Activational Effects Of Testosterone Research Articles

The digit ratio (2D:4D) and testosterone co-predict vertical jump performance in athletic boys: Evidence of organizational and activational effects of testosterone on physical fitness

The digit ratio (2D:4D) is a negative correlate of boy's physical fitness, and thought to arise from organizational effects of prenatal testosterone on different bodily systems. During human ontogeny, activational effects of testosterone on body size and strength offers another pathway to physical fitness. We tested these hypotheses by examining the organizational and activational effects of testosterone on vertical jump performance in athletic boys. Using a cross-sectional design, 173 boys (aged 9 to 18 years) were tested for standing height, body mass, body fat, fat-free mass, weekly training activity, training history, salivary testosterone and cortisol, R2D:4D, L2D:4D, and right-left 2D:4D (Dr-1), and vertical height in 3 different countermovement jump (CMJ) tests. A generalized additive model was employed to delineate age-related trajectories and predict CMJ performance. Our models yielded significant non-linear increases (or changes) in body size, current hormone concentration, training outcomes, and CMJ performance with chronological age. All 2D:4D measures were age invariant. The R2D:4D and testosterone were significant non-linear predictors of CMJ height with (R2 = 66.2%) or without (R2 = 54.3%) covariates, whereby a higher current testosterone concentration (up to a certain level) and a lower or higher R2D:4D were linked to better performance. The L2D:4D and Dr-1 had no predictive value. In conclusion, the R2D:4D and testosterone were co-predictors of CMJ height among athletic boys, with non-linear performance effects that differed in timing, tempo, and direction. Our findings confirm that testosterone can regulate a simple measure of boy's physical fitness through both an activational and organizational pathway.

Parental care in male degus (Octodon degus) is flexible and contingent upon female care

Parents in many animal species provide care to their offspring as a mechanism to enhance their own fitness. In mammals, this behavior is expressed mostly by the females, but also by males of some species. Proximally, rates of paternal offspring care have been linked to organizational and activational effects of testosterone. Specifically, intrauterine position of male fetuses is associated with differential exposure to testosterone, leading to development of males with different levels of masculinization (assessed through differences in the length of the anogenital distance (AGD). The relative roles played by organizational and activational effects of testosterone on male parental care remain unclear. In this study, we aimed to determine if male sex-biased uterine environment and testosterone levels across the breeding period explain variation in paternal care in the social rodent, Octodon degus. Neither quantity (time with the offspring) nor quality (frequency of grooming and retrieving) of paternal care was affected by male sex-biased uterine environment, nor did paternal care significantly differ across the different stages of male reproduction. In contrast, paternal care was associated with maternal care. Quantity of male care decreased with increasing quantity of maternal care, and quality of male care increased with increasing quality of maternal care. While serum testosterone did not differ between males with different sex-biased uterine environment, male testosterone tended to increase during mating and decrease when pregnant females or offspring were present.

On the Role of Testosterone in Anxiety-Like Behavior Across Life in Experimental Rodents.

Testosterone affects brain functions and might explain some of the observed behavioral sex differences. Animal models may help in elucidating the possible involvement of sex hormones in these sex differences. The effects of testosterone have been intensively investigated, especially in anxiety models. Numerous experiments have brought inconsistent results with either anxiolytic or anxiogenic effects. Besides methodological variations, contradictory findings might be explained by the divergent metabolism of testosterone and its recognition by neurons during prenatal and postnatal development. Gonadectomy and subsequent supplementation have been used to study the role of sex hormones. However, the variable duration of hypogonadism might affect the outcomes and the effect of long-term androgen deficiency is understudied. Testosterone can be metabolized to dihydrotestosterone strengthening the androgen signaling, but also to estradiol converting the androgen to estrogen activity. Moreover, some metabolites of testosterone can modulate γ-aminobutyric acid and serotonergic neurotransmission. Here we review the currently available experimental data in experimental rodents on the effects of testosterone on anxiety during development. Based on the experimental results, females are generally less anxious than males from puberty to middle-age. The anxiety-like behavior of females and males is likely influenced by early organizational effects, but might be modified by activational effects of testosterone and its metabolites. The effects of sex hormones leading to anxiogenesis or anxiolysis depend on factors affecting hormonal status including age. The biological and several technical issues make the study of effects of testosterone on anxiety very complex and should be taken into account when interpreting experimental results.

An increase in estradiol facilitates the onset of paternal behavior in the dwarf hamster (Phodopus campbelli)

In the dwarf hamster (Phodopus campbelli), activational effects of testosterone (T) and estradiol (E2) in the regulation of paternal behavior have been repeatedly rejected because peripheral concentrations of E2 do not change across the reproductive cycle of males. Further, castration no affected paternal behavior despite that both T and E2 concentrations decreased significantly. However, the role of these hormones has not been evaluated in models of castration and hormonal replacement in virgin males. Here, we analysed the effects of E2 and T in paternal behavior in virgin male dwarf hamster (Phodopus campbelli). Thirty paternal (PAT) males were bilaterally castrated; of them, 10 were implanted with T, 10 with E2 and 10 males received no treatment. Other 10 PAT males underwent sham-castration. Seventeen aggressive (AGG) males were also bilaterally castrated; of these, 10 AGG received E2 replacement, 7 were not treated. Other 7 AGG males were submitted to sham-castration. Following treatments, paternal behavior tests were conducted again. T and E2 levels in plasma were quantified by radioimmunoassay (RIA). The results showed that the treatments did not affect the paternal behavior of males that were initially paternal. Neither castration nor sham-castration surgery affected the behavior of AGG males. However, when these males were treated with E2 and the concentrations of this hormone increase significantly they became paternal. Our data suggest that an increase in E2 levels shifted infanticidal behavior to paternal behavior in dwarf hamster.

Effects of testosterone dose on spatial memory among castrated adult male rats

Previous research on the activational effects of testosterone on spatial memory has produced mixed results, possibly because such effects are dose-dependent. We tested a wide range of testosterone doses using two spatial memory tasks: a working-reference memory version of the radial-arm maze (RAM) and an object location memory task (OLMT). Adult male Sprague-Dawley rats were castrated or sham-castrated and given daily injections of drug vehicle (Oil Sham and Oil GDX) or one of four doses of testosterone propionate (0.125, 0.250, 0.500, and 1.000 mg T) beginning seven days before the first day of behavioral tests and continuing throughout testing. For the RAM, four arms of the maze were consistently baited on each day of testing. Testosterone had a significant effect on working memory on the RAM, with the Oil Sham, 0.125 mg T, and 0.500 mg T groups performing better than the Oil GDX group. In contrast, there was no significant effect of testosterone on spatial reference memory on the RAM. For the OLMT, we tested long-term memory using a 2 h inter-trial interval between first exposure to two identical objects and re-exposure after one object had been moved. Only the 0.125 and 0.500 mg T groups showed a significant increase in exploration of the moved object during the testing trials, indicating better memory than all other groups. Testosterone replacement restored spatial memory among castrated male rats on both behavioral tasks, but there was a complex dose-response relationship; therefore, the therapeutic value of testosterone is likely sensitive to dose.

Male-typical visuospatial functioning in gynephilic girls with gender dysphoria - organizational and activational effects of testosterone.

Sex differences in performance and regional brain activity during mental rotation have been reported repeatedly and reflect organizational and activational effects of sex hormones. We investigated whether adolescent girls with gender dysphoria (GD), before and after 10 months of testosterone treatment, showed male-typical brain activity during a mental rotation task (MRT). Girls with GD underwent fMRI while performing the MRT twice: when receiving medication to suppress their endogenous sex hormones before onset of testosterone treatment, and 10 months later during testosterone treatment. Two age-matched control groups participated twice as well. We included 21 girls with GD, 20 male controls and 21 female controls in our study. In the absence of any group differences in performance, control girls showed significantly increased activation in frontal brain areas compared with control boys (pFWE = 0.012). Girls with GD before testosterone treatment differed significantly in frontal brain activation from the control girls (pFWE = 0.034), suggesting a masculinization of brain structures associated with visuospatial cognitive functions. After 10 months of testosterone treatment, girls with GD, similar to the control boys, showed increases in brain activation in areas implicated in mental rotation. Since all girls with GD identified as gynephilic, their resemblance in spatial cognition with the control boys, who were also gynephilic, may have been related to their shared sexual orientation rather than their shared gender identity. We did not account for menstrual cycle phase or contraceptive use in our analyses. Our findings suggest atypical sexual differentiation of the brain in natal girls with GD and provide new evidence for organizational and activational effects of testosterone on visuospatial cognitive functioning.

Contribution of Endogenous Spinal Endomorphin 2 to Intrathecal Opioid Antinociception in Rats Is Agonist Dependent and Sexually Dimorphic

Interactions between exogenous and endogenous opioids are not commonly investigated as a basis for sexually dimorphic opioid analgesia. We investigated the influence of spinal endomorphin 2 (EM2), an endogenous mu-opioid receptor (MOR) ligand, on the spinal antinociception produced by intrathecally administered opioids. Activation of spinal MORs facilitated spinal EM2 release. This effect was sexually dimorphic, occurring in males but not in females. Although activational effects of testosterone were required for opioid facilitation of spinal EM2 release in males, the absence of this facilitation in females did not result from either insufficient levels of testosterone or mitigating effects of estrogens. Strikingly, in males, the contribution of spinal EM2 to the analgesia produced by intrathecally applied MOR agonists depended on their analgesic efficacy relative to that of EM2. Spinal EM2 released by the higher efficacy MOR agonist sufentanil diminished sufentanil's analgesic effect, whereas EM2 released by the lower efficacy morphine had the opposite effect on spinal morphine antinociception. Understanding antithetical contributions of endogenous EM2 to intrathecal opioid antinociception not only enlightens the selection of opioid medications for pain management but also helps to explain variable sex dependence of the antinociception produced by different opioids, facilitating the acceptance of sexually dimorphic antinociception as a basic tenet. PerspectiveThe male-specific MOR-coupled enhancement of spinal EM2 release implies a parallel ability to harness endogenous EM2 antinociception. The inferred diminished ability of females to utilize the spinal EM2 antinociceptive system could contribute to their greater frequency and severity of chronic pain syndromes.

Maturation of social reward in adult male Syrian hamsters does not depend on organizational effects of pubertal testosterone

The rewarding value of female sexual stimuli develops across puberty, as sexually-naïve adult, but not prepubertal, male hamsters show a conditioned place preference (CPP) for both vaginal secretions and a receptive female. Similarly, only adults show an endogenous testosterone surge when they encounter vaginal secretions. Testosterone by itself can condition a place preference in male rodents. Therefore, Experiment 1 assessed whether the endogenous testosterone surge elicited by vaginal secretions is necessary to show a CPP. Both gonad-intact and gonadectomized, testosterone-treated adult males showed a CPP for vaginal secretions, indicating that the rewarding value of this social cue is independent of an endogenous testosterone surge. However, organizational effects of pubertal testosterone could be necessary for adolescent development of social reward, as pubertal testosterone organizes adult-typical expression of sexual behavior. To investigate this possibility, in Experiment 2, sexually-naïve prepubertal and adult male hamsters were gonadectomized and received testosterone-filled capsules four weeks later. Testing began after two weeks of testosterone replacement. Adult males showed a CPP for both vaginal secretions and a receptive female, whether or not they experienced pubertal testosterone. Thus, the acquisition of positive valence of sexual stimuli is not organized by pubertal testosterone. Taken together, the ability of female sexual stimuli to serve as an unconditioned reward to adult male hamsters is independent of the chemosensory-induced endogenous testosterone surge and also organizational effects of pubertal testosterone. Instead, sexual reward may be dependent either on activational effects of testosterone or gonadal hormone-independent mechanisms.

Pubertal testosterone organizes regional volume and neuronal number within the medial amygdala of adult male Syrian hamsters

The medial amygdala plays a key role in regulating adult social behavior and undergoes structural changes during puberty that may be driven by gonadal hormone secretion during this developmental period. The current study sought to investigate potential organizational effects of testosterone during puberty, activational effects of testosterone in adulthood, and any interactions on regional volume and neuronal number of the medial amygdala. Male Syrian hamsters either did or did not experience endogenous testosterone during pubertal brain development, and then received either testosterone-filled or blank capsules during adulthood 2weeks before tissue collection. The results show that pubertal testosterone has long-term organizational effects on volume of specific subregions of the medial amygdala such that the presence of pubertal testosterone resulted in 1) decreased volume of the anterior ventral amygdala and, to a lesser extent, the anterior dorsal medial amygdala; and 2) increased volume of the posterior dorsal medial amygdala. Both effects were independent of the presence of testosterone during adulthood. Pubertal testosterone also decreased neuronal number in the anterior dorsal medial amygdala, suggesting a possible mechanism by which pubertal testosterone decreases volume in this subregion. In addition, there was a significant interaction between pubertal and adult testosterone, such that testosterone in adulthood increased the number of neurons in the posterior ventral medial amygdala only in males that did not experience endogenous pubertal testosterone. In conclusion, pubertal testosterone organizes the medial amygdala in a subregion-specific manner, which may contribute to the maturation of adult-typical social behavior.

Organizational and Activational Effects of Testosterone on Masculinization of Female Physiological and Behavioral Stress Responses

The prevalence of affective disorders is two times greater in women than in men. The onset of anxiety and depression occurs at different ages that may correspond to key developmental periods when the brain is more vulnerable to hormonal and exogenous influences. Because stressful life events can precipitate disease onset, the development of greater stress sensitivity in females may contribute to their increased vulnerability. Gonadal hormone exposure in males during early development and again from puberty onward plays a prominent role in sexually dimorphic brain formation, possibly contributing to sex differences in stress responsivity. Therefore, organizational effects of testosterone propionate (TP) administered postnatally and activational effects of TP administered beginning at puberty on adult female physiological and behavioral stress responses were examined in mice. Although the activational effects of TP in females ameliorated the sex difference in the hypothalamic-pituitary-adrenal axis stress response, there was no effect of postnatal TP. Similarly, higher immobile time in intact females in the tail suspension test was blunted by activational TP in the absence of postnatal TP. However, in the marble-burying test of anxiety-like behaviors, organizational and activational TP independently resulted in increased burying behaviors. These results show that TP administration has distinct effects on reducing physiological and behavioral stress responsivity in rodent models and suggest that sex differences in these responses may partially result from the absence of testosterone in females.

Organizational and activational effects of testosterone on carrageenan-induced inflammatory pain and morphine analgesia

Men are typically reported to have higher pain thresholds than women. Gonadal hormones, particularly testosterone for males, may contribute to this effect. This study tested whether changes in the male hormonal milieu early or late in development alter the inflammatory pain induced by carrageenan (CARR, 3%, intraarticular). Male rats were either gonadectomized or sham gonadectomized neonatally. Once adults, the same rats underwent either sham surgery or gonadectomy, and received a testosterone or oil implant. After baseline testing two weeks later, animals were tested in response to mechanical and thermal stimulation following CARR-induced inflammation and injection of saline, 1 mg/kg, or 5 mg/kg morphine. Hormone alterations did not affect baseline responses, but CARR induced mechanical and thermal hyperalgesia in the injured limb. Gonadectomy in adult males injected with saline enhanced inflammation-induced sensitivity to mechanical but not thermal stimulation and the effect was reversed by testosterone. After inflammation, saline-treated males gonadectomized neonatally displayed lower mechanical threshold than control sham animals but this effect was not reversed by testosterone. Both doses of morphine increased mechanical and thermal thresholds. However, compared with the control group, 1 mg/kg morphine was equally effective in reducing mechanical hyperalgesia among groups of animals gonadectomized as adults, but less effective in males gonadectomized neonatally. The results suggest that in males: 1. the antihyperalgesic effect of testosterone (or its metabolites) in CARR-induced inflammation is established during development and maintained by circulating levels of testosterone in adulthood; 2. the nociception-related interaction between the opioid and gonadal systems influences the sensitivity to mechanical stimuli and is likely established during the period of sexual differentiation.

Testosterone suppresses circadian responsiveness to social cues in the diurnal rodent Octodon degus.

The diurnal, social rodent Octodon degus displays a robust sex difference in the ability to use social cues to facilitate reentrainment following a phase advance of the light cycle. Adult females housed with a female social cue donor reentrained 25% to 40% faster than did females reentraining alone. However, reentrainment rates of males were unaffected by exposure to female social cues during reentrainment. The authors hypothesized that males were less sensitive to the reentrainment-enhancing effects of social cues and that their higher threshold to the stimuli could be overcome if the social cues were either increased in strength or salience. Housing a male with two females significantly shortened the time to reentrain following a 9-h phase advance (p = 0.002). Housing with a sister had no effect on reentrainment. Therefore, male degus are able to respond to social cues but require the stimulus to be stronger than that for females. The effect of testosterone was tested by comparing reentrainment rates of castrated males before and after testosterone replacement both with and without a female social cue donor. Castrated males responded to a single female social cue donor, reentraining 35% faster than when housed alone (p = 0.006), whereas the time to reentrainment of intact males and males with testosterone capsule implants did not differ. Intact females were also implanted with testosterone and phase shifted with and without donors. Testosterone treatment eliminated the increase in reentrainment rates in the presence of social cues. The authors conclude that the rate of recovery from odor-enhanced phase shifts is modulated by activational effects of testosterone in male degus. Testosterone is also effective in suppressing social cue responsiveness in females, suggesting that testosterone's effects on responsiveness are not sexually dimorphic. This hormonal effect likely occurs by altering sensory system functions or CNS response to sensory information.

The Interaction between Organizational and Activational Effects of Testosterone in the Control of Early Aggression in Birds: A Comment on Sasvári, Hegyi & Péczely

Corresponding author: Albert F. H. Ros, Unidade de InvestigacE aA o em EcoEtologo a, Instituto Superior de Psicologia Aplicada, Rua Jardim do Tabaco, 34, 1149±041 Lisboa, Portugal. E-mail: aros@ispa.pt Recently, Sasva ri et al. (1999) published a paper in this journal on the relationship between brood reduction and testosterone levels in the asynchronously hatching chicks of the white stork (Ciconia ciconia) in which they showed that levels of testosterone in plasma, drawn at 5 and 15 d after hatching, decreased with laying order. They compared nests in which one or more chicks died at between the age of 5 and 15 d after hatching with nests in which no chick died in this period. In correlation with the mortality, parents of the ®rst group were in lower physical condition and delivered less food to the chicks than parents of the second group. Interestingly, in the ®rst group relative to the second group, levels of testosterone were increased nearly twofold in chicks that hatched ®rst and decreased about twofold in chicks that hatched last. Furthermore, chicks that hatched ®rst were twice as likely to be the ®rst to be fed in the ®rst group as compared with the second group. They did not observe overt aggression between siblings between the age of 5 and 15 d after hatching. The authors argued that the mortality di€erence in nests was a€ected by testosterone-dependent competition between the chicks, which in turn was a result of maternal transmission of hormones to the egg yolk. However, they did not take measurements of androgen concentrations in yolk samples to substantiate this rather complicated mechanism. Since testosterone levels were still elevated at day 5 after hatching and increased from day 5 to day 15 after hatching, a maternal Ethology 107, 851Ð853 (2001) O 2001 Blackwell Wissenschafts-Verlag, Berlin ISSN 0179±1613

Activational effects of testosterone on cognitive function in men

Objectives: The effect of testosterone (T) on sexual function in men is well established. However, less is known about its effects on cognitive function. The aim of this study is to investigate the relationship between T levels and sex-typed cognitive abilities in both eugonadal and hypogonadal men. Design: A single-blind placebo-controlled design was employed in this study. Methods: Thirty healthy eugonadal men and seven hypogonadal men participated in the study. Eugonadal men were randomised into one of two treatment regimens: (1) active group – receiving 200 mg of T enanthate i.m. weekly for 8 weeks (raising T levels into the supraphysiological range) or (2) placebo group – receiving 200 mg of sodium chloride i.m. weekly for 8 weeks. The hypogonadal group received the physiological replacement dose of 200 mg T enanthate i.m. bi-weekly for 8 weeks. All groups underwent a battery of neuropsychological tests and had circulating T measured at baseline, and at weeks 4 and 8 during treatment. Results: A significant time by group interaction effect was found in the measure of spatial ability (i.e., block design test) indicating that the active group's performance declined significantly at week 4, compared to placebo group ( F(4,64)=3.78, P<0.01). Conversely, the active group performed significantly better than the placebo group in the measure of verbal fluency (i.e., the Controlled Oral Word Association Test) at week 4 ( F(4,64)=2.54, P<0.05). No significant changes were found on any of the other tests. Generally, the hypogonadal group performed less well than the eugonadal groups on all tests. Conclusions: These results offer support to the notion that increased T has a differential effect on cognitive function, inhibiting spatial abilities while improving verbal fluency in eugonadal men.

Sex differences in EEG in adult gonadectomized rats before and after hormonal treatment.

EEG activity was recorded from the left and right parietal cortex in adult male and female Wistar rats that were gonadectomized (GNX) after puberty during 2 days without and 3 days with hormonal treatment (either testosterone propionate, 5 alpha-DHT or vehicle in males and progesterone, estradiol benzoate or vehicle in females). In contrast to EEG characteristics reported for intact rats, GNX abolished right over left parietal activation in both sexes and, sex differences in EEG interhemispheric correlation and in theta and delta relative power in the right parietal; additionally GNX males showed higher absolute power than females. Hormonal treatment reestablished interparietal asymmetry in both sexes and a lack of sex differences in absolute power, however, it was not enough to reestablish sex differences in delta and theta proportion in the right parietal nor in interhemispheric correlation. Differential effects were obtained with testosterone propionate and 5 alpha-DHT in males suggesting that activational effects of testosterone on EEG are probably exerted through testosterone or its aromatized metabolites. The results of our study indicate that the activational effects of gonadal steroids after puberty are necessary for maintaining sex differences in the EEG of the adult rat.

Brain aromatase and the control of male sexual behavior

The activational effects of testosterone (T) on male copulatory behavior are mediated by its aromatization into estradiol. In quail, we have shown by stereotaxic implantation of steroids and metabolism inhibitors and by electrolytic lesions that the action of T and its aromatization take place in the sexually dimorphic medial preoptic nucleus (POM). The distribution and regulation of brain aromatase was studied in this species by product-formation assays measuring aromatase activity (AA) in microdissected brain regions and by immunocytochemistry (ICC). Aromatase-immunoreactive (ARO-ir) neurons were found in four brain regions: the POM, the septal region, the bed nucleus of the stria terminals (BNST) and the tuberal hypothalamus. ARO-ir cells actually outline the POM boundaries. ARO-ir material is found not only in the perikarya of neurons but also in the full extension of their cellular processes including the axons and the presynaptic boutons. This is confirmed at the light level by the demonstration of immunoreactive fibers and punctate structures in brain regions that are sometimes fairly distant from the closest ARO-ir cells. A lot of ARO-ir cells in the POM and BNST do not contain immunoreactive estrogen receptors (ER-ir) as demonstrated by double label ICC. These morphological data suggest an unorthodox role for the enzyme or the locally formed estrogens. In parallel with copulatory behavior, the preoptic AA decreases after castration and is restored by T to levels seen in sexually mature males. This probably reflects a change in enzyme concentration rather than a modulation of the activity in a constant number of molecules since the maximum enzymatic velocity ( V max) only is affected while the affinity ( K m ) remains unchanged. In addition, T increases the number of ARO-ir neurons in POM and other brain areas suggesting that the concentration of the antigen is actually increased. This probably involves the direct activation of aromatase transcription as demonstrated by RT-PCR studies showing that aromatase mRNA is increased following T treatment of castrates. These activating effects of T seem to result from a synergistic action of androgenic and estrogenic metabolites of the steroid. The anatomical substrate for these regulations remains unclear at present especially in POM where ARO-ir cells do not in general contain ER-ir while androgen receptors appear to be rare based on both [ 3H] dihydrotestosterone autoradiography and ICC. Transynaptic mechanisms of control may be considered. A modulation of brain aromatase by catecholamines is also suggested by a few pharmacological studies. This notion is further supported by anatomical data demonstrating dense projections of dopamine β-hydroxylase and tyrosine hydroxylase-immunoreactive fibers around ARO-ir cells.

Uterine position and conditioned taste aversion.

Three experiments were designed to determine the influence of uterine position on the performance of female rats in a conditioned taste aversion paradigm. The first and second experiments confirmed a differential behavioral response by males and females during acquisition and extinction of the conditioned taste aversion. However, no differences were found between females that had caudal male littermates in utero (MF) and females that had no caudal male littermates (FF). In the third experiment, in which testosterone was administered to females throughout testing, MF females showed an increased sensitivity to testosterone and a more prolonged rate of extinction than FF females. Exposure to testosterone during prenatal development heightened postnatal responsiveness to testosterone in female rats. The results are discussed in terms of the organizational and activational effects of testosterone on behavior in a conditioned taste aversion situation.