpf & Sar 1976). Androgens have been reported to selectively stimulate neurons of the somatomotor system and circuits associated with aggression (Stumpf & Sar 1976). Androgen receptors are located on µ motor neurons (Sar & Stumpf 1977), and play a role in regulating their length in adulthood (Kurz et al. 1986). Androgens also facilitate the release of acetylcholine at the neuromuscular junction of the bulbocavernosus (Vyskocil & Gutmann 1977).

Itil et al. (1974) have demonstrated quantitatively the physiological correlates of certain previously reported behavioural effects of an anabolic-androgenic steroid (mesterolone) such as an increase of mental alertness, mood elevation, improvement of memory and concentration, and reduction of sensations of fatigue, all of which can partly be related to the central nervous system (CNS) ‘stimulatory’ effects of mesterolone. Electroencephalographic profiles of varying dosages of mesterolone were found to be very similar to those seen with psychostimulants such as dextroamphetamine and the tricyclic antidepressants. Single oral doses as low as 1 mg were shown to affect brain function. Others (Broverman et al. 1968; Klaiber et al. 1967; Stenn et al. 1972) have concluded that the adrenergic-like effects of testosterone on brain function are as a result of an elevation of the brain noradrenaline (norepinephrine) level, which might be the result of the inhibition of brain monamine oxidase (MAO) activity. Further speculation indicates that the ‘heightened’ state of behavioural reactivity which facilitates the automatisation of behaviour may well be due to an increased level of brain noradrenaline.

Hannan et al. (1988) have examined plasma homovanillic acid changes following 6 weekly intramuscular injections of 100 or 300mg of testosterone enanthate or nandrolone decanoate administration in 25 males and found significant increases in homovanillic acid for both of the nandrolone but neither of the testosterone treatments. Since a large proportion of plasma homovanillic acid originates from CNS metabolism of dopamine, the demonstrated change associated with nandrolone administration confirms an anabolic-androgenic steroid-induced alteration in CNS neurotransmitter metabolism and suggests a mechanism to explain reported altered behaviour in some anabolic-androgenic steroid users. Interestingly in this regard the deletion of the 19-methyl group in nandrolone produces a more planar steroid than testosterone that thus, like 5µ -dihydrotestosterone, has altered receptor binding affinities, as well as unique metabolites. It must be added that estrogens are also known to alter central nervous system neurotransmitters through inhibition of monamine oxidase activity, so aromatisation of testosterone to estrogen could also play a role (Klaiber 1972).

Inasmuch as improvements in muscle strength and power can in part be accounted for by neural factors, including neurotransmitter levels (Hakkinen & Komi 1983; Moritani & deVries 1979), findings that androgens may in some manner modify neural and neuromuscular functions support the concept of a significant role for these mechanisms in the production of ergogenic effects (Alen et al. 1984; Brooks 1980; Hakkinen & Alen 1986; Wilson 1988).

3. Plasma Testosterone Levels and Aggression

3.1 Testosterone and Aggression in Animals

Numerous studies have shown relationships between testosterone levels, dominance, and aggressive behaviour in various species of animals (Allee et al. 1939; Barfield et al. 1972; Bouissou 1983; Bouissou & Gaudioso 1982; Hamilton 1938; Kurischko & Oettel 1977; Payne & Swanson 1973; Rose et al. 1971; Simon et al. 1985; Steklis et al. 1985; Svare 1983; van de Poll et al. 1981, 1986; Zumpe & Michael 1985) including nonhuman primates (Joslyn 1973; Rejeski et al. 1988a; Steklis et al. 1985; Zumpe & Michael 1985).

It has been argued by some reviewers that primates are less dependent on androgens for the expression of aggression than ungulates or other animals lower in the evolutionary chain (Bouissou 1983). However, Rejeski et al. (1988a) determined that intramuscular injection of testosterone propionate increased the frequency of aggressive behaviour in monkeys. 10 cynomolgus monkeys were assigned to either an experimental (n=5) or a control group (n=5) and given biweekly injections; the experimental group received testosterone propionate 4 mg/kg, and the controls a sham solution. Prior to and upon completion of an 8-week treatment period, behavioural observations (slapping, grabbing, stare threat, chasing, fleeing, etc.) were conducted. Although the administration of testosterone propionate resulted in a significant increase in aggression, more important was the finding that changes in behaviour were mediated by social status; that is, the incidence of both contact and noncontact aggression in dominant monkeys was far greater than the frequency of these behaviours in subordinate monkeys.

Joslyn (1973) has reported that injecting 3 infant female rhesus monkeys with 2mg of testosterone propionate intramuscularly 3 times per week over 8 months increased their aggressive behaviour so much so that they replaced males in top positions of the social hierarchy. Since this behaviour persisted for a year after the last hormone injection, the author suggests either that the male hormone may have directly induced a permanent change in the nervous system or alternatively that the socially dominant behaviour was so well learned during hormone treatment that it became independent of hormonal support.

Indeed, Bernstein et al. (1974) have evaluated in a series of experiments the converse of this relationship, i.e. the influence of multiple environmental and social variable upon circulating testosterone levels in the male rhesus monkey. Factors shown to significantly influence levels of circulating testosterone included among others, alterations in social rank and ‘successful’ and ‘unsuccessful’ agonistic encounters.

In general, these and other studies indicate that the level of testosterone, particularly in the prenatal period, but also during puberty and even in adulthood are important in establishing a biological readiness for normal aggressive behaviour and in facilitating the expression of aggression in ‘appropriate’ social settings in adult animals. They also indicate that both social factors and learning significantly influence the actual expression of aggression in adulthood (Rada et al. 1976a). However, the extent to which exposure to testosterone or other anabolic-androgenic steroid at any phase of the life cycle, and particularly during adulthood, is related to altered moods and feelings in humans, to the expressions of aggression in humans and even other primates, relative to animals lower in the evolutionary chain, is not well known.

3.2 Testosterone, Mood and Aggression in Humans

Relative to the animal literature, fewer studies have assessed the relationship of endogenous or exogenous androgens to aggression or violent behaviour in humans. In general, the relationship is less clear than in animal research for a variety of reasons. First, it is difficult to show that animals, possibly excluding primates, experience emotional states that are qualitatively similar to human experiences such as euphoria, depression, anger and others. Second, the effects of sex hormones vary considerably among individuals as well as species. Consequently, conclusions drawn from animal models must be applied cautiously to humans. Lastly, human subjects cannot be subjected to many of the same stringent controls and manipulations used in animal research. Nevertheless, aggressive behaviour and other feelings of hostility have been demonstrated to be related to endogenous testosterone levels in a number of studies using human subjects.

Testosterone is thought to have an activating effect on human aggressive behaviour. The action of testosterone on the central nervous system apparently contributes to the elevated aggressiveness of males compared to females. However, among males, there is the question of whether the level of testosterone reaching the brain and interacting with receptors determines the level of aggressive feelings and behaviour. Attempts to answer this question have included investigations correlating levels of testosterone with aggressive behaviour in normal and incarcerated males, studies examining men with genetic differences in testosterone production for differences in levels of aggression, and research into the effects on behaviour of administered testosterone and antiandrogenic agents.

3.2.1 Testosterone Levels and Aggression in Adolescents and Young Athletes

Susman and associates (1985, 1987a,b) have reported on the relationship between hormone levels (gonadotrophins, gonadal steroids and adrenal androgens) and emotional dispositions and aggressive attributes for young adolescents in several reports. Participants were 9- to 14-year-old boys (n=56) and girls (n=52). Assessments of physical maturation consisted of pubertal staging according to Tanner criteria and serum determinations of luteinising hormone, follicle-stimulating hormone, testosterone, estradiol, dehydroepiandrosterone, dehydroepiandrosterone sulphate, and androstenedione. The psychological measures were the Psychopathology and Emotional Tone subscales from the Offer Self-Image Questionnaire for Adolescents and interview questions to assess interactions with peers. Psychopathology and emotional tone (sad affect) scores were higher for boys with high-for-age adrenal androgens (androstenedione) and lower for boys with high-for-age sex steroids (testosterone). Behavioural manifestations of sexuality, interest in dating, was higher for boys with higher-for-age adrenal androgens. Dating and spending time with friends were higher for boys with high-for-age gonadotrophins. Psychopathology and emotional tone were higher for girls with high-for-age gonadotrophins. The results indicate that high-for-age hormone level or early timing of puberty generally was related to adverse psychological consequences for boys and girls, with relations being stronger for boys than girls. Udry et al. (1985), using self-rating questionnaires describing adolescent pubertal development, sexual motivation, and details of sexual behaviour, found that serum testosterone was a strong predictor of sexual motivation and behaviour (with no additional contribution of other hormones) in a sample of 102 boys in grades 8, 9 and 10. No such relationship, however, could be detected in healthy young adult men (Brown et al. 1978).

Olweus et al. (1980) examined serum testosterone, aggression [Olweus Multi-Faceted Aggression Inventory for boys (Olweus 1973), Olweus Q Inventory (Olweus 1975), Thurstone Temperament Schedule (Thurstone 1950)], physical characteristics (pubertal stage, height, weight, chest circumference, and physical strength) and personality dimensions [Eysenck Personality Questionnaire (Eysenck & Eysenck 1975), Situation-Oriented Questionnaires (Schalling et al. 1975), Multi-Component Anxiety Inventory (Schalling et al. 1975)] in 58 normal, healthy 16-year-old adolescent males and found a significant association between testosterone and self-reports of physical and verbal aggression (Olweus Aggression Inventory, Olweus Q Inventory) mainly reflecting responsiveness to provocation and threat. ‘Lack of frustration tolerance’ was also significantly related to testosterone levels, but several other aggressive dimensions such as antisocial behaviour and impulsiveness were not significantly correlated with testosterone.

Data from a study designed to examine the relationship between serum testosterone levels and aggressive behaviours in a noncompetitive setting using 14 varsity college male hockey players were reported by Scaramella and Brown (1978). They found a significant positive correlation between only 1 of 7 aggressive items (response to threat) on their own aggression questionnaire and serum testosterone.

While these results appear to support the hypothesis of Elias (1981) that testosterone levels fluctuate with alterations in mood, it must be noted that testosterone levels fluctuate from minute to minute in ‘normal’ individuals, with the most marked changes occurring during puberty (Doering et al. 1975). The other side of the question of the relationship of testosterone and mood and behaviour and an important consideration, is to what extent aggressive behaviour or successful ‘expression’ of aggression or nonaggressive success produce higher levels of testosterone.

3.2.2 Testosterone and Mood in Adult Males

Persky et al. (1971) determined the plasma testosterone level and testosterone production rate in a group of 18 healthy young men, 15 healthy older men, and 6 hospitalised dysphoric men. A battery of anxiety [IPAT Anxiety Scale (Cattell & Scheier 1963), Multiple Affect Adjective Check List (Zuckerman & Lubin 1965), Manifest Anxiety Scale (Dahlstron & Welsh 1960)], depression [Minnesota Multiphasic Personality Inventory (Dahlstron & Welsh 1960)] and hostility tests [Buss-Durkee Hostility Inventory (BDHI; Buss & Durkee 1957)] were administered simultaneously. In the younger men, production rate of testosterone (determined by the constant infusion method) was found to be significantly correlated with both the sum of the hostility responses (Total Hostility) of the BDHI (r=0.66) and the IPAT Anxiety Scale (r=0.52). A multivariate regression equation was obtained for testosterone production rate using 4 subscale psychological measures of aggression and hostility (BDHI Factors I and II, MAACL-H, and IPAT-Q4) which accounted for 82% of the variance in the production rate of testosterone for the younger but not the older group. In the older men, age was the primary (negative) correlate of production rate. Persky et al. (1971) suggest that aggression and age are both important but opposite correlates of testosterone production.

Brown and Davis (1975) also found a significant correlation of the BDHI subscale of irritability with plasma testosterone level in 15 healthy college males. These authors nevertheless suggested that, although testosterone may be related to feeling angry, the translation of such feelings into behaviour is highly dependent upon other factors and did not occur in any of their subjects based on self-reports of aggressive behaviour.

The association between mood (MAACL, MMPI, BDHI) and testosterone levels in 20, normal young men was also investigated by Doering et al. (1975), who found only a very weak positive relationship (r=0.415, p < 0.10) between affect (BDHI Indirect Aggression Scale) and testosterone. Houser (1979) examined the inter- and intrasubject correlations between testosterone and various measures of behaviour (reaction time, arm-hand steadiness, time estimation), affect (MAACL, Nowlis Mood Adjective Checklist, Gottschalk Verbal Anxiety Scale), and physical discomfort (Moos Menstrual Stress Questionnaire) in 5 young males over a 10-week period and found that there was a general deterioration of central nervous system motor functioning and a decrease in positive affect associated with higher testosterone levels. There was also a general decrease in the level of social and general activity associated with rising testosterone values. As the author suggests, the results of this pilot study are obviously limited by the small sample size and a large intersubject variability.

In contrast to the above studies, Meyer-Bahlburg et al. (1974) in a replication of the Persky et al. Study, with a sample of normal male undergraduate students selected on the basis of 4 BDHI subscales which constitute Buss and Durkee’s factor II, found no significant differences in the blood production rate, plasma levels, or urinary levels of androgens in 5 low-aggression and 6 high-aggression subjects. Monti et al. (1977) likewise failed to find any correlation between aggression (as measured by the BDHI or as derived from observer ratings) and the concentration of circulating testosterone in 101 healthy 20- to 30-year-old males, who displayed a wide range of both testosterone values and BDHI responses.

3.2.3 Testosterone Levels and Aggression in Prisoners

Relating testosterone levels to mood, behaviour, and psychological inventories in other populations has been somewhat easier and is no doubt responsible for the seeming consensus that testosterone levels are related to aggression in humans. In 1972, Kreuz and Rose (1972) studied levels of plasma testosterone, fighting and verbal aggression in prison, and past criminal behaviour in 21 young prisoners. Several psychological tests [BDHI, IPAT Anxiety Scale, and Marlow-Crowne Social Desirability Scale (Crowne & Marlow 1960)] were administered. Although plasma testosterone levels, measured over 2 weeks, did not differ in those classified as fighting and nonfighting individuals based upon prison records, the 10 prisoners with histories of more violent and aggressive crimes in adolescence did exhibit significantly higher levels of testosterone than the 11 prisoners without such a history. Unlike Persky et al. (1971), Kreuz and Rose found that, although there were significant correlations among psychological tests, none of the test scales (hostility, anxiety, and social desirability) correlated with plasma testosterone. Nor did any test scales correlate with fighting behaviour. Perhaps the most important contribution of the Kreuz and Rose study is the presentation of the hypothesis that within a population that is predisposed by virtue of social factors to develop antisocial behaviours, levels of testosterone may be an important additional factor (a promoter rather than an initiator) in placing individuals at risk for violent or criminal behaviour.

Ehrenkranz et al. (1974) also examined plasma testosterone levels in 36 male prisoners: 12 with chronic aggressive behaviour, 12 socially dominant without physical aggressiveness, and 12 who were neither physically aggressive nor socially dominant. Subjects were selected from the general inmate population of a large state penal institution and grouped according to the type of aggressivity of their criminal behaviour: aggravated assault and murder; nonviolent crimes such as theft, cheque passing, and drug-related felonies; and level of social dominance. Classification of subjects was based upon agreement of the study’s investigators, the senior prison psychologist, the senior prison administrator, and inmates participating in the study. Although an attempt was made to halt prisoner medications 1 week prior to the study, several subjects continued to use various types of tranquillising drugs, such as a mixture of phenothiazine and barbiturate, and benzodiazepine. A battery of psychological tests including the BDHI was also administered. Both the aggressive and the socially dominant groups had significantly higher mean testosterone levels than the nonaggressive group. The aggressive group also had a significantly higher level of testosterone than the nondominant group, but not the socially dominant group, and higher than the other 2 groups combined. The aggressive group also scored significantly higher than either of the other 2 groups in the total hostility score of the BDHI. Unfortunately, any conclusions must be tentative based upon the use of other drugs, including barbiturates and all other drugs of abuse, which are known to affect the reproductive axis.

Rada et al. (1976b) also found, within imprisoned sex offenders, that a group of 5 violent rapists had significantly higher testosterone levels than 12 child molesters, 47 other ‘less violent’ rapists, or a control group of 48 healthy male prison employees. The mean BDHI score for all rapists was significantly higher than the mean for normals, but there was no correlation between individual hostility scores and plasma testosterone. Also, there were no significant correlations between age, race or length of incarceration and plasma testosterone level.

As part of a much larger, double-blind, controlled study of sex chromosome anomalies, hormones, and aggressivity in 4591 men, Schiavi et al. (1984) noted a proportionately significant increase in levels of testosterone when subjects were divided into smaller groups of nondelinquents (n=63), delinquents without violent convictions (n=11), and delinquents with violent convictions (n=4). However, the relation between testosterone level and criminal behaviour was not reflected in measures of aggression derived either from psychological interviews or projective tests (Rorschach Test, Word Association Test, Thematic Apperception Test).

3.3 Relationship of Testosterone to Moods Other Than Aggression

In a study of serum testosterone levels, social status and mood in male graduate students between the ages of 22 and 35, Mazur and Lamb (1980) reported that changes in testosterone levels did show a relationship to the subject’s moods. Specifically, their results suggest that when a man achieves a ‘rise in status through his own efforts’ (either graduation form medical school, winning a tennis match, or winning a lottery), and he has an elevation of mood as a result of the achievement, then that person is ‘likely’ to have a rise in testosterone. A recent study by Tanaka et al. (1989) found that positive mental health [vigour as measured by the Profile of Mood States (POMS) (McNair et al. 1971)] and athletic achievement motivation (challenge to higher goals, ‘fighting spirit’, and value athletics as determined by the Taikyo Sports Motivation Inventory) were each significantly correlated with higher levels of plasma testosterone. Elias (1981) has measured levels of circulating cortisol, testosterone and testosterone-binding globulin in 15 male wrestlers in relation to the outcome of wrestling bouts and found that concentrations of cortisol and testosterone increased consistently during wrestling bouts, while levels of testosterone-binding globulin dropped. Winners of competitive matches showed significantly greater increases in both hormones than losers. Although greater effort and/or haemoconcentration in the winners cannot be ruled out as an explanation, these findings are suggestive that humans, like other social mammals, might undergo specific endocrine changes in response to victory or defeat.

3.4 Testosterone Levels and Stress

An association between stress and levels of testosterone has been demonstrated in several studies. Kreuz et al. (1972) found plasma testosterone levels in 18 young men attending a military training course were significantly lower during a stressful period when compared with a less stressful phase. Likewise, Aakvaag et al. (1978) studied the effect of physical and psychological stress (a 5-day combat course) on 8 young male military cadets and found a significant and prolonged reduction in plasma testosterone levels. Francis (1981), in examining the relationship between high and low trait psychological stress, serum testosterone and serum cortisol, found males (30 to 55 years), classified as experiencing high psychological stress [State-Trait Anxiety Inventory (Spielberger et al. 1970)], possessed significantly lower testosterone levels than did their low stress counterparts. Morville et al. (1979) have demonstrated reduced testosterone levels following intense physical effort (100km running races) in male endurance athletes. Testosterone levels were also significantly decreased in 5 male athletes participating in a 20-day 1100km foot race (Schurmeyer et al. 1984).

In summary, a pattern of association between plasma testosterone and both subjectively-perceived and observed aggressive behaviour has been revealed in many of the preceding studies. However, the relationships between plasma testosterone and psychometric indices of aggression and hostility have been less consistent. The results of studies in this section are summarised in table I.

4. Anabolic Steroid Therapy and Moods

Hermann and Beach (1976), in a review of the psychotropic effects of androgens, concluded that ‘…androgen deficiency appears to cause a slowing down of both physical and mental functions, a reduction in libido and potency, and a tendency towards moodiness and depression. Conversely, androgen excess seems to stimulate physical and mental function, and to induce assertiveness rather than passivity, although the degree to which these people are overtly aggressive is somewhat unclear.’ Hermann and Beach also concluded that, ‘As yet no work, to our knowledge, has been done on the possible contribution that the reported variations in hormone levels make to the changed behaviour of those who become mentally disordered, nor to their exact role in metabolic changes which are supposed to accompany such illness.’ Unfortunately, although a number of studies have been conducted over the intervening years, little can be added to their conclusion at this point in time. This following section summarises research and clinical observations and effects in individuals with androgen deficiencies receiving androgen therapy.

Franchi et al. (1978) reported a marked increase in libido and sexual, physical and/or mental activities in all 34 hypogonadal male patients (18 to 49 years) given testosterone undecanoate (40 to 60 mg/day, orally) for 8 months when compared with a withdrawal period (3 weeks). Unfortunately, no information concerning the questionnaires used to assess the behavioural and mood changes is provided. No side effects were reported by any of the patients throughout the 8 months of therapy.

Franchimont et al. (1978) found improved mental and physical activity at 3-week intervals over 9 weeks in 7 and 2 of 10 hypogonadal male patients (16 to 51 years), respectively, undergoing therapy with oral testosterone undecanoate (120 to 240 mg/day). Again, no information is provided concerning how behavioural and mood changes were measured.

Luisi and Franchi (1980) in a double-blind, randomised, group comparative study of testosterone undecanoate (120 mg/day orally) and mesterolone (150 mg/day orally) in hypogonadal male patients found that testosterone undecanoate but not mesterolone induced a marked improvement in both sexual activity and mental state (unpublished modified Koch’s Mood Questionnaire) after 2 weeks. These improvements continued for the duration of the 4-week study. No side effects were reported in either group of patients. Using the Lorr and McNair Mood Check List in a double-blind crossover design, Skakkebaek et al. (1981) found significantly improved self-ratings of tension/anxiety and fatigue, a higher level of vigour, but no change in depression with androgen replacement (testosterone undecanoate 160 mg/day orally) versus placebo capsules (oleic acid) in 6 hypergonadotrophic (castration or primary testicular failure) and 6 hypogonadotrophic (hypothalamic or pituitary deficiency) men with hypogonadism. The study was conducted over a 4-month period (2 months on placebo and 2 months on testosterone undecanoate). In addition, there was a significant reduction in self-rated anger during testosterone administration. O’Carroll et al. (1985) also reported significantly improved well-being (4 of 10 self-reported visual analogue scales) with androgen replacement (testosterone undecanoate) in 8 hypogonadal men. A significant does response relationship for well-being was demonstrated with increasing doses (40, 80, 120, 160 mg/day orally) over 4 months.

Wu et al. (1982) using a double blind crossover design and the Lorr and McNair Mood Adjective Check List found no significant change in self-reported mood (anxiety/tension, depression, anger, vigour, fatigue) or energy in 4 adult men (30 to 48 years) with Klinefelters syndrome, low normal testosterone levels and normal sexual activity and interest given testosterone undecanoate (160 mg/day orally) for 8 weeks compared to placebo (8 weeks) and a baseline period of no treatment (8 weeks).

In a double-blind experiment, Davidson et al. (1979) found no consistent relationship between mood (Profile of Mood States) and androgen administration in 6 adult hypogonadal males receiving testosterone enanthate (100 or 400 mg/month in 2 doses) and a placebo treatment in randomly assigned 4-week periods over a 5-month period. Although frequencies of erections showed significant dose-related responses which closely followed the fluctuations in the serum testosterone levels, individual records showed only 1 clear instance of change in mood (POMS) related to treatment (1 subject showed peak increases in anger 1 week after receiving treatment after guessing that he was on placebo). Salmimies et al. (1982) also found no significant differences in biweekly mood ratings when comparing 15 adult hypogonadal male patients administered increasing doses of testosterone enanthate (25, 50, 100, 250mg or placebo) injected over a 5-month period. Each dose was given twice (every 2 weeks) over 4 weeks.

Results from the preceding studies are mixed (table II). Some demonstrate significant positive psychological changes with anabolic-androgenic steroids, others do not. However, no adverse or undesired psychological or behavioural effects were observed in these studies. Interestingly, 5 of the 6 studies which administered oral androgens reported improved mood states following therapy (with the exception of the mesterolone group of Luisi and Franchi); the results of the 2 studies using intramuscular injections of various testosterone esters found no change. However, it should be noted that only perhaps 1 or 2 of the doses administered in these 2 studies (200mg biweekly and 250mg biweekly) would restore and maintain normal physiological testosterone levels and full androgenic function for the entire duration between injections.

O’Carroll and Bancroft (1984), in a carefully controlled double-blind crossover comparison of biweekly injections of 250mg of testosterone esters (‘Sustanon’) or placebo in 2 groups of men (n=20) with normal testosterone levels, likewise found no significant change in mood ratings (10 self-reported visual analogue scales) following 12 weeks of treatment (half the subjects in each group received 6 weeks of testosterone followed by 6 weeks placebo, and the other half vice versa).

5. Steroids and Mental Health

Research and anecdotal information suggested some time ago that steroids have among their many side effects various mental disturbances including schizophrenic symptoms and manic depressive illnesses even though estrone was used successfully in both males and females in the treatment of depression and other mental disturbances occurring with menopause and what would now probably be referred to as andropause beginning in the mid-1930s. Glass (1950) reported that psychoneurotic patients responded more favourably to androgen-estrogen mixtures because these mixtures impart an optimum sense of well-being. 35 years later, Sherwin and Gelfand (1985) reported similar findings of increased energy level and well-being in female surgical menopause patients receiving either a combined estrogen-androgen drug or androgen alone as compared with those receiving estrogen alone or placebo. Although quantification of mood states was generally lacking, it is noteworthy that 23 of 24 studies cited by Kopera (1976) report improvements in psychic as well as physical state, appetite and weight gain in surgical and chronically ill patients treated with anabolic-androgenic steroids. Another 11 of 17 controlled and 11 of 14 uncontrolled clinical trials in geriatric patients cited by Kopera also showed positive anabolic-androgenic steroid effects on physical activity, energy and mood.

It is now well known that, in excess, glucocorticoids can produce extreme emotional instability, ranging from euphoria to suicidal despondency (Hall 1980). Studies of patients with Cushing’s disease indicate that up to 20% could be termed psychotic. Depression is the most common manifestation and suicidal attempts are reported in approximately 10% of cases. Other psychological manifestations include irritability, insomnia, difficulty concentrating, paranoid delusions, hallucinations, and less often, excitement, anxiety, apathy, disorientation, loss of recent memory, and acute organic brain syndrome. Schizophrenic symptoms may also, but rarely, occur. With drug-induced Cushing’s syndrome, in contrast, the most common psychological effect is euphoria, although acute toxic psychosis can also occur.

Mental disorders associated with corticosteroid administration have been documented since the early 1950s (Borman & Schmallenberg 1951; Brody 1952; Byyny 1976; Clark et al. 1952; Glasser 1953). Rome and Braceland (1952) commented that the occurrence of a certain small percentage of psychotic reactions as a compilation of the diseases for which various steroids are administered was to be expected. Train and Winkler (1962) reported a case of homicide involving a woman who had psychotic depression while on corticotrophin and killed her son. Reports continue with still another corticosteroid-related psychotic episode and attempted homicide in 1989 (d’Orban 1989).

Ling et al. (1981) have reviewed the literature to determine the characteristics of corticosteroid-induced mental disturbances and have concluded that: (a) while dosage may be related to the risk of developing mental disturbances, neither dosage nor duration of treatment seems to affect the time of onset, duration, severity, or type of mental disturbances; (b) euphoria as well as depression and psychotic reactions are the most common manifestations of corticosteroid-induced mental disturbances; (c ) females seem to be more prone to these disturbances than males; (d) patients with past mental illness are not necessarily predisposed to such disturbances; and (e) corticosteroid-induced mental disturbances are usually reversible upon dose reduction or discontinuation of the drug. Ling et al. (1981) concluded that there are no simple models to explain the psychotic reactions, anxiety, or agitation seen in corticosteroid-induced mental disturbances. Kaufmann et al. (1982) concluded, in their case report and brief overview, that there are apparently no characteristic symptoms of corticosteroid psychosis. Lewis and Smith (1983) reported in a subsequent review of 14 previously unreported cases of steroid-induced psychiatric syndromes, 79 cases from the medical literature and 29 studies of the clinical efficacy of steroids in various medical illnesses that severe psychiatric reactions occur in approximately 5% of steroid-treated patients, but their review [which contained additional cases not included in Ling et al. (1981)] indicated that a significant proportion of these patients already have existing affective and/or psychotic symptoms. None of their 14 cases had a past history of psychiatric illness unrelated to steroid therapy; 6 (43%) of their 14 cases were thought to have evidence of a premorbid personality disorder; of 41 cases in the literature, 17% had a prior history of psychiatric illness unrelated to steroids; and 52% of the 29 cases were reported to have had an abnormal premorbid personality. Alcena and Alexopoulos (1985) also recently concluded both from their data and a review of the literature on corticosteroid-induced psychiatric disorders that: (a) the pathogenesis of psychiatric symptoms during corticosteroid therapy is unknown; (b) development of psychiatric complications in patients receiving corticosteroids is probably dose-dependent; (c ) the type of psychiatric manifestations is variable; (d) it is unclear whether a history of psychiatric disorders increases the risk for psychiatric problems from corticosteroids; and (e) in the majority of patients, psychiatric complications remit when the dosage of corticosteroids is reduced or administration discontinued.

With respect to withdrawal symptoms, it is worth noting that symptoms of Addison’s disease include apathy, depression, fatigue, a general lack of interest, initiative and motivation, and an overall negativism (Hall 1980). In acute Addison’s disease a typical organic psychosis develops with memory deficit and clouding of consciousness. Administration of aldosterone improves electrolyte balance, but corticosteroid administration is necessary to correct the personality disturbance, EEG abnormalities and altered sensory thresholds.

Considering then the structural similarities of cortical and anabolic steroids and their multiple additive and synergistic as well as competitive actions, it is not surprising that their administration would result in some similar effects on mood and behaviour. Furthermore, anabolic-androgenic steroid administration has been reported to alter glucocorticoid metabolism (James et al. 1962), and high doses of anabolic-androgenic steroids given to athletes have been shown to dramatically elevate serum and urinary cortisol levels (Hervey et al. 1976), although other studies have not corroborated this latter finding (Alen et al. 1985).

Androgens, on the other hand, have been used in the treatment of mental disorders for over 50 years. Werner et al. (1934) used theelin (estrone) to treat female patients suffering from involutional melancholia (depression) and reported improvement in 18 of the 20 cases attended. 90% (versus 16% in a control treatment) of the 39 female patients (34 to 58 years) with involutional melancholia treated with daily intramuscular injections of theelin over 6 months showed slight to marked improvement in a study by Werner et al. (1936). Using larger doses, Ault et al. (1937) later treated 14 female cases of involutional melancholia with a recovery rate of 92%. However, although no adverse reactions were reported, the results for treatment of mental disorders with theelin was not always successful (Schube et al. 1937).

In a review of the literature, Danziger (1942) reported that while estrone therapy was not highly successful for the treatment of female involutional melancholia, the incidence of recovery or marked improvement was better than no treatment and, in his own investigation, found 4 of 7 female patients benefited from the daily oral administration over several month of diethylstilbestrol.

Schmitz (1937) produced improvement with testosterone propionate in 86% of 42 cases with symptoms such as depression and impotence in males in the involutional age. Foss (1937) relieved depression in a eunuch by the daily injection of 20mg of testosterone propionate.

Hamilton (1937) reported that a 27-year-old male hypogonadal subject treated with testosterone acetate (a total of 550mg over a period of 1 month) became more energetic, virile and self-assured during therapy. Testosterone propionate 10mg 3 times weekly relieved the subjective symptoms (anxiety, depression, fatigue) in 2 male climacteric patients (Werner 1939). Two cases diagnosed as male climacteric (involutional melancho