Androgen administration to hypogonadal and eugonadal men—effects on measures of sensation seeking,personality and spatial ability

A group of hypogonadal and a group of eugonadal (endocrinologically normal) men complaining of sexual dysfunction were treated with androgens. Psychometric measures of sensation seeking, personality and spatial ability were made before and after treatment. Short-term androgen administration had little effect on these measures. However when the two patient groups were compared while receiving no androgen treatment, the eugonadal men produced significantly higher scores on the Sensation Seeking Scale.     

The role of endocrines in isolation-induced lntermale fighting in albino laboratory mice. II. Sex steroid influences in aggressive mice

Isolation-induced intermale fighting in laboratory mice can be dramatically reduced under most circumstances by castration. This behavior in castrates may, however, be restored, or even accentuated, by androgen replacement. Experiments on the effects of sex steroids on such fighting in castrated mice, which, for want of a better term, are designated as “aggressive,” have been recently described. These mice are housed with a female until 10 days after siring a litter and are, thereafter, housed individually for a further 14 days before castration and subsequent hormone treatment. Such mice show substantial levels of fighting in “standard-opponent” tests even before isolation. Although castration results in reduced fighting in these mice, this behavior is rarely completely abolished in all individuals. It seems likely that steroid treatment of aggressive mice maintains or intensifies an already present motivation. Treatments in these studies consisted of daily oil-based intramuscular injections for 14 days preceding and throughout behavioral testing. The standard-opponent tests were 7 min encounters with adult, subordinate, grouped males in the cleaned home cages of experimental mice. The steroids investigated included estradiol benzoate (EB), 19-hydroxytestosterone (19-OHT), androstenedione (A), testosterone (T), and Sα-dihydrotestosterone (DHT), either singly or in combination. The results suggest that (a) on a dosage basis, estrogens were at least as effective as androgens in maintaining fighting in castrated aggressive mice; (b) 19-OHT (one of the metabolic intermediates between testosterone and 17 β-estradiol) was also effective but somewhat less so than the same dose of EB; (c) the three naturally occurring androgens investigated all effectively maintained fighting at comparatively low doses (50 μg/day) which compares with a replacement dose of 500 μg/day of T in some studies in traditional castrated mice (e.g., Luttge and Hall, 1973); (d) aromatization is not essential for a behavioral action of androgens as DHT, a nonaromatizable androgen, maintained fighting in these mice; (e) whereas a two-site (central motivational and peripheral penile) action seems probable in the influence of androgens on sexual behavior in castrated rats (e.g., Parrott, 1975), DHT did not augment the action of EB on fighting in castrated aggressive mice, indicating that only a central action of steroids was required in the aggressor.     

Cardiovascular responses to open-field stress in rats: sex differences and effects of gonadal hormones

We studied sex differences in cardiovascular responses to stress using a new radio-telemetry model in which freely-moving Spontaneously Hypertensive rats (SHR) are exposed to open-field novelty stress. This model allowed simultaneous assessment of cardiovascular and behavioural responses to psychological stress. Female SHR in the diestrous stage of their estrous cycle had markedly greater pressor and tachycardic responses to open-field exposure when compared to either female rats not in diestrous or male SHR. Treatment of ovariectomized SHR with estrogen alone had no significant effect on cardiovascular reactivity, while a combined treatment of estrogen and progesterone slightly, but significantly attenuated their pressor response to open-field stress. In addition, treatment of castrated male rats with testosterone significantly enhanced their pressor responses to stress when compared to values obtained before treatment. None of the hormone treatments had any significant effect on heart rate responses to stress. Neither at different stages of the estrous cycle nor after hormone treatments were there any marked changes in behavioural responses in the open-field, making it unlikely that the differences in cardiovascular stress responses were caused by changes in behavioural activity. These data demonstrate differences in cardiovascular stress responses that seem to be dependent on the stage of the estrous cycle. They suggest that particularly androgens, such as testosterone, may enhance pressor responses to stress. On the other hand, a combination of estrogen and progesterone, rather than estrogen alone, may have a small attenuating effect on cardiovascular reactivity.     

Neonatal androgenic stimulation and adult sexual behavior in male and female golden hamsters.

Neonatally and adult castrated male hamsters as well as neonatally androgenized and nonandrogenized female hamsters were tested for both mounting and lordosis behaviors during treatment with either testosterone or ovarian hormones. Neonatal androgenization facilitated mounting behavior in adult animals administered either testosterone or ovarian hormones and suppressed lordosis behavior in adult ovarian-hormone-treated animals. Early androgen effects on the display of lordosis behavior during adult testosterone treatment were complex and varied with the exact timing of perinatal endogenous or exogenous androgenization. Species differences in hormone-behavior relationships and the possible role of perinatal androgenization in the development of rodents' ability to aromatize androgens were discussed.     

Anger and aggression in women: Influence of sports choice and testosterone administration

We report on two studies of anger and aggression in women. One study concerns an experimental study of anger induction in aggressive and non-aggressive sportswomen. It was found that sports choice in itself, contrary to expectation, does not predict anger arousal and aggressive behavior in the laboratory. However, at an individual level the anger proneness of the subject, as measured by a questionnaire we developed, was related to the intensity of aggressive behavior and subjectively reported anger. The second study concerns the activating effects of androgens on aggression and anger proneness. In a group of 22 female-to-male transsexuals, a battery of anger proneness and aggression questionnaires was administered twice: shortly before and 3 months after the start of androgen treatment. Administration of androgens was clearly associated with an increaese in anger proneness, although there were no changes in several aspects of overt aggressive behavior. © 1994 Wiley-Liss, Inc.     

Chronic sildenafil (Viagra) administration reduces anxiety in intact and castrated male rats

Epidemiological research indicates that sildenafil (Viagra) abuse is associated with increased risk behaviors. The present study employs the open field, a standard animal model used in the field of anxiety research, to examine whether chronic exposure to sildenafil affects anxiety and risk-taking behaviors in gonadally intact and castrated male Wistar rats. Sildenafil (10 mg/kg) or saline were administered three times a week for three weeks. Animals were tested once a week in the open field during and after drug treatment. Sildenafil treatment increased the number of center entries and time spent in the center in intact and castrated animals during and after treatment, suggesting that repeated drug use decreases anxiety. Sildenafil also restored the deficits in exploration and locomotion produced by castration, indicating that sildenafil effects on open field behaviors are independent of endogenous androgens. We caution against generalizing from this study to human behaviors, but propose that the behavioral effects produced by a chronic high dose of sildenafil warrant further studies into its abuse potential.     

Early experience of sex hormones as a predictor of reading, phonology, and auditory perception

Previous research has indicated possible reciprocal connections between phonology and reading, and also connections between aspects of auditory perception and reading. The present study investigates these associations further by examining the potential influence of prenatal androgens using measures of digit ratio (the ratio of the lengths of the index and ring fingers). Those with low digit ratios (shorter index finger and therefore in the masculine direction) are hypothesised to have experienced greater "masculinisation" in the uterus. ANCOVA analyses using a verbal reasoning task as a covariate showed that only phonology was influenced by digit ratio in the right hand indicating that hypothesised androgen effects were inhibiting phonology; however this effect in the left hand was reduced and instead there was an effect indicating an inhibition of androgens on reading. Furthermore, subjects with low right-hand digit ratios were also impaired compared to those with high right-hand digit ratios in an auditory saltation task. These findings are discussed in terms of the possible effects of androgens on early brain development impairing aspects of the temporal processing of sounds by the left hemisphere, which could also have a secondary influence on developing phonology and literacy skills.     

A role for ovarian hormones in sexual differentiation of the brain

Historically, studies of the role of endogenous hormones in developmental differentiation of the sexes have suggested that mammalian sexual differentiation is mediated primarily by testicular androgens, and that exposure to androgens in early life leads to a male brain as defined by neuroanatomy and behavior. The female brain has been assumed to develop via a hormonal default mechanism, in the absence of androgen or other hormones. Ovarian hormones have significant effects on the development of a sexually dimorphic cortical structure, the corpus callosum, which is larger in male than in female rats. In the females, removal of the ovaries as late as Day 16 increases the cross-sectional area of the adult corpus callosum. Treatment with low-dose estradiol starting on Day 25 inhibits this effect. Female callosa are also enlarged by a combination of daily postnatal handling and exogenous testosterone administered prior to Day 8. The effects of androgen treatment are expressed early in development, with males and testosterone-treated females having larger callosa than control females as early as Day 30. The effects of ovariectomy do not appear until after Day 55. These findings are more consistent with other evidence of a later sensitive period for ovarian feminization as compared to androgenic masculinization.     

Androgens and aggression in man: A controlled case study

A controlled case study is reported of the behavioural effects of androgen treatment in an institutionalised hypogonadal mentally retarded male patient. This man was previously treated with intramuscular depot injections of testosterone esters; however, treatment had to be stopped as the androgens allegedly precipitated frequent bouts of violent behaviour. Using ratings of behaviour by hostel staff, replacement therapy was restarted using the new orally effective androgen, testosterone undecanoate (TU). Gradually increasing the replacement dose of TU in a double-blind fashion resulted in no stimulatory effect on aggressive behaviour. Possible reasons for the differential behavioural response to the two androgen preparations are presented.     

Indications, contraindications and legal problems in antiandrogen treatment]

The author in his present paper gives an outline of the indications, contraindications, and legal problems of Androcur treatment. Androcur (cyproterone acetate) is an antiandrogen that is capable of competitively inhibiting androgens in the organism. Accordingly, the effects obtained by drug therapy, of which the purpose is to reduce the sexual desire or libido, are similar to those produced by operative castration. The use of such drugs makes it possible to control abnormal sex drives and desires and prevent sexual offenders from becoming recidivous. Since treatment with Androcur is an intervention in the deeply personal sphere and there is not yet availability any reliable data on the full reversibility of the phenomena involved (for example, alterations to the testicles) especially in the case of long-time treatment, such therapy should be carried out on the principle of absolute voluntariness and after suitable suggestions have been furnished as to the proper treatment of the respective subject.     

Androgens are neuroprotective in the dentate gyrus of adrenalectomized female rats

Neuroprotective effects of androgens have not been well-characterized, but there is evidence that 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol) has anti-seizure effects. To further examine androgens' neuroprotective effects, testosterone (T), dihydrotestosterone (DHT), 3 alpha-diol (1.0 mg/kg SC daily), or sesame oil vehicle was administered to adrenalectomized or sham-operated, young, female Long Evans rats (N = 52). After seven days, animals were perfused and trunk blood was collected for radioimmunoassay of plasma corticosterone and androgens. No pyknotic cells were seen in the dentate of the sham-operated animals or those animals that had incomplete adrenalectomies (n = 20); however, cresyl violet and TUNEL stains revealed pyknotic cells in the granule layer of the dentate gyrus of adrenalectomized rats (n = 28). Testosterone, DHT, or 3 alpha-diol significantly reduced the number of pyknotic cells in the dentate gyrus compared to vehicle administered, adrenalectomized rats. Steroid-administered animals had levels of T, DHT, or 3 alpha-diol within physiological concentrations. These findings suggest that T, DHT, or 3 alpha-diol may have neuroprotective effects via a common mechanism of action.     

Effects of neonatal treatment with cyproterone acetate on aggressive behavior induced by footshock in adult male rats

High levels of androgens are required to organize aggressive behavior in adult male rats. Footshock-induced aggression was tested in Wistar rats allocated to one of three experimental groups: control (oil-injected) males (M), males neonatally injected with the antiandrogen cyproterone acetate (CA), and males treated as in the CA group but gonadectomized just before puberty (CAG). An antiaggressive effect of CA in those adult male rats neonatally treated with this compound was found. Neonatal exposure to cyproterone acetate exerts an antiandrogenic effect over the expression of shock-induced aggressive behavior. The behavioral effects of CA were not countered by adult treatment with testosterone propionate.     

Peripheral and central sex steroids have differential effects on the HPA axis of male and female rats

Sex differences in hypothalamic-pituitary-adrenal (HPA) function were examined in gonadectomized male and female rats given equivalent sex hormone replacement regimens either using subcutaneous silastic implants (Experiment 1) or cannula implants in the medial preoptic area (MPOA) (Experiment 2) containing either dihydrotestosterone (DHT), testosterone propionate (TP), estradiol benzoate (EB), or left empty (control). Plasma was obtained before and after 20 min of restraint stress to determine plasma ACTH, corticosterone, and CBG levels as measures of HPA function. Consistent with the literature, androgens decreased, and estrogen increased these measures of HPA function, although peripheral implants were more effective than MPOA implants. Gonadectomy and sex hormone treatment did not eliminate sex differences; overall, females had higher levels than males on measures of HPA function. Analyses of variance (ANOVA) indicated interactions of sex and sex hormone treatment on CBG levels and post-stress corticosterone levels in Expt. 1. The results suggest that sexual dimorphisms influence HPA function even when males and females are given equivalent physiological doses of gonadal steroids, and that the relevant sexual dimorphisms involve both the periphery and the CNS.     

Combined cognitive and parent training interventions for adolescents with ADHD and their mothers: A randomized controlled trial

This study examined the individual and combined effects of two nonpharmacological treatments for attention deficit/hyperactivity disorder (ADHD): Cogmed working memory training (CWMT) for adolescents and behavioral parent training (BPT) for mothers. Ninety-one adolescents (ages 11–15) and their mothers were randomized to one of four CWMT and BPT treatment and active control (placebo) group combinations of 5-week interventions. At pre- and posttest, mothers and teachers completed rating forms, and adolescents completed neuropsychological measures of working memory (WM). Individual intervention effects showed that treatment CWMT significantly improved WM spans, whereas there were no significant differences for treatment or control BPT on reports of parent-related outcomes. Combined treatment effects indicated an overall pattern of greatest improvements for the control CWMT/treatment BPT group, as compared to the other three groups, on adolescent WM deficit, behavioral regulation problems, and global executive deficit. Most significant effects for outcomes were main effects of improvements over time. A combination of CWMT and BPT did not result in increased treatment gains. However, potential effects of combined treatment may have been masked by greater perceived benefits arising from lack of struggle in the nonadaptive, CWMT active control condition. Future combined intervention research should focus on specific, theoretically driven WM deficits among individuals with ADHD, should include possible adaptations to the standard CWMT program, should examine effectiveness of cognitive treatments combined with contextual interventions and should utilize appropriate control groups to fully understand the unique and combined effects of interventions.     

Evidence that a factor besides progesterone, prolactin, or plasma-estradiol-binding protein inhibits estrogen-induced sexual receptivity in pregnant rats.

Daily administration of estradiol benzoate stimulated significantly less lordotic behavior in rats during the second half of pregnancy than in ovariectomized females that received subcutaneous progesterone implants, pituitary grafts that raised plasma prolactin, or both treatments combined. Following an initial facilitation of receptivity, females with progesterone implants showed only moderate reductions in lordosis quotients over 3 test days. The capacity of plasma from pregnant rats to bind estradiol was found to increase significantly during the second half of pregnancy. However, daily administration to pregnant rats of a synthetic estrogen, R 2858, which is not bound by plasma protein, was no more effective than estradiol benzoate in stimulating receptive behavior. Administration of estradiol benzoate also stimulated significantly lower levels of sexual behavior in pregnant females than in females in which pseudopregnancy had been prolonged by previous hysterectomy or induction of uterine decidualization. These findings suggest that some endocrine factor other than progesterone, prolactin, or estradiol-binding protein is primarily responsible for the potent suppression of behavioral responsiveness to estrogen which occurs in pregnant rats. It is suggested that 5 alpha-reduced androgens may cause these behavioral effects.     

Sequential combinations of drug and cognitive behavioral therapy for chronic insomnia: an exploratory study

This study explores the efficacy of sequential treatments involving medication and cognitive behavioral treatment (CBT) for primary insomnia. Seventeen participants took part in a multiple baseline design and were assigned to: (a) medication for 5 weeks, followed by combined medication plus CBT for 5 weeks; (b) combined treatment for 5 weeks, followed by CBT alone; or (c) CBT alone. Each treatment sequence produced significant sleep improvements, but at different points in time. For the first sequence, most of the sleep improvement was obtained after the introduction of CBT, while for the other sequence and CBT alone, improvement appeared during the first weeks. These results suggest that sleep improvement seems affected by the way treatments are combined. Also, a sequence beginning with a combined treatment followed by CBT alone seems to produce the best outcome. Additional research should be conducted with larger samples to determine the most effective sequence.     

Treatment of pharmacotherapy-refractory posttraumatic stress disorder among Cambodian refugees: a pilot study of combination treatment with cognitive-behavior therapy vs sertraline alone

Cambodian refugees with posttraumatic stress disorder (PTSD) represent a cohort in severe need of treatment, but little information is available to guide treatment choices. We selected a sample of pharmacotherapy-refractory individuals to test the efficacy of combination treatment with sertraline and cognitive-behavior therapy (CBT) for treating PTSD. Participants in this pilot study were ten Khmer-speaking women who had been at a mean age of 22-26 years during the Pol Pot period (1975-1979). These patients were randomly assigned to either sertraline alone or combined treatment. We found that combined treatment offered additional benefit in the range of medium to large effect sizes for PTSD and associated symptoms. Our findings indicate that substantial gains can be achieved by adding CBT to pharmacotherapy for PTSD, and that a program of CBT emphasizing information, exposure, and cognitive-restructuring can be successfully modified for Khmer-speaking refugees.     

The Role of Maternal Depression on Treatment Outcome for Children with Externalizing Behavior Problems

Studies have shown that, on average, Parent Management Training combined with cognitive-behavioral therapy decreases children’s externalizing behavior, but some children do not improve through treatment. The current study aimed to examine the role of maternal depression in understanding this variability in treatment outcome. Children with externalizing behavioral problems and their parents were recruited from combined Parent Management Training and Cognitive-Behavioral programs in “real-world” clinical settings. At pre- and post treatment, maternal depression and children’s externalizing behavior were assessed. Results showed that treatment was less effective for children of depressed mothers compared to non-depressed mothers and that improvements in maternal depression were associated with improvements in children’s externalizing behavior. These findings suggest that treatment programs for children with externalizing problems may be able to improve outcomes if maternal depression is a target of intervention.     

Posttraining androgens' enhancement of cognitive performance is temporally distinct from androgens' increases in affective behavior

Steroid hormone-induced variations in spatial learning and memory tasks have been reported. In this study, androgens’ effects in various cognitive and affective tasks were investigated in order to determine whether any observed differences in cognitive performance could be due to affective changes produced by the hormones. Ovariectomized rats (N = 72) received 0.0, 3.0, or 7.5 mg/kg subcutaneously, of testosterone (T), dihydrotestosterone (DHT), or 5α-androstane-3α, 17β-diol (3a-Diol) suspended in 10% ethanol/sesame oil v/v. For the cognitive tasks (Y maze, inhibitory avoidance, and object recognition), subjects were injected after training trials. For the affective tasks (open field, elevated plus maze, and tailflick), subjects were injected 1 or 24 h before testing. Posttraining injections that produced physiological concentrations of androgens - T, DHT, and 3α-Diol - 1 h later increased the percentage of correct choices in the Y maze, the latencies to cross to the shock-associated side of the inhibitory avoidance chamber, and percentage of time exploring novel objects 24 h later, when androgen levels were no longer increased. Administration of T, DHT, and 3α-Diol also increased the number of entries into the center squares of a brightly lit open field, open-arm time in the elevated plus maze, and tailflick latencies 1 but not 24 h following administration. These findings suggest that these androgens, when administered following training, can enhance cognitive performance in the tasks investigated 24 h later when androgen levels nadir, but overt changes in the affective behaviors examined occurred at the time of physiological concentrations 1 h but not 24 h following androgen administration. These findings suggest posttraining androgens can enhance consolidation and cognitive performance, independent of their anxiolytic actions.     

Androgens and aggressive behavior in primates: A review

This review deals with possible central and peripheral effects of androgens upon primate aggressive behavior. One problem that clouds interpretation of experimental work is that measurements of dominance have often been employed, such as competition tests for food and water. Such measures often do not correlate with those obtained by quantifying aggressive interactions. It should be remembered that very few of the 188 primate species have been studied experimentally and that great behavioral and physiological diversity occurs within the order. Therefore, generalizations about the effects of androgens upon aggressive behavior in primates (including man) should be made with caution. Testosterone has an organizing influence upon the foetal brain of rhesus monkeys and may affect the development of neural mechanisms which govern aggression in males. More data are required on primates, however, since rhesus monkeys show some important differences from rodents as regards the effects of androgen upon sexual differentiation of the hypothalamus. In future, marmosets may provide a suitable model for such studies, because there is evidence that sexual differentiation of brain by androgen occurs postnatally in these monkeys. At puberty, male primates show a variety of behavioral changes and, during adulthood, males of seasonally breeding species may be more aggressive during the mating season, when testosterone levels are maximal. This does not indicate a causative relationship between testosterone and aggressive responses, because castration and androgen treatments have little effect upon aggression in prepubertal or adult males of several primate species. Androgens have pronounced effects on sexual responses in adult male monkeys, but their central effects upon aggression are much less important than among rodents. Elec trical stimulation of hypothalamic pathways has been employed to evoke aggressive behavior in marmosets and rhesus monkeys. In the rhesus, preliminary evidence indicates that such pathways show some sensitivity to androgens. In rodents it is known that these areas are richly supplied with monoaminergic neurons, which play an important role in aggressive behavior. There is little evidence on primates, however, and this remains a crucial topic for future research. Peripheral effects of androgens should also be considered. Many prosimians and New World monkeys use scent-marking behaviors and, in males, androgen-dependent chemical cues may be involved in sexual recognition and territorial behavior. This possibility awaits investigation. Finally, plasma testosterone levels may alter as a function of aggression itself; thus levels decrease if male rhesus monkeys are defeated by conspecifics. This might occur because neural events associated with giving (or receiving) aggression also influence pituitary function and hence alter gonadal testosterone secretion. Theoretically, it is possible that such changes in circulating testosterone might affect aggressive behavior via a feedback action on the brain, but the experimental evidence does not support such a view.