Activational Effects Of Sex Hormones Research Articles

Unveiling the Influence of the Menstrual Cycle on Mental Rotation Abilities: A Comparative Analysis of Three-Dimensional vs. Two-Dimensional Tasks

The activational effects of sex hormones on spatial ability have been well documented. It has been suggested that these effects might be related to hormonally induced changes in interhemispheric communication. In this EEG study, we opted to explore menstrual cycle-related changes in the efficacy of solving mental rotation tasks and laterality indices while participants were engaged with the tasks. We compared 2D and 3D mental rotation tasks, as they differ both psychometrically and in terms of lateralization. A group (n = 39) of healthy young women was tested twice, once during the mid-luteal (high estrogen and progesterone) and once during the early follicular (low levels of sex hormones) phase of menstrual cycle. The differences in power within the same frequency band on homologous sites of the left and right hemispheres were then calculated. Participants were faster, more accurate, and showed higher laterality scores when solving 3D mental rotation tasks in the early follicular phase compared to the mid-luteal phase. This indicates a higher lateralization of this specific spatial function when the levels of sex hormones are low. However, for 2D mental rotation tasks, participants showed neither shifts in efficacy nor in hemispheric laterality as a function of the menstrual cycle. This pattern of results provides further support for the notion that fluctuations in sex hormones affect laterality, and consequently, the expression of lateralized cognitive abilities.

Sexual Differentiation Specifies Cellular Responses to DNA Damage.

Significant sex differences exist across cellular, tissue organization, and body system scales to serve the distinct sex-specific functions required for reproduction. They are present in all animals that reproduce sexually and have widespread impacts on normal development, aging, and disease. Observed from the moment of fertilization, sex differences are patterned by sexual differentiation, a lifelong process that involves mechanisms related to sex chromosome complement and the epigenetic and acute activational effects of sex hormones. In this mini-review, we examine evidence for sex differences in cellular responses to DNA damage, their underlying mechanisms, and how they might relate to sex differences in cancer incidence and response to DNA-damaging treatments.

Considerations for Studying Sex as a Biological Variable in Spinal Cord Injury

In response to NIH initiatives to investigate sex as a biological variable in preclinical animal studies, researchers have increased their focus on male and female differences in neurotrauma. Inclusion of both sexes when modeling neurotrauma is leading to the identification of novel areas for therapeutic and scientific exploitation. Here, we review the organizational and activational effects of sex hormones on recovery from injury and how these changes impact the long-term health of spinal cord injury (SCI) patients. When determining how sex affects SCI it remains imperative to expand outcomes beyond locomotor recovery and consider other complications plaguing the quality of life of patients with SCI. Interestingly, the SCI field predominately utilizes female rodents for basic science research which contrasts most other male-biased research fields. We discuss the unique caveats this creates to the translatability of preclinical research in the SCI field. We also review current clinical and preclinical data examining sex as biological variable in SCI. Further, we report how technical considerations such as housing, size, care management, and age, confound the interpretation of sex-specific effects in animal studies of SCI. We have uncovered novel findings regarding how age differentially affects mortality and injury-induced anemia in males and females after SCI, and further identified estrus cycle dysfunction in mice after injury. Emerging concepts underlying sexually dimorphic responses to therapy are also discussed. Through a combination of literature review and primary research observations we present a practical guide for considering and incorporating sex as biological variable in preclinical neurotrauma studies.

The role of sex hormones and of 2D:4D ratio in individual differences in cognitive abilities

ABSTRACTThe present study aimed at investigating the role of sex hormones in individual differences in cognitive abilities. This was achieved by a combination of two methods, reflecting 2 critical periods of hormonal secretion: prenatal, based on the 2D:4D ratio, and postnatal, based on circulating hormone levels. Both methods were tested in 39 men and 41 women, who completed a battery of 6 cognitive tasks. Results showed significant sex differences on the mental rotation task, with men outperforming women. A positive correlation was found between testosterone and performance on the mental rotation task for the combined sample (men and women). A significant interaction was found between sex and estrogen on mental rotation task. Findings also revealed a significant interaction between sex and right hand 2D:4D ratio on different memory tasks. Findings regarding between- and within-sex differences in cognition are discussed in light of the organisational and activational effects of sex hormones.

Sex and the development of Alzheimer's disease.

Men and women exhibit differences in the development and progression of Alzheimer's disease (AD). The factors underlying the sex differences in AD are not well understood. This Review emphasizes the contributions of sex steroid hormones to the relationship between sex and AD. In women, events that decrease lifetime exposure to estrogens are generally associated with increased AD risk, whereas estrogen-based hormone therapy administered near the time of menopause may reduce AD risk. In men, estrogens do not exhibit age-related reduction and are not significantly associated with AD risk. Rather, normal age-related depletions of testosterone in plasma and brain predict enhanced vulnerability to AD. Both estrogens and androgens exert numerous protective actions in the adult brain that increase neural functioning and resilience as well as specifically attenuating multiple aspects of AD-related neuropathology. Aging diminishes the activational effects of sex hormones in sex-specific manners, which is hypothesized to contribute to the relationship between aging and AD. Sex steroid hormones may also drive sex differences in AD through their organizational effects during developmental sexual differentiation of the brain. Specifically, sex hormone actions during early development may confer inherent vulnerability of the female brain to development of AD in advanced age. The combined effects of organizational and activational effects of sex steroids yield distinct sex differences in AD pathogenesis, a significant variable that must be more rigorously considered in future research. © 2016 Wiley Periodicals, Inc.

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.

Sex differences in ischemic stroke sensitivity are influenced by gonadal hormones, not by sex chromosome complement.

Epidemiologic studies have shown sex differences in ischemic stroke. The four core genotype (FCG) mouse model, in which the testes determining gene, Sry, has been moved from Y chromosome to an autosome, was used to dissociate the effects of sex hormones from sex chromosome in ischemic stroke outcome. Middle cerebral artery occlusion (MCAO) in gonad intact FCG mice revealed that gonadal males (XXM and XYM) had significantly higher infarct volumes as compared with gonadal females (XXF and XYF). Serum testosterone levels were equivalent in adult XXM and XYM, as was serum estrogen in XXF and XYF mice. To remove the effects of gonadal hormones, gonadectomized FCG mice were subjected to MCAO. Gonadectomy significantly increased infarct volumes in females, while no change was seen in gonadectomized males, indicating that estrogen loss increases ischemic sensitivity. Estradiol supplementation in gonadectomized FCG mice rescued this phenotype. Interestingly, FCG male mice were less sensitive to effects of hormones. This may be due to enhanced expression of the transgene Sry in brains of FCG male mice. Sex differences in ischemic stroke sensitivity appear to be shaped by organizational and activational effects of sex hormones, rather than sex chromosomal complement.

Sex chromosome complement influences operant responding for a palatable food in mice.

The procurement and consumption of palatable, calorie-dense foods is influenced by the nutritional and hedonic value of foods. Although many factors can influence the control over behavior by foods rich in sugar and fat, emerging evidence indicates that biological sex may play a particularly crucial role in the types of foods individuals seek out, as well as the level of motivation individuals will exert to obtain those foods. However, a systematic investigation of food-seeking and consumption that disentangles the effects of the major sex-biasing factors, including sex chromosome complement and organizational and activational effects of sex hormones, has yet to be conducted. Using the four core genotypes mouse model system, we separated and quantified the effects of sex chromosome complement and gonadal sex on consumption of and motivation to obtain a highly palatable solution [sweetened condensed milk (SCM)]. Gonadectomized mice with an XY sex chromosome complement, compared with those with two X chromosomes, independent of gonadal sex, appeared to be more sensitive to the reward value of the SCM solution and were more motivated to expend effort to obtain it, as evidenced by their dramatically greater expended effort in an instrumental task with progressively larger response-to-reward ratios. Gonadal sex independently affected free consumption of the solution but not motivation to obtain it. These data indicate that gonadal and chromosomal sex effects independently influence reward-related behaviors, contributing to sexually dimorphic patterns of behavior related to the pursuit and consumption of rewards.

Effect of neonatal ovariectomy and estradiol treatment on corticosterone release in response to stress in the adult female rat

Although organizational effects of sex hormones in early life on hypothalamic–pituitary–adrenal function have been reported for males, the findings are mixed for females, likely the result of not controlling for adult gonadal status. In experiment 1, females were ovariectomized (OVX) either on postnatal day 1 or as adults and given estradiol benzoate (EB) and progesterone implants or not as adults. Corticosterone release in response to restraint stress was responsive to hormonal replacement irrespective of timing of OVX: without replacement, both OVX groups had lower corticosterone concentrations after restraint stress than did OVX groups with replacement and gonadally intact females. Thus, neonatal OVX did not alter the activational effects of sex hormones in adulthood. In a second experiment, females administered a dose of EB on postnatal day 1 had a more rapid decline of corticosterone concentrations after restraint as adults compared to oil-treated females, irrespective of whether they were OVX as neonates or as adults (all groups were given estradiol replacement as adults). Thus, evidently there are organizational effects of the sex hormonal milieu of the neonatal female, although this is a modest effect compared to previous reports in males.

Activational effects of sex hormones on cognition in men

Changing world demographic patterns, such as the increasing number of older people and the growing prevalence of cognitive impairment, present serious obstacles to preserving the quality of life and productivity of individuals. The severity of dementia varies from subclinical, mild cognitive impairment to neurodegenerative diseases such as Alzheimer's. In normally ageing men, these age-related cognitive declines are accompanied by gradual but marked decreases in androgen levels and changes in other hormone profiles. While developmental effects of sex hormones on cognition in the pre- and early postnatal period have been demonstrated, their activational effects in later life are still a focus of contemporary research. Although there is a plethora of published research on the topic, results have been inconsistent with different studies reporting positive, negative or no effects of sex hormones on various aspects of mental agility. This review summarizes the evidence supporting the biological plausibility of the activational effects of sex hormones upon cognition and describes the mechanisms of their actions. It offers a comprehensive summary of the studies of the effects of sex hormones on fluid intelligence in men utilizing elements from the Cochrane Collaboration Guidelines for Reviews. The results of both observational (cross-sectional and longitudinal) and interventional studies published to date are collated in table form and further discussed in the text. Factors contributing to the difficulties in understanding the effects of sex hormones on cognition are also examined. Although there is convincing evidence that steroid sex hormones play an organizational role in brain development in men, the evidence for activational effects of sex hormones affecting cognition in healthy men throughout adult life remains inconsistent. To address this issue, a new multifactorial approach is proposed which takes into account the status of other elements of the sex hormones axis including receptors, enzymes and other hormones.

Sex Hormones and Cognitive Functioning of Women

This paper discusses the organisational and activational effects of sex hormones, and their influence on cognitive functioning. Previous studies have shown gender differences in specific cognitive abilities. Women generally show an advantage in verbal fluency, perceptual speed and accuracy, as well as in fine motor skills, while men generally show an advantage in spatial and mathematical abilities. These differences in cognitive functioning are thought to occur as a result of foetal brain exposure to different levels of sex hormones during prenatal life. Additional evidence of organisational effects of sex hormones on cognitive functioning also comes from studies of subjects with genetic disorders, such as androgen insensitivity syndrome, congenital adrenal hyperplasia, and Tyrner syndrome.Furthermore, former investigations have shown that increase in female sex hormone in the late follicular and/or luteal phase of the menstrual cycle intensifies the typical female cognitive pattern of functioning with improved efficiency in tasks which are usually better performed by women. At the same time, low levels of such hormones that characterise the menstrual phase of the cycle intensify the typical male cognitive pattern of functioning with better efficiency in tasks which usually better performed by men.This paper also points to methodological differences between investigations of organizational and activational effects of sex hormones on cognitive functioning, as well a to the direction of future investigations.

Sex differences in emotionality in C3H/HeH mice, with hypogonadal mutant to distinguish activational effects of gonadal hormones

The C3H/HeH mouse strain has a mutant hypogonadal (hpg) variant, providing an animal model to examine the activational effects of sex hormones because reproductive maturation is arrested at a neonatal stage. Thus in the adult mouse, the circulating concentrations of sex steroids are extremely low. The present study used a series of tests to distinguish sex differences in behaviour: open field, locomotor activity, hyponeophagia, and novel location recognition. The results showed some evidence for a role of sex hormones in emotionality underscoring the potential utility of the hpg model, to distinguish activational effects in the C3H/HeH strain. However, the direction that the sex differences took varied by task: whilst males showed the predicted sex difference of relatively greater anxiety in the open field, hyponeophagia tests suggested higher emotionality in females. The hpg mice of both sexes showed a reduction in anxiety measured as hyponeophagia. Overall it can be concluded that this set of experiments supports the potential of the hpg model to investigate hormonal influences on emotionality.

Sex differences in formalin-induced pain in prenatally stressed infant rats

The aim of this work was to study the effects of prenatal stress on nociceptive responses in the formalin test in female and male infant (7-day-old) Long-Evans hooded rats. Prenatally stressed infant rats displayed biphasic flinching+ shaking behavior whereas non-stressed animals showed only a weak second phase. Pain sensitivity in prenatally stressed males was significantly greater than that of prenatally non-stressed males during the second phase only; there were no differences in pain sensitivity between prenatally stressed and non-stressed females. Moreover prenatally stressed male rats pups demonstrated that the second phase of the response to formalin was enhanced relative to the second phase in stressed females. The current and previous data [Butkevich IP, Barr GA, Mikhailenko VA, Otellin VA. Increased formalin-induced pain and expression of fos neurons in the lumbar spinal cord of prenatally stressed infants rats. Neurosci Lett 2006a;403:222–226] show increased tonic pain in prenatally stressed infant rats and a large increase in the number of formalin-induced fos-like immunoreactivity in the spinal cord dorsal horn. There is a concomitant decrease in serotonin-like immunoreactivity in the lumbar spinal cord dorsal horn [Butkevich IP, Barr GA, Otellin VA. Effect of prenatal stress on behavioral and neural indices of formalin-induced pain in infant rats. Abstracts, 35th Annual Meeting of Soc. For Neurosci. 2005a. Program No. 512.4 Washington, DC: Society for Neuroscience]. Given the decreased level of perinatal testosterone in prenatally stressed rats to which infant males are more sensitive than females, we suggest that these hormonal, behavioral and neuronal indices are strongly interrelated in prenatally stressed 7-day-old rat pups and that the decreased surge of testosterone may contribute to the increased behavioral response in the second phase in male rat pups. Mechanisms underlying the behavioral pain response induced by inflammation in prenatally stressed rat pups are characterized by sexual dimorphism even prior to the activational effects of sex hormones.

The organizational and activational effects of sex hormones on tactile and thermal hypersensitivity following lumbar nerve root injury in male and female rats

Considerable evidence exists for sex differences in human pain sensitivity. Women typically report a higher incidence of various painful conditions and report that the conditions are more painful when compared to men. In the present study, we sought to determine whether sex differences in pain sensitivity are observed using a lumbar radiculopathy model of low back pain in the rat and whether removal or alteration of gonadal hormones at specific timepoints can modulate these sex differences. Pubertal and adult male and female Sprague–Dawley rats were castrated 2 or 6 weeks prior to L5 nerve root injury to determine the activational hormonal effects. In a separate study, neonatal male and female Sprague–Dawley rats were either castrated or injected with testosterone, respectively, on postnatal day one to determine the organizational effects of gonadal hormones on L5 nerve root injury-induced behavioral hypersensitivity. Our results demonstrate that there was a statistically significant sex difference in the magnitude of mechanical allodynia and thermal hyperalgesia following experimentally induced radiculopathy in the rat: females demonstrated decreased thresholds to tactile and thermal stimuli as compared to males. Furthermore, the enhanced female hypersensitivity was reversed in pubertal and adult animals ovariectomized 6 weeks, but not 2 weeks prior to L5 nerve root injury. Our results demonstrate that the activational effects of gonadal hormones mediate the enhanced female tactile and thermal hypersensitivity following L5 nerve root injury. These results suggest that manipulation of gonadal hormones may be a potential source for novel therapies for chronic pain in women.

Variation in symptom severity over the menstrual cycle of Schizophrenics

Numerous gender differences have been noted in schizophrenia, although the illness is equally common in both sexes. It has been suggested that these differences reflect prenatal organizational effects and subsequent activational effects of sex hormones (Seeman and Lang ! 990). One activational effect may be a protective influence of estrogens via their reduction of dopamine iDA) neurotransmission (Seeman 1982). Several observations can be explained via this mechanism (for review see Seeman and Lang 1990). For example, premenopausal women experience less severe expression of the illness and their psychotic symptoms respond to lower neuroleptic doses. Furthermore, fluctuations in estrogen levels correlate with schizophrenic ep;.sodes: relapse is relatively uncommon during pregr.ancy when estrogens levels are high; in contrast, vulnerability increases postpartum and after menopause--both are times of decreased estrogen. Exogenous estrogens may also help reduce schizophrenic symptomatology in women, especially recurrent exacerbations related to the menstrual cycle (for review see Felthous and Robinson 1981). Evidence from animal studies suggests that the protective effects of estrogens may relate to down-regulation of central nervous system (CNS) DA-D2 receptor sensitivity (Hafner et al 1991). Cor, sistent with this is the report that the rat's anterior pituitary contains fewer D2 receptors during the proestrus phase of its estrous cycle, when plasma estrogen is elevated (Pasqualini et al 1984; Pazos et al 1985). Reports that psychosis can exacerbate perimenstrually also implicate influences of sex hormones; however, specific menstrual phase as well as diagnosis (e.g., undetermined, mania, schizophrenia) varied both between and within studies (Brockingon et al 1988; Dennerstein et al 1983; Gerada and Reveley 1988; Glick and Stewarl 1980; Felthous and Robinson 1981).

Variations in sex-related cognitive abilities across the menstrual cycle

Sex differences in human cognitive and motor skills may in part be due to organizational or activational effects of sex hormones on the brain. In this study, an extensive battery of cognitive and motor tests was administered to normally cycling women at two phases of the menstrual cycle, in order to detect any hormone-mediated changes in performance. Results confirmed changes across the menstrual cycle on a variety of speeded manual and articulatory measures, and on some nonverbal/spatial tests. The results provide qualified support for the hypothesis that the high levels of gonadal steroids present at the luteal phase of the cycle may facilitate skills favoring females, but be detrimental to skills favoring males. The implications of these results for research in the area of human sex differences are discussed.

Developmental and activational effects of sex hormones on the attractiveness of dog urine

Adult male dogs were exposed to urine from five types of experimental donors: females ovariohysterectomized as adults (FOA), females treated with testosterone in utero (FTU), females treated with testosterone in early infancy (FTI), females treated with testosterone in utero and in early infancy (FTUI), males castrated as adults (MCA); and also to control urine from intact stud males (SM). Urine was collected from the five experimental groups of donors during three phases of the experiment: (a) during a period of no hormone treatment (NH); (b) following treatment with estradiol (E); and (c) following treatment with testosterone (T). Intact males were given no hormonal treatment and served as subjects and urine donors. Subjects spent about the same amounts of time investigating control SM urine in all three phases. In the NH phase, the investigation times for the five experimental samples were significantly greater than that of the SM sample. However, there were no significant differences between the investigation times of the five samples. During the E phase, in comparison with the NH phase, the investigation times were greater for all experimental samples. The increase in attractiveness was significant for FOA and FTU urine. During the T phase, compared with the NH phase, the investigation times were less for four experimental samples (FTU, FTI, FTUI and MCA urine), and FTI, FTUI and MCA urine were no longer preferred to the SM control. However, the decrease in attractiveness was significant for MCA urine only.

Gonadal hormones and sex differences in nonreproductive behaviors in rodents: Organizational and activational influences

Sex differences in many nonreproductive behaviors have been described in rodents. Among the behaviors that are sexually dimorphic in the rat are activity, aggression, pain, and taste sensitivity, food intake and body weight regulation, the learning and retention of certain kinds of mazes, avoidance responses, taste aversion, and performance on certain schedules of reinforcement. Gonadal hormones seem to be responsible, in part, for sex differences in these behaviors, but their contribution varies greatly with the behavior in question. Frequently, these sexually dimorphic behaviors are influenced both by organizational and activational actions of sex hormones. In other instances (e.g., maze learning and the acquisition of shuttle-box avoidance responses) organizational influences predominate. And while there is no sexually dimorphic behavior surveyed that can be shown to be influenced only by activational effects, wheel-running activity is clearly more strongly subject to activational than to organizational effects of the gonadal hormones. In general, only rudimentary information exists regarding the temporal limits of the period in development when organizational influences on nonsexual behaviors occur. The suggestion can be made that organizational influences often occur outside of the critical period for differentiation of the neuroendocrine system regulating cyclic release of gonadotrophins. Even for behaviors where organizational effects usually occur during a roughly delimited period of development, data for other behavioral systems suggest that the time limits during which organizational effects can occur are not rigidly fixed. Very little information exists regarding biochemical or neural mechanisms by which organizational or activational effects on sexually dimorphic nonreproductive behaviors are expressed. It is important to recognize for many of the sexually dimorphic behaviors in the rat that differences between the sexes are neither large nor absolute. This is especially true of several kinds of learning situations where groups of males and females typically differ in average levels of performance. Ostensibly minor variations in test procedure can abolish or accentuate the average difference in performance between the sexes. We are a long way from an adequate understanding of what factors are important, but such information could be quite helpful in estimating whether sex differences in certain laboratory learning tasks have any adaptive significance. Sex differences in nonreproductive behaviors may be influenced by many factors other than hormonal status. This greatly complicates a comparative analysis, but such an analysis will ultimately be necessary. What limited data exist on rodents suggest that: (1) Sexually dimorphic responses in the rat are often not similarly differentiated in the hamster, the gerbil, or the mouse; and (2) major differences exist among rodent species in hormonal effects on such responses. Over the last decade it has become clear that the behavioral effects of deliberate neurological insult are not necessarily the same in male and female rats (or in one case, in rhesus monkeys). Sex differences in the behavioral effects of ventromedial hypothalamic, lateral hypothalamic, septal, and striatal lesions in the rat and of orbital prefrontal cortex lesions in the monkey have been described. While information regarding hormonal modulation of these differences in response to brain damage is very limited, available data suggest both organizational and activational effects of sex hormones may be involved. It is too early to tell where this line of research may ultimately lead, but rather striking sex differences in the incidence of certain neurological disorders in humans suggest that further research may have both practical and theoretical significance.