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Interpreting sex differences in enamel hypoplasia in human and non-human primates: Developmental, environmental, and cultural considerations.

The purpose of this review is to provide a synoptic, critical evaluation of the evidence of, and potential etiological factors contributing to, sex differences in the expression of enamel hypoplasia (EH). Specifically, this review considers theoretical expectations and empirical evidence bearing on two central issues. The first of these is the impact of a theorized inherent male vulnerability to physiological stress on sex differences in EH. The second issue is the potential contribution to sex differences in EH of intrinsic differences in male and female enamel composition and development. To address this first issue, EH frequencies by sex are examined in samples subject to a high degree of physiological stress. Based on the concept of inherent male vulnerability (or female buffering), males in stressful environments would be expected to exhibit higher EH frequencies than females. This expectation is evaluated in light of cultural practices of sex-biased investment that mediate the relationship between environmental stress and EH expression. Defects forming prenatally afford an opportunity to study this relationship without the confounding effects of sex-biased postnatal investment. Data bearing on this issue derive from previously conducted studies of EH in permanent and deciduous teeth in both modern and archaeological samples as well as from new data on Indian schoolchildren. To address the second issue, fundamental male-female enamel differences are evaluated for their potential impact on EH expression. A large sex difference in the duration of canine crown formation in non-human primates suggests that male canines may have greater opportunity to record stress events than those of females. This expectation is examined in great apes, whose canines often record multiple episodes of stress and are sexually dimorphic in crown formation times. With respect to the first issue, in most studies, sex differences in EH prevalence are statistically nonsignificant. However, when sex differences are significant, there is a slight trend for them to be greater in males than in females, suggesting a weak influence of greater male vulnerability. Cultural practices of sex-biased investment in children appear to have greater impact on EH expression than does male vulnerability/female buffering. With respect to the second issue, sex differences in the composition and development of enamel were reviewed and determined to have limited or unknown impact on EH expression. Of these factors, only the duration of crown formation was expected to affect EH expression by sex within the great apes. The data support an association between higher defect counts in the canines of great ape males relative to those of females that may be the result of longer crown formation times in the canines of great ape males. This review concludes with an assessment of the nature of the evidence currently available to examine these issues and suggests future avenues for research focused on elucidating them.

Adaptation, Physiological↗

A developmental perspective of self-construals and sex differences: comment on Cross and Madson (1997)

S. E. Cross and L. Madson (1997) proposed that women and men differ in self-construals, with women as interdependent and men as independent, and that these construals are seen to underlie many sex differences in social behavior. In this article, the authors address the issues of sex differences in self-construals, the stability of self-construals, and the centrality of interdependence-independence to sex differences. They examine the proposal next from a developmental perspective, suggesting that development of the self does not precede children's gender-related behavior. Evidence regarding the socialization processes that may contribute to sex differences in self-construals is largely inconclusive, especially regarding the differential treatment of boys and girls by parents. Their developmental perspective provides insights into ways that Cross and Madson's approach can be elaborated to explain sex differences in social behavior.

Adult↗

Sex differences in the central nervous system actions of ethanol.

For many years, researchers have avoided including females in their research because of the poorly understood influences of cycling hormones. However, we are becoming increasingly aware that sex matters, showing that it is important to conduct studies in females as well as males. This review will focus on the central nervous system (CNS) actions of alcohol (ethanol) because we have found significant sex differences in ethanol actions at the molecular as well as the behavioral level. Most recently, in our studies of ethanol dependence and withdrawal, we found that female rats displayed a shorter time for recovery from ethanol withdrawal, assessed by measuring seizure susceptibility. We now report that this finding was confirmed with a second convulsant agent. Moreover, GABAA receptor function was differentially altered in ethanol-withdrawn female compared to male rats. Studies by other investigators have reported additional significant sex differences in ethanol seeking and drinking behaviors and across several measures of ethanol dependence and withdrawal. We are gaining a better understanding of how the actions of ethanol in the CNS overlay sex differences in brain architecture and the hormonal milieu. Therefore, it is not surprising to observe sex-selective effects on cellular and behavioral outcomes from ethanol consumption. While current research is focused on characterizing sex differences in the actions of ethanol, it has not yet reached the point where we can integrate our findings into a unifying concept of how being female differentially regulates CNS responses to ethanol. This is likely a result of the complexity of ethanol actions, involving multiple neurotransmitter systems and responses covering the spectrum from drug seeking behaviors to neuropathological consequences of ethanol misuse. Regardless, the observed sex differences in ethanol withdrawal are noteworthy because they suggest that treatment of alcoholism should be managed differently in women than in men. Finally, it remains important to compare and contrast responses in males and females because recent studies of sex differences in basic physiology have made it clear that being female impacts health and disease.

Alcohol Drinking↗

Sex differences in the hypothalamus in the different stages of human life.

Quite a number of structural and functional sex differences have been reported in the human hypothalamus and adjacent structures that may be related to not only reproduction, sexual orientation and gender identity, but also to the often pronounced sex differences in prevalence of psychiatric and neurological diseases. One of the recent focuses of interest in this respect is the possible beneficial effect of sex hormones on cognition in Alzheimer patients. The immunocytochemical localization of estrogen receptors (ER) alpha, beta and androgen receptors has shown that there are indeed numerous targets for sex hormones in the adult human brain. Observations in the infundibular nucleus have, however, indicated that in this brain area the hyperactivity resulting from a lack of estrogens in the menopause seems to protect females against Alzheimer changes, in contrast to males. It is thus quite possible that estrogen replacement therapy may, in these brain areas, lead to inhibition of neuronal metabolism and thus to the same proportion of Alzheimer changes as are observed in men. Knowledge about the functional sex differences in the brain and the effect of sex hormones on neuronal metabolism may thus provide clues not only for the possible beneficial effects of these hormones (e.g., on cognition or hypertension), but also on possible central side effects of estrogen replacement therapy.

Aging↗

Sex differences in opioid and N-methyl-D-aspartate mediated non-opioid biting fly exposure induced analgesia in deer mice.

There is evidence for sex differences in responses to noxious stimuli and in the expression and mediation of analgesia. In particular, results of investigations with swim stress and the more ethologically appropriate stress of predator odor exposure have suggested sex differences in N-methyl-D-aspartate (NMDA) receptor system involvement in the mediation of analgesia. Whether or not this sex difference generalizes to other environmental stressors is, however, not clear. Biting flies are a natural aversive stimuli commonly encountered by wild and domestic animals and humans. The present study examined the opioid and non-opioid mediated nociceptive (50 degrees C hot plate) responses of reproductive male and female deer mice, Peromyscus maniculatus, exposed to biting fly attack. A 30 min exposure to biting flies (stable flies, Stomoxys calcitrans (L.)) elicited a naloxone sensitive, opioid-mediated analgesia that was of a greater magnitude in males than in female deer mice. In contrast, a 5 min exposure to biting flies elicited a 'on-opioid' analgesia that was of similar magnitude in both sexes and insensitive to both naloxone and the specific kappa opiate antagonist, nor-binaltorphimine. In male mice this non-opioid analgesia was antagonised by the competitive NMDA antagonist, NPC 1262, while in reproductive females the biting fly-induced analgesia was insensitive to NPC 12626. These results show that there are sex differences in NMDA involvement in the mediation of the non-opioid analgesia arising from brief exposure to the stress of biting fly attack. These data from a common, natural environmental challenge support the presence of basic sex difference in NMDA involvement in the mediation of stress-induced analgesia.

Amino Acids↗

Sex difference in perceptual-verbal ability in relation to body size.

Sex difference in verbal ability was reconsidered in relation to body size. The perceptual-verbal ability (PVA) was assessed using the A's Test. For the raw data, women excelled men, as expected. PVA positively correlated with height and weight of the subjects, but only for women. As a covariate of height, sex difference increased by increasing the women's score; men's score did not change. Tall women had much higher scores than short men. It was concluded that sex difference in PVA is stable despite the smaller body size of females than males, and body height may be predictive for this ability, but only in women.

Adolescent↗

Task-specific sex differences in vigilance performance: subjective workload and boredom.

Participants (24 men, 24 women) were asked to perform either a spatial or temporal vigilance task. Task-related Boredom and NASA-Task Load Index scores were collected. The results replicate Dittmar, Warm, Dember, and Ricks' 1993 finding of task-specific sex differences in vigilance performance and subjective workload. The present study also showed task-specific sex differences for boredom ratings. These results suggest that two explanations may account for the sex differences. More accurate perceptual discriminations may account for some of the differences in performance; however, sex differences in perceived boredom may more likely be responsible for the task-specific sex differences in vigilance performance and subjective workload.

Adolescent↗

Sex differences in the responses of spinal wide-dynamic range neurons to subcutaneous formalin and in the effects of different frequencies of conditioning electrical stimulation.

The purpose of this study was to investigate sex-related differences in nociception elicited by s.c. injection of different concentrations (1-5%) of formalin. S.c. formalin-induced biphasic (early and late phases) persistent nociception was assessed by extracellularly recording the spontaneous activities of single spinal dorsal horn wide-dynamic range neurons in anesthetized male and female rats. The nociceptive responses of the dorsal horn wide-dynamic range neurons following s.c. injection of 5%, but not 1% and 2.5%, formalin in female rats were significantly stronger than the responses obtained in male rats. However, these concentration-dependent differences with respect to different sexes existed only in the late, but not the early, phase of formalin-induced nociception in intact, not spinal rats. The 5% formalin-induced late phase nociception in male rats was significantly depressed by 15 min of repeated conditioning electrical stimulation at a frequency of 5 Hz as well as 50 Hz during and after the period of conditioning electrical stimulation (intensity: 1 mA; pulse duration: 1 ms). In contrast, the inhibitory effect of 50 Hz conditioning electrical stimulation on the 5% formalin-elicited late phase response in female rats was markedly greater in magnitude and longer in duration than that of 5 Hz conditioning electrical stimulation. No significant depressive effects of 5 Hz conditioning electrical stimulation on formalin-induced nociception were found in female rats, indicating that the distinct effects of conditioning electrical stimulation at different frequencies are different in animals of opposite sexes. In conclusion, s.c. administration of different concentrations of formalin shows a distinct sex-related difference in its late tonic nociception of spinal nociceptive sensory neurons. Sex differences in formalin-induced tonic nociception are stimulus intensity dependent and related to the modulation from the supraspinal regions. S.c. formalin-induced late phase nociception in female rats is only sensitive to depression at a frequency of 50 Hz, but not 5 Hz, of conditioning electrical stimulation. This suggests that the involvement of the central mechanisms in the antinociceptive effects of conditioning electrical stimulation may be different at various frequencies of stimulation.

Afferent Pathways↗

Sex differences in delayed onset muscle soreness.

AIM: There is agreement that females report greater pain in response to typical experimental pain stimuli than males. However, investigations of sex differences in the sensation of delayed onset muscle soreness (DOMS) have equivocal RESULTS: The objective of this investigation was to examine sex differences in the pain from DOMS with an adequate sample size, quantification of stimulus intensity, and 2 measures of pain. METHODS: Sixty-seven participants (52% females) completed a 2-session protocol. DOMS was induced using eccentric resistance exercises in the elbow flexors of the non-dominant arm. The intensity of the eccentric contractions was based upon concentric strength. Pain response was measured 48 hrs later. The dependent variables were pressure threshold, which was assessed using a dolorimeter, and pain intensity when the arm was moved through full active range of motion, which was assessed with a visual analog scale. RESULTS: The occurrence of DOMS was confirmed by a decrease in pressure threshold after the eccentric contractions and higher pain intensity in the arm that performed the eccentric contractions than the arm that did not. Females reported lower pain intensities (M=3.41, SD=2.13) compared to males (M=5.12, SD=2.05), but no significant sex difference was found in pressure threshold. CONCLUSION: In this investigation, females reported lower muscle pain intensity than males, but showed no sex difference in pressure threshold. These and previous findings suggest that the detection of a sex difference in muscle pain depends upon the methodology of inducing DOMS and measuring sensation.

Adult↗

The contingent smile: a meta-analysis of sex differences in smiling.

The authors present a meta-analysis of sex differences in smiling based on 448 effect sizes derivedfrom 162 research reports. There was a statistically significant tendency for women and adolescent girls to smile more than men and adolescent boys (d = 0.41). The authors hypothesized that sex differences in smiling would be larger when concerns about gender-appropriate behavior were made more conspicuous, situational constraints were absent or ambiguous, or emotion (especially negative) was salient. It was also predicted that the size of the sex difference in smiling would vary by culture and age. Moderator analysis supported these predictions. Although men tend to smile less than women, the degree to which this is so is contingent on rules and roles.

Adolescent↗

Sex differences in emotional and psychophysiological responses to musical stimuli.

Although it is known that men and women differ in their music preferences and emotional reactions to music, little is known about sex differences in physiological reactions to music. In our study, we therefore set out to examine the differential reactivity to two musical stimuli that elicit distinct psychological and physiological reaction patterns. Fifty-three healthy subjects (mean age: 26.13, SD: 3.97; 26 males, 27 females) were examined. Heart rate, electrodermal activity, skin temperature, salivary cortisol, salivary alpha-amylase, and psychological variables were assessed during the course of the whole study. Following baseline assessment, two musical stimuli, which were carefully selected and rated in a pre-study as relaxing and pleasant (renaissance music) and arousing and unpleasant (heavy metal), respectively, were introduced. They were presented on two different days in a randomized order. Whereas psychological variables did not differ between men and women, results of electrophysiological measures indicate significantly different reactivity patterns between men and women. Women displayed elevated response curves to the arousing and unpleasant stimulus, whereas men did not. However, no differences were found with regards to endocrine measures in saliva. Our results demonstrate sex differences in reactivity patterns to musical stimuli in psychophysiological measures. In our study, we were able to show that women tend to show hypersensitivity to aversive musical stimuli. This finding is in accordance with previous literature on sex differences in emotion research. Furthermore, our study indicates that the confounding effects of sex differences have to be considered when using musical stimuli for emotion induction.

Acoustic Stimulation↗

Seeing the unexpected: how sex differences in stress responses may provide a new perspective on the manifestation of psychiatric disorders.

In this report, the authors propose that underlying sex differences in the biobehavioral response to stress may contribute to the variance in prevalence of some psychiatric disorders based on sex. The authors begin with a discussion of stress physiology and review a new theory on sex differences in stress responses (ie, the "tend-and-befriend" response), which may provide a recent framework for considering sex differences in the manifestation of some psychiatric illnesses. The authors then move to a discussion of major depression and attention deficit hyperactivity disorder as examples of how sex differences in stress responses may influence the behavioral symptoms of psychiatric disorders that are more often diagnosed in one sex compared with another. The authors conclude with a brief discussion of the implications of this new perspective on treatment approaches and encourage further inquiry into the importance of sex-based differences in the behavioral manifestation of some psychiatric illnesses.

Adrenocorticotropic Hormone↗

Sex differences in androgen receptor mRNA levels and regulation in hamster facial motoneurons.

We have previously shown that testosterone propionate augments hamster facial nerve regeneration to a greater extent in males than females. Further, sex differences in facial nerve regeneration have been observed. From those studies, we hypothesized that sex differences in nerve regeneration could be due to inherent differences in androgen receptor (AR) mRNA content within facial motor neurons (FMN) of male and female hamsters. In the present study, that hypothesis was tested using in situ hybridization, and computerized image analysis to quantify levels and regulation of AR mRNA in individual FMN of hamsters of both sexes. Intact and gonadectomized (gdx) male and female hamsters were used in the initial experiments in the study. In subsequent experiments, exogenous testosterone propionate (TP) was administered to the aforementioned groups of animals by subcutaneous implantation of one 10-mm Silastic capsule for 1, 2 or 7 days. FMN of intact females contained approximately 50% less AR mRNA than their male counterparts. Gonadectomy in males downregulated AR mRNA levels by approximately 50%, whereas no effects of gonadectomy were observed in females. Thus, in all paradigms where TP levels were low relative to the intact males, AR mRNA levels were approximately half of those in the intact male FMN. TP administration induced AR mRNA levels in gdx males within 1 day. Significant effects of TP were not detected in gdx females, and only after 7 days in the intact females. To our knowledge, the results of this study are the first quantitative demonstration of sex differences in steroid receptor mRNA content in a given neuronal population and substantiate the idea that sex differences in the effects of androgens on peripheral nerve regeneration are based on intrinsic sex differences in the levels and regulation of receptor mRNA in motor neurons.

Animals↗

Sex differences on spontaneous alternation in prepubertal rats: implications for an animal model of obsessive-compulsive disorder.

UNLABELLED: Sex differences in the prevalence of obsessive-compulsive disorder (OCD) in prepubertal children have been described. Deficits on spontaneous alternation behavior (SAB) have been proposed as an animal model of OCD. OBJECTIVES: To explore possible sex differences in the ontogeny of SAB and in the effect of the 5-HT1A agonist, 8-OH-hydroxy-2 (di-n-propylamino)-tetralin (8-OH-DPAT) in an animal model of OCD. METHODS: The ontogeny of SAB and the perseveration produced by 8-OH-DPAT were compared between male and female prepubertal rats. RESULTS: Males alternated their arm choose from postnatal day 32 onwards, while females perseverated in the chosen arm until postnatal day 38. The mean number of repetitive choices remained close to 1 in males from postnatal day 23 onwards, but females showed a mean number of repetitive choices higher than 1.5 until the end of the test. The 8-OH-DPAT (0.125, 0.5 and 2.0 mg/kg, 15 min) produced perseveration in males but not in females. CONCLUSIONS: These data show important sex differences in the ontogeny of SAB and the effect of 8-OH-DPAT in a model of OCD. Such differences could be relevant for the sex differences in the prevalence of childhood OCD.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

Sex differences in CYP3A activity using intravenous and oral midazolam.

BACKGROUND: Studies examining sex differences in CYP3A activity have produced conflicting results. Our objective is to investigate whether sex differences exist in CYP3A activity as assessed by intravenous (IV) or oral midazolam pharmacokinetic analysis in healthy volunteers. METHODS: Data from 13 previous studies were used. A single dose of IV midazolam (0.025 mg/kg) was administered to 66 white adults (37 women and 29 men; mean age, 36.3+/-7.7 years). A single dose of oral midazolam, 0.075 mg/kg (5 studies), 0.15 mg/kg (1 study), or 5 mg (1 study), was administered to 72 adults (71 white and 1 Asian; 37 women and 35 men; mean age, 38.3+/-8.9 years). Pharmacokinetic parameters were determined via population methods by use of a nonparametric adaptive grid program and a 2-compartment IV and 1-compartment oral absorption model. The maximum a posteriori probability Bayesian method was used to estimate each subject's pharmacokinetic parameters. Monte Carlo simulation was performed to determine the probability distribution of the area under the concentration-time curves (AUCs). RESULTS: Women exhibited 11% higher mean weight-corrected total body midazolam clearance and 28% higher oral clearance compared with men (P<or=.01). The median AUC of IV midazolam was 0.05 mg.h/L (range, 0.02-0.14 mg.h/L) in women and 0.06 mg.h/L (range, 0.02-0.14 mg.h/L) in men. The median AUC of oral midazolam was 0.11 mg.h/L (range, 0.02-0.60 mg.h/L) in women and 0.12 mg.h/L (range, 0.04-0.45 mg.h/L) in men. CONCLUSIONS: Although women showed significantly greater hepatic and intestinal CYP3A activity, only a minor sex difference in AUC was noted. Therefore the observed disparity may be of negligible clinical importance.

Administration, Oral↗

Sex differences in the contribution of nicotine and nonpharmacological stimuli to nicotine self-administration in rats.

RATIONALE: Sex differences have been reported for the impact of nicotine and nonpharmacological cues on smoking. While nonpharmacological environmental stimuli have also been shown to influence nicotine self-administration in rats, there have been no attempts to examine the impact of sex differences in the contributions of nicotine and nondrug stimuli to this behavior. OBJECTIVES: This experiment investigated sex differences in operant responding for nicotine in rats when drug infusions were delivered either in the absence of, or in combination with, a nonpharmacological stimulus. METHODS: Initially, male and female rats acquired self-administration for nicotine alone across a range of doses (0.03, 0.06, and 0.15 mg kg(-1) inf(-1), freebase). After stable acquisition, nicotine infusions were combined with a weakly reinforcing, compound visual stimulus. RESULTS: While there was no overall effect of dose on active lever responding for nicotine in the absence of the visual stimulus, female rats responded more on the reinforced lever than males at 0.06 and 0.15 mg kg(-1) inf(-1) on an FR5 schedule. However, they also showed increased responding on the nonreinforced lever compared to males at the same doses. Combining nicotine infusions with the visual stimulus doubled responding compared to nicotine alone at 0.03 and 0.06, but not at 0.15 mg kg(-1) inf(-1): this effect was significantly greater for female rats. CONCLUSIONS: These data highlight the prominent contribution of nonpharmacological stimuli to nicotine-reinforced behavior across a range of doses in both male and female rats. They also reveal sex differences in operant responding for nicotine under conditions where a nonpharmacological stimulus is either absent, or combined with drug delivery.

Animals↗

Sex differences in the effects of pubertal development on responses to a corticotropin-releasing hormone challenge: the Pittsburgh psychobiologic studies.

We propose that sex differences in HPA regulation may emerge during puberty and help to explain sex differences in depression. In this study, we examined sex differences in cortisol responses to CRH challenge across pubertal stages in carefully screened control subjects from the Pittsburgh Psychobiologic Studies. Participants were 7-16 years of age, physically healthy, and had no personal or family history of psychiatric disorder. Physician-rated Tanner staging was conducted, followed by CRH challenge sessions including 30-40 minutes pre-infusion baseline, 1 microg/kg CRH infusion, 90-180 minutes of post-infusion measures, and 9-10 plasma cortisol samples. Girls showed increasing total cortisol responses to CRH across Tanner stages, explained by slower recovery from peak cortisol levels, while boys showed similar total responses across Tanner stages. Results show subtle sex differences in the influence of puberty on HPA regulation at the pituitary level, which may represent one factor underlying the emergence of girls' greater rates of depression during this time.

Adolescent↗

Sex differences in the induction of physical dependence on pentobarbital in the rat.

Sex differences in physical dependence on sodium pentobarbital in the rat were studied by the drug-admixed food (DAF) method. With male rats, the concentration of pentobarbital in the food was gradually increased from 2 to 30 mg/g over a period of 50 days. The final level of drug intake was approximately 1.7 g/kg/day. At pentobarbital concentrations of 20 and 22 mg/g of food, sedation and mild muscle relaxation were observed. At the highest drug concentration, 30 mg/g of food, marked muscle relaxation was noted. With female rats, the concentration of pentobarbital in the food was gradually increased from 1 to 16 mg/g over a period of 47 days. The final level of intake was approximately 1.0 mg/kg/day. At drug concentrations of 12 and 14 mg/g, sedation and mild muscle relaxation appeared. At 16 mg/g, female rats showed marked muscle relaxation similar to that of the male rats. To produce severe loss of muscle tone, the male rats required twice as much pentobarbital as the female rats. After substitution of normal food for the pentobarbital-admixed food, various signs of pentobarbital withdrawal occurred in both sexes. These signs included vocalization, irritability, muscle rigidity, tremors and convulsions. Onset of withdrawal was more rapid in the females, and the maximum weight loss was greater, 8.0% compared to 3.8% in the males. Physical dependence on pentobarbital was easily developed in both sexes by the DAF method. There was a marked sex difference in withdrawal which we attribute to sex differences in drug metabolizing enzyme activity.

Animals↗