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1.  A potential mechanism for the sexual dimorphism in the onset of puberty and incidence of idiopathic central precocious puberty in children: sex-specific kisspeptin as an integrator of puberty signals 
The major determinants of the variability in pubertal maturation are reported to be genetic and inherited. Nonetheless, nutritional status contributes significantly to this variability. Malnutrition delays puberty whereas obesity has been associated to a rise in Idiopathic Central Precocious Puberty (ICPP) in girls. However, epidemiology data indicate that contribution of obesity to early puberty varies significantly among ethnic groups, and that obesity-independent inheritable genetic factors are the strongest predictors of early puberty in any ethnic group. In fact, two human mutations with confirmed association to ICPP have been identified in children with no history of obesity. These mutations are in kisspeptin and kisspeptin receptor, a ligand/receptor pair with a major role on the onset of puberty and female cyclicity after puberty. Progressive increases in kisspeptin expression in hypothalamic nuclei known to regulate reproductive function has been associated to the onset of puberty, and hypothalamic expression of kisspeptin is reported to be sexually dimorphic in many species, which include humans. The hypothalamus of females is programmed to express significantly higher levels of kisspeptin than their male counterparts. Interestingly, incidence of ICPP and delayed puberty in children is markedly sexually dimorphic, such that ICPP is at least 10-fold more frequent in females, whereas prevalence of delayed puberty is about 5-fold higher in males. These observations are consistent with a possible involvement of sexually dimorphic kisspeptin signaling in the sexual dimorphism of normal puberty and of pubertal disorders in children of all ethnicities. This review discusses the likelihood of such associations, as well as a potential role of kisspeptin as the converging target of environmental, metabolic, and hormonal signals, which would be integrated in order to optimize reproductive function.
PMCID: PMC3521239  PMID: 23248615
central precocious puberty; kisspeptin receptor signaling; reproduction; LH surge; sexual differentiation of the brain
2.  Anti-Müllerian hormone may regulate the number of calbindin-positive neurons in the sexually dimorphic nucleus of the preoptic area of male mice 
The male brain is putatively organised early in development by testosterone, with the sexually dimorphic nucleus of the medial preoptic area (SDN) a main exemplifier of this. However, pubescent neurogenesis occurs in the rat SDN, and the immature testes secrete anti-Müllerian hormone (AMH) as well as testosterone. We have therefore re-examined the development of the murine SDN to determine whether it is influenced by AMH and/or whether the number of calbindin-positive (calbindin+ve) neurons in it changes after pre-pubescent development.
In mice, the SDN nucleus is defined by calbindin+ve neurons (CALB-SDN). The number and size of the neurons in the CALB-SDN of male and female AMH null mutant (Amh-/-) mice and their wild-type littermates (Amh+/+) were studied using stereological techniques. Groups of mice were examined immediately before the onset of puberty (20 days postnatal) and at adulthood (129–147 days old).
The wild-type pre-pubertal male mice had 47% more calbindin+ve neurons in the CALB-SDN than their female wild-type littermates. This sex difference was entirely absent in Amh-/- mice. In adults, the extent of sexual dimorphism almost doubled due to a net reduction in the number and size of calbindin+ve neurons in females and a net increase in neuron number in males. These changes occurred to a similar extent in the Amh-/- and Amh+/+ mice. Consequently, the number of calbindin+ve neurons in Amh-/- adult male mice was intermediate between Amh+/+ males and Amh+/+ females. The sex difference in the size of the neurons was predominantly generated by a female-specific atrophy after 20 days, independent of AMH.
The establishment of dimorphic cell number in the CALB-SDN of mice is biphasic, with each phase being subject to different regulation. The second phase of dimorphism is not dependent on the first phase having occurred as it was present in the Amh-/- male mice that have female-like numbers of calbindin+ve neurons at 20 days. These observations extend emerging evidence that the organisation of highly dimorphic neuronal networks changes during puberty or afterwards. They also raise the possibility that cellular events attributed to the imprinting effects of testosterone are mediated by AMH.
PMCID: PMC3852321  PMID: 24119315
Sexual dimorphic nucleus; Anti-Müllerian hormone; Puberty; Development; Childhood; Calbindin; Medial preoptic area; Imprinting
3.  Gonadal and Non-Gonadal Regulation of Sex Differences in Hypothalamic Kiss1 Neurons 
Journal of neuroendocrinology  2010;22(7):682-691.
The brains of males and females differ anatomically and physiologically, including sex differences in neuron size or number, synapse morphology, and specific patterns of gene expression. Brain sex differences may underlie critical sex differences in physiology or behavior, including several aspects of reproduction, such as the timing of sexual maturation (earlier in females than males) and the ability to generate a preovulatory gonadotropin surge (in females only). The reproductive axis is controlled by afferent pathways that converge upon forebrain gonadotropin-releasing hormone (GnRH) neurons, but GnRH neurons are not sexually dimorphic. Although most reproductive sex differences probably reflect sex differences in the upstream circuits and factors that regulate GnRH secretion, the key sexually-dimorphic factors that influence reproductive status have remained poorly defined. The recently-identified neuropeptide kisspeptin, encoded by the Kiss1 gene, is an important regulator of GnRH secretion, and Kiss1 neurons in rodents are sexually dimorphic in specific hypothalamic populations, including the anteroventral periventricular nucleus—periventricular nucleus continuum (AVPV/PeN) and the arcuate nucleus (ARC). In the adult AVPV/PeN, Kiss1 neurons are more abundant in females than males, a sex difference which is regulated by estradiol signaling during critical periods of postnatal and pubertal development. In contrast, Kiss1 neurons in the ARC are not sexually differentiated in adult rodents, but in mice, the regulation of ARC Kiss1 cells by gonadal hormone-independent factors is sexually dimorphic during prepubertal development. These various sex differences in hypothalamic Kiss1 neurons may relate to known sex differences in reproductive physiology, such as puberty onset and positive feedback.
PMCID: PMC3096441  PMID: 20492362
kisspeptin; Kiss1; GPR54; Kiss1r; sexual differentiation; sex differences; development; puberty; hypothalamus; hormone; estrogen
4.  A Pair of Mouse KRAB Zinc Finger Proteins Modulates Multiple Indicators of Female Reproduction1 
Biology of Reproduction  2009;82(4):662-668.
Krüppel-associated box-zinc finger proteins (KRAB-ZFPs) are the largest class of transcriptional regulators in mammals, yet few have been assigned biological roles. Cloning the genes underlying the regulator of sex-limitation (rsl) phenotype, in which the normally male-specific sex-limited protein (SLP) is expressed in female mice, identified two KRAB-ZFPs, Rsl1 and Rsl2, as influencing sexually dimorphic liver gene expression. Combined absence of both repressors in rsl mice leads to increased expression in female liver of major urinary proteins (MUPs) and certain enzymes of steroid metabolism, as well as SLP. We hypothesized that this altered gene expression might affect reproductive physiology in rsl females. Urinary MUP (uMUP) concentration varied with the estrous cycle in both wt and rsl females but was consistently higher in rsl urine. A behavioral odor test revealed that wild-type (wt) males preferred rsl to wt females, possibly due to elevated uMUPs providing greater pheromone presentation. To ascribe activity to Rsl1, Rsl2, or both, the genes were individually expressed as liver-specific transgenes. RSL2 overexpression accentuated uMUP fluctuations across the estrous cycle, whereas RSL1 overexpression did not. In addition, puberty onset, as indicated by vaginal opening (VO), occurred 2 days earlier in rsl females, and excess RSL2, but not RSL1, restored VO timing to wt. Hence, transcriptional repression by RSL in liver modifies female mouse reproduction via targets that likely impact both hormonal and pheromonal cues. The large and rapidly diversifying KRAB-ZFP family may modulate biological processes, including reproduction, to confer individual differences that may isolate populations and ultimately lead to speciation.
The KRAB-zinc finger transcriptional repressors, regulator of sex-limitation (RSL) 1 and RSL2, influence timing of female puberty and MUP levels through estrous by effects on liver gene expression.
PMCID: PMC2842485  PMID: 20042539
gene regulation; major urinary protein; mechanisms of hormone action; pheromones; pubertal timing; puberty; regulator of sex-limitation; sexual dimorphism; sexually dimorphic gene expression
5.  Abnormal anthropometric measurements and growth pattern in male adolescent idiopathic scoliosis 
European Spine Journal  2011;21(1):77-83.
The progression of adolescent idiopathic scoliosis is closely correlated with longitudinal growth during puberty. A decreased incidence of curve progression has been found in male patients with adolescent idiopathic scoliosis compared with female patients with the condition. This finding implies that there might be a sexual dimorphism in the pubertal growth patterns of adolescent idiopathic scoliosis patients. Abnormal pubertal growth in female adolescent idiopathic scoliosis patients has been well characterized; however, the pubertal growth patterns of male adolescent idiopathic scoliosis patients have not been reported. We conducted a cross-sectional study of anthropometric measurements to compare the growth patterns of male patients with adolescent idiopathic scoliosis with those of healthy boys during puberty and explore the difference in the pubertal growth patterns of female and male patients with adolescent idiopathic scoliosis.
A total of 688 subjects were involved in the study, including 332 male adolescent idiopathic scoliosis patients and 356 age-matched healthy boys. The subjects were categorized according to their chronological ages. Their body weights, heights and arm spans were obtained using standard methods; the corrected body heights of the adolescent idiopathic scoliosis boys were determined using Bjour’s equation. The inter-group differences in the anthropometric parameters were analyzed. Multivariate regression analysis was carried out in the adolescent idiopathic scoliosis patients to identify the anthropometric parameters that influence curve severity.
The corrected standing heights and arm spans of male adolescent idiopathic scoliosis patients were similar to those of the matched controls during puberty. However, the body weights of the adolescent idiopathic scoliosis patients who were more than 14 years old were significantly less than those of the control group. The body mass index of the adolescent idiopathic scoliosis patients between the ages of 15 and 17 were also significantly less than those of the control subjects. Moreover, a significantly higher incidence of underweight was found in adolescent idiopathic scoliosis patients (8.6%) than in the controls (3.4%). Upon multivariate regression analysis, body weight and chronological age were identified as independent predictors of curve magnitude in male adolescent idiopathic scoliosis patients. The male adolescent idiopathic scoliosis patients with variable curve patterns exhibited no significant differences in their anthropometric parameters.
The results showed abnormal pubertal growth in the male adolescent idiopathic scoliosis patients compared with their age- and gender-matched normal controls. Despite similar longitudinal growth, the male patients with adolescent idiopathic scoliosis exhibited significantly lower body weights and a higher incidence of underweight during the later stage of puberty compared with their normal controls. These abnormalities in the pubertal growth of male patients were different from those observed in female patients with adolescent idiopathic scoliosis. Body weight could be an important parameter for further longitudinal studies on the prognostication of curve progression in adolescent idiopathic scoliosis.
PMCID: PMC3252435  PMID: 21826498
Adolescent idiopathic scoliosis; Male; Anthropometric measurement; Underweight; Pubertal growth
6.  An Evolutionarily Conserved Sexual Signature in the Primate Brain 
PLoS Genetics  2008;4(6):e1000100.
The question of a potential biological sexual signature in the human brain is a heavily disputed subject. In order to provide further insight into this issue, we used an evolutionary approach to identify genes with sex differences in brain expression level among primates. We reasoned that expression patterns important to uphold key male and female characteristics may be conserved during evolution. We selected cortex for our studies because this specific brain region is responsible for many higher behavioral functions. We compared gene expression profiles in the occipital cortex of male and female humans (Homo sapiens, a great ape) and cynomolgus macaques (Macaca fascicularis, an old world monkey), two catarrhine species that show abundant morphological sexual dimorphism, as well as in common marmosets (Callithrix Jacchus, a new world monkey) which are relatively sexually monomorphic. We identified hundreds of genes with sex-biased expression patterns in humans and macaques, while fewer than ten were differentially expressed between the sexes in marmosets. In primates, a general rule is that many of the morphological and behavioral sexual dimorphisms seen in polygamous species, such as macaques, are typically less pronounced in monogamous species such as the marmosets. Our observations suggest that this correlation may also be reflected in the extent of sex-biased gene expression in the brain. We identified 85 genes with common sex-biased expression, in both human and macaque and 2 genes, X inactivation-specific transcript (XIST) and Heat shock factor binding protein 1 (HSBP1), that were consistently sex-biased in the female direction in human, macaque, and marmoset. These observations imply a conserved signature of sexual gene expression dimorphism in cortex of primates. Further, we found that the coding region of female-biased genes is more evolutionarily constrained compared to the coding region of both male-biased and non sex-biased brain expressed genes. We found genes with conserved sexual gene expression dimorphism in the occipital cortex of humans, cynomolgus macaques, and common marmosets. Genes within sexual expression profiles may underlie important functional differences between the sexes, with possible importance during primate evolution.
Author Summary
The contribution of genetics versus environment to behavioral differences between the sexes is a fundamental question in neuroscience. We hypothesized that some differences between the sexes might be partially explained by sexually dependent gene expression differences in the brain. We further speculated that if differences in gene expression between males and females are functionally important, they may be conserved in the evolution of primates. To test these hypotheses, we measured gene expression in the brains of male and female primates from three species: humans (Homo sapiens), macaques (Macaca fascicularis), and marmosets (Callithrix jacchus). Our results point to a conserved signature of sexual gene expression dimorphism in the brains of primates. Interestingly, we found that genes with conserved sexual gene expression dimorphism in the brain also evolve under more evolutionary constraint, compared with other genes, suggesting that they may have important roles during evolution of sex in primates. Moreover, we found higher evolutionary constrains in the coding regions of female-biased genes as compared to both male-biased and non sex-biased brain expressed genes. The study of sex dimorphic genes may in the future shed light on the basis of psychiatric diseases with differences in prevalence between the sexes.
PMCID: PMC2413013  PMID: 18566661
7.  Sex-specific processing of social cues in the medial amygdala 
eLife  2014;3:e02743.
Animal–animal recognition within, and across species, is essential for predator avoidance and social interactions. Despite its essential role in orchestrating responses to animal cues, basic principles of information processing by the vomeronasal system are still unknown. The medial amygdala (MeA) occupies a central position in the vomeronasal pathway, upstream of hypothalamic centers dedicated to defensive and social responses. We have characterized sensory responses in the mouse MeA and uncovered emergent properties that shed new light onto the transformation of vomeronasal information into sex- and species-specific responses. In particular, we show that the MeA displays a degree of stimulus selectivity and a striking sexually dimorphic sensory representation that are not observed in the upstream relay of the accessory olfactory bulb (AOB). Furthermore, our results demonstrate that the development of sexually dimorphic circuits in the MeA requires steroid signaling near the time of puberty to organize the functional representation of sensory stimuli.
eLife digest
Many animals emit and detect chemicals known as pheromones to communicate with other members of their own species. Animals also rely on chemical signals from other species to warn them, for example, that a predator is nearby. Many of these chemical signals—which are present in sweat, tears, urine, and saliva—are detected by a structure called the vomeronasal organ, which is located at the base of the nasal cavity.
When this organ detects a particular chemical signal, it broadcasts this information to a network of brain regions that generates an appropriate behavioral response. Two structures within this network, the accessory olfactory bulb and the medial amygdala, play an important role in modifying this signal before it reaches its final destination—a region of the brain called the hypothalamus. Activation of the hypothalamus by the signal triggers changes in the animal's behavior. Although the anatomical details of this pathway have been widely studied, it is not clear how information is actually transmitted along it.
Now, Bergan et al. have provided insights into this process by recording signals in the brains of anesthetized mice exposed to specific stimuli. Whereas neurons in the accessory olfactory bulb responded similarly in male and female mice, those in the medial amygdala showed a preference for female urine in male mice, and a preference for male urine in the case of females. This is the first direct demonstration of differences in sensory processing in the brains of male and female mammals.
These differences are thought to result from the actions of sex hormones, particularly estrogen, on brain circuits during development. Consistent with this, neurons in the medial amygdala of male mice with reduced levels of estrogen showed a reduced preference for female urine compared to control males. Similarly, female mice that had been previously exposed to high levels of estrogen as pups showed a reduced preference for male urine compared to controls.
In addition to increasing understanding of how chemical signals—including pheromones—influence the responses of rodents to other animals, the work of Bergan et al. has provided clues to the neural mechanisms that underlie sex-specific differences in behaviors.
PMCID: PMC4038839  PMID: 24894465
medial amygdala; sensory representation; sexual dimorphism; vomeronasal system; pheromones; behavior; mouse
8.  Environmental and social influences on neuroendocrine puberty and behavior in macaques and other nonhuman primates 
Hormones and behavior  2013;64(2):226-239.
Puberty is the developmental period when the hypothalamic-pituitary-gonadal (HPG) axis is activated, following a juvenile quiescent period, and reproductive capacity matures. Although pubertal events occur in a consistent sequence, there is considerable variation between individuals in the onset and timing of pubertal events, with puberty onset occurring earlier in girls than in boys. Evidence in humans demonstrates that social and environmental context influences the timing of puberty onset and may account for some of the observed variation. This review analyzes the nonhuman primate literature, focusing primarily on rhesus macaques (Macaca mulatta), to examine the social and environmental influences on puberty onset, how these factors influence puberty in males and females, and to review the relationship between puberty onset of adult neuroendocrine function and sexual behavior. Social and environmental factors influence the timing of puberty onset and pubertal events in nonhuman primates, as in humans, and the influences of these factors differ for males and females. In nonhuman primates, gonadal hormones are not required for sexual behavior, but modulate the frequency of occurrence of behavior, with social context influencing the relationship between gonadal hormones and sexual behavior. Thus, the onset of sexual behavior is independent of neuroendocrine changes at puberty; however, there are distinct behavioral changes that occur at puberty, which are modulated by social context. Puberty is possibly the developmental period when hormonal modulation of sexual behavior is organized, and thus, when social context interacts with hormonal state to strongly influence the expression of sexual behavior.
PMCID: PMC3762264  PMID: 23998667
Puberty onset; Social influence; Environmental influence; Sex differences; Nonhuman primate; Sexual behavior
9.  Reproductive Hormone-Dependent and -Independent Contributions to Developmental Changes in Kisspeptin in GnRH-Deficient Hypogonadal Mice 
PLoS ONE  2010;5(7):e11911.
Kisspeptin is a potent activator of GnRH-induced gonadotropin secretion and is a proposed central regulator of pubertal onset. In mice, there is a neuroanatomical separation of two discrete kisspeptin neuronal populations, which are sexually dimorphic and are believed to make distinct contributions to reproductive physiology. Within these kisspeptin neuron populations, Kiss1 expression is directly regulated by sex hormones, thereby confounding the roles of sex differences and early activational events that drive the establishment of kisspeptin neurons. In order to better understand sex steroid hormone-dependent and -independent effects on the maturation of kisspeptin neurons, hypogonadal (hpg) mice deficient in GnRH and its downstream effectors were used to determine changes in the developmental kisspeptin expression. In hpg mice, sex differences in Kiss1 mRNA levels and kisspeptin immunoreactivity, typically present at 30 days of age, were absent in the anteroventral periventricular nucleus (AVPV). Although immunoreactive kisspeptin increased from 10 to 30 days of age to levels intermediate between wild type (WT) females and males, corresponding increases in Kiss1 mRNA were not detected. In contrast, the hpg arcuate nucleus (ARC) demonstrated a 10-fold increase in Kiss1 mRNA between 10 and 30 days in both females and males, suggesting that the ARC is a significant center for sex steroid-independent pubertal kisspeptin expression. Interestingly, the normal positive feedback response of AVPV kisspeptin neurons to estrogen observed in WT mice was lost in hpg females, suggesting that exposure to reproductive hormones during development may contribute to the establishment of the ovulatory gonadotropin surge mechanism. Overall, these studies suggest that the onset of pubertal kisspeptin expression is not dependent on reproductive hormones, but that gonadal sex steroids critically shape the hypothalamic kisspeptin neuronal subpopulations to make distinct contributions to the activation and control of the reproductive hormone cascade at the time of puberty.
PMCID: PMC2912854  PMID: 20689830
10.  Sex-dimorphism in Cardiac Nutrigenomics: effect of Trans fat and/or Monosodium Glutamate consumption 
BMC Genomics  2011;12:555.
A paucity of information on biological sex-specific differences in cardiac gene expression in response to diet has prompted this present nutrigenomics investigation.
Sexual dimorphism exists in the physiological and transcriptional response to diet, particularly in response to high-fat feeding. Consumption of Trans-fatty acids (TFA) has been linked to substantially increased risk of heart disease, in which sexual dimorphism is apparent, with males suffering a higher disease rate. Impairment of the cardiovascular system has been noted in animals exposed to Monosodium Glutamate (MSG) during the neonatal period, and sexual dimorphism in the growth axis of MSG-treated animals has previously been noted. Processed foods may contain both TFA and MSG.
We examined physiological differences and changes in gene expression in response to TFA and/or MSG consumption compared to a control diet, in male and female C57BL/6J mice.
Heart and % body weight increases were greater in TFA-fed mice, who also exhibited dyslipidemia (P < 0.05). Hearts from MSG-fed females weighed less than males (P < 0.05). 2-factor ANOVA indicated that the TFA diet induced over twice as many cardiac differentially expressed genes (DEGs) in males compared to females (P < 0.001); and 4 times as many male DEGs were downregulated including Gata4, Mef2d and Srebf2. Enrichment of functional Gene Ontology (GO) categories were related to transcription, phosphorylation and anatomic structure (P < 0.01). A number of genes were upregulated in males and downregulated in females, including pro-apoptotic histone deacetylase-2 (HDAC2). Sexual dimorphism was also observed in cardiac transcription from MSG-fed animals, with both sexes upregulating approximately 100 DEGs exhibiting sex-specific differences in GO categories. A comparison of cardiac gene expression between all diet combinations together identified a subset of 111 DEGs significant only in males, 64 DEGs significant in females only, and 74 transcripts identified as differentially expressed in response to dietary manipulation in both sexes.
Our model identified major changes in the cardiac transcriptional profile of TFA and/or MSG-fed mice compared to controls, which was reflected by significant differences in the physiological profile within the 4 diet groups. Identification of sexual dimorphism in cardiac transcription may provide the basis for sex-specific medicine in the future.
PMCID: PMC3238303  PMID: 22078008
11.  Involvement of Gonadal Steroids and Gamma Interferon in Sex Differences in Response to Blood-Stage Malaria Infection†  
Infection and Immunity  2006;74(6):3190-3203.
To examine the hormonal and immunological mechanisms that mediate sex differences in susceptibility to malaria infection, intact and gonadectomized (gdx) C57BL/6 mice were inoculated with Plasmodium chabaudi AS-infected erythrocytes, and the responses to infection were monitored. In addition to reduced mortality, intact females recovered from infection-induced weigh loss and anemia faster than intact males. Expression microarrays and real-time reverse transcription-PCR revealed that gonadally intact females exhibited higher expression of interleukin-10 (IL-10), IL-15Rα, IL-12Rβ, Gadd45γ, gamma interferon (IFN-γ), CCL3, CXCL10, CCR5, and several IFN-inducible genes in white blood cells and produced more IFN-γ than did intact males and gdx females, with these differences being most pronounced during peak parasitemia. Intact females also had higher anti-P. chabaudi immunoglobulin G (IgG) and IgG1 responses than either intact males or gdx females. To further examine the effector mechanisms mediating sex differences in response to P. chabaudi infection, responses to infection were compared among male and female wild-type (WT), T-cell-deficient (TCRβδ−/−), B-cell-deficient (μMT), combined T- and B-cell-deficient (RAG1), and IFN-γ knockout (IFN-γ−/−) mice. Males were 3.5 times more likely to die from malaria infection than females, with these differences being most pronounced among TCRβδ−/−, μMT, and RAG1 mice. Male mice also exhibited more severe weight loss, anemia, and hypothermia, and higher peak parasitemia than females during infection, with WT, RAG1, TCRβδ−/−, and μMT mice exhibiting the most pronounced sexual dimorphism. The absence of IFN-γ reduced the sex difference in mortality and was more detrimental to females than males. These data suggest that differential transcription and translation of IFN-γ, that is influenced by estrogens, may mediate sex differences in response to malaria.
PMCID: PMC1479253  PMID: 16714546
12.  Long-term effects of pubertal stressors on female sexual receptivity and estrogen receptor-α expression in CD-1 female mice 
Hormones and behavior  2011;59(4):565-571.
Exposure to stress during puberty can lead to long-term behavioral alterations. Female mice of the inbred C57BL/6 strain have been shown to display lower levels of sexual receptivity in adulthood when exposed to shipping stress or to an immune challenge during puberty. The present study investigated whether this effect can be extended to CD1 outbred mice and examined a possible mechanism through which exposure to stressors could suppress sexual receptivity. The results revealed that CD1 mice injected with lipopolysaccharide (LPS) or exposed to shipping stress at six weeks old display lower levels of sexual receptivity in response to estradiol and progesterone in adulthood than control mice. Moreover, mice exposed to shipping stress at eight weeks old also displayed reduced sexual receptivity, but those injected with LPS at that time showed slightly reduced effects, suggesting that the sensitive pubertal period extends to eight weeks of age in this strain of mice. The examination of estrogen receptor-α (ER-α) expression revealed that mice exposed to shipping stress during the sensitive period (six weeks) display lower levels of ER-α expression in the medial preoptic area and the ventromedial nucleus and the arcuate nucleus of the hypothalamus than mice shipped at a younger age. These findings support the prediction that exposure to shipping stress or LPS during puberty decreases behavioral responsiveness to estradiol and progesterone in adulthood in an outbred strain of mice through enduring suppression of ER-α expression in some brain areas involved in the regulation of female sexual behavior.
PMCID: PMC3085923  PMID: 21376052
Puberty; Stress; Female sexual behavior; Estrogen receptor-α; CD1 mice
13.  Sexual Dimorphic Regulation of Body Weight Dynamics and Adipose Tissue Lipolysis 
PLoS ONE  2012;7(5):e37794.
Successful reduction of body weight (BW) is often followed by recidivism to obesity. BW-changes including BW-loss and -regain is associated with marked alterations in energy expenditure (EE) and adipose tissue (AT) metabolism. Since these processes are sex-specifically controlled, we investigated sexual dimorphisms in metabolic processes during BW-dynamics (gain-loss-regain).
Research Design
Obesity was induced in C57BL/6J male (m) and female (f) mice by 15 weeks high-fat diet (HFD) feeding. Subsequently BW was reduced (-20%) by caloric restriction (CR) followed by adaptive feeding, and a regain-phase. Measurement of EE, body composition, blood/organ sampling were performed after each feeding period. Lipolysis was analyzed ex-vivo in gonadal AT.
Male mice exhibited accelerated BW-gain compared to females (relative BW-gain m:140.5±3.2%; f:103.7±6.5%; p<0.001). In consonance, lean mass-specific EE was significantly higher in females compared to males during BW-gain. Under CR female mice reached their target-BW significantly faster than male mice (m:12.2 days; f:7.6 days; p<0.001) accompanied by a sustained sex-difference in EE. In addition, female mice predominantly downsized gonadal AT whereas the relation between gonadal and total body fat was not altered in males. Accordingly, only females exhibited an increased rate of forskolin-stimulated lipolysis in AT associated with significantly higher glycerol concentrations, lower RER-values, and increased AT expression of adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Analysis of AT lipolysis in estrogen receptor alpha (ERα)–deficient mice revealed a reduced lipolytic rate in the absence of ERα exclusively in females. Finally, re-feeding caused BW-regain faster in males than in females.
The present study shows sex-specific dynamics during BW-gain-loss-regain. Female mice responded to CR with an increase in lipolytic activity, and augmented lipid-oxidation leading to more efficient weight loss. These processes likely involve ERα-dependent signaling in AT and sexual dimorphic regulation of genes involved in lipid metabolism.
PMCID: PMC3360591  PMID: 22662224
14.  The Phenotype of Hormone-Related Allergic and Autoimmune Diseases in the Skin: Annular Lesions That Lateralize 
Journal of Allergy  2012;2012:604854.
Introduction. Sexual dimorphism with an increased prevalence in women has long been observed in various autoimmune, allergic, and skin diseases. Recent research has attempted to correlate this female predilection to physiologic changes seen in the menstrual cycle in order to more effectively diagnose and treat these diseases. Cases. We present five cases of cutaneous diseases in women with annular morphology and distributive features that favor one side over the other. In all cases, skin disease improved with ovarian suppression. Conclusion. Sexual dimorphism in the innate and adaptive immune systems has long been observed, with females demonstrating a more vigorous immune response compared to males. Female sex hormones promote T and B lymphocyte autoreactivity and favor the humoral arm of adaptive immunity. In addition to ovarian steroidogenesis and immunity, intricate pathways coexist in order to engage a single oocyte in each cycle, while simultaneously sustaining the ovarian reserve. Vigorous proinflammatory, vasoactive, and pigment-related cytokines emerge during the demise of the corpus luteum, influencing peripherical sex hormone metabolism of the level of the macrophage and fibroblast. We propose that annular and lateralizing lesions are important manifestations of hormone-related inflammation and recognition of this linkage can lead to improved immune and reproductive health.
PMCID: PMC3534378  PMID: 23316250
15.  Immunological Basis for the Gender Differences in Murine Paracoccidioides brasiliensis Infection 
PLoS ONE  2010;5(5):e10757.
This study aimed to investigate the immunological mechanisms involved in the gender distinct incidence of paracoccidioidomycosis (pcm), an endemic systemic mycosis in Latin America, which is at least 10 times more frequent in men than in women. Then, we compared the immune response of male and female mice to Paracoccidioides brasiliensis infection, as well as the influence in the gender differences exerted by paracoccin, a P. brasiliensis component with carbohydrate recognition property. High production of Th1 cytokines and T-bet expression have been detected in the paracoccin stimulated cultures of spleen cells from infected female mice. In contrast, in similar experimental conditions, cells from infected males produced higher levels of the Th2 cytokines and expressed GATA-3. Macrophages from male and female mice when stimulated with paracoccin displayed similar phagocytic capability, while fungicidal activity was two times more efficiently performed by macrophages from female mice, a fact that was associated with 50% higher levels of nitric oxide production. In order to evaluate the role of sexual hormones in the observed gender distinction, we have utilized mice that have been submitted to gonadectomy followed by inverse hormonal reconstitution. Spleen cells derived from castrated males reconstituted with estradiol have produced higher levels of IFN-γ (1291±15 pg/mL) and lower levels of IL-10 (494±38 pg/mL), than normal male in response to paracoccin stimulus. In contrast, spleen cells from castrated female mice that had been treated with testosterone produced more IL-10 (1284±36 pg/mL) and less IFN-γ (587±14 pg/mL) than cells from normal female. In conclusion, our results reveal that the sexual hormones had a profound effect on the biology of immune cells, and estradiol favours protective responses to P. brasiliensis infection. In addition, fungal components, such as paracoccin, may provide additional support to the gender dimorphic immunity that marks P. brasiliensis infection.
PMCID: PMC2873977  PMID: 20505765
16.  Regulatory T cells inhibit Fas ligand-induced innate and adaptive tumour immunity 
European Journal of Immunology  2007;37(3):758-767.
CD4+CD25+ regulatory T cells (Treg) are known to influence T cell responses to tumours. Here we have explored the role of Treg in inhibiting not only adaptive, but also innate immune responses to tumours. To this end we used a Fas ligand (FasL)-expressing melanoma cell line in a mouse model. In this system, innate immunity is sufficient to reject the tumour. All mice depleted of Treg and challenged with FasL-expressing melanoma remained tumour-free. Investigation of the underlying cellular effector mechanisms revealed that depletion of Treg enhanced an NK cell response capable of tumour lysis. Furthermore, this initial innate immune response primed mice to make an effective adaptive immune response leading to complete rejection of challenge with the parental melanoma. Both antigen-specific antibody and CD4+ T cells were implicated in protection via adaptive immunity. We conclude that removal of Treg and vaccination with whole tumour cells expressing FasL activates multiple arms of the immune system, leading to efficient tumour rejection. These findings highlight a novel role for FasL in inducing innate immune responses that are normally inhibited by Treg and uncover an adjuvant effect of FasL that can be used to stimulate tumour immunity after depletion of Treg.
PMCID: PMC2435420  PMID: 17294404
Fas ligand; Innate tumour immunity; Regulatory T cells
17.  Characterization of growth hormone-responsive transcription factors preferentially expressed in adult female liver* 
Endocrinology  2007;148(7):3327-3337.
Plasma growth hormone (GH) profiles regulate the sexually dimorphic expression of cytochromes P450 and many other genes in rat and mouse liver, however, the proximal transcriptional regulators of these genes are unknown. Presently, we characterize three liver transcription factors that are expressed in adult female rat and mouse liver at levels up to 16-fold (Tox), 73-fold (Trim24/TIF1α), and 125-fold (Cutl2/Cux2) higher than in adult males, depending on the strain and species, with Tox expression only detected in mice. In rats, these sex differences first emerged at puberty, when the high prepubertal expression of Cutl2 and Trim24 was extinguished in males but was further increased in females. Rat hepatic expression of Cutl2 and Trim24 was abolished by hypophysectomy and, in the case of Cutl2, was restored to near-female levels by continuous GH replacement. Cutl2 and Trim24 were increased to female-like levels in livers of intact male rats and mice treated with GH continuously (female GH pattern), while Tox expression reached only about 40% of adult female levels. Expression of all three genes was also elevated to normal female levels or higher in male mice whose plasma GH profile was feminized secondary to somatostatin gene disruption. Cutl2 and Trim24 both responded to GH infusion in mice within 10–24 h and Tox within 4 d, as compared to at least 4–7 d required for the induced expression of several continuous GH-regulated cytochromes P450 and other female-specific hepatic genes. Cutl2, Trim24 and Tox were substantially up-regulated in livers of male mice deficient in either of two transcription factors implicated in GH regulation of liver sex specificity, namely, signal transducer and activator of transcription 5b (STAT5b) and hepatocyte nuclear factor 4α (HNF4α), with sex-specific expression being substantially reduced or lost in mice deficient in either nuclear factor. Cutl2 and Trim24 both display transcriptional repressor activity and could thus contribute to the loss of GH-regulated, male-specific liver gene expression seen in male mice deficient in STAT5b or HNF4α. Binding sites for Cutl1, whose DNA-binding specificity is very close to that of Cutl2, were statistically over-represented in STAT5b-dependent male-specific mouse genes, lending support to this hypothesis.
PMCID: PMC2585771  PMID: 17412818
growth hormone; STAT5b; HNF4α; liver gene expression; sex-specificity
18.  Sex and inflammation in respiratory diseases: a clinical viewpoint 
This review discusses sex differences in the prognosis of acute or chronic inflammatory diseases. The consequences of severe inflammation vary in relation to sex, depending on illness duration. In the majority of acute diseases, males present higher mortality rates, whereas continuous chronic inflammation associated with tissue damage is more deleterious in females. The recruitment of cells, along with its clinical expression, is more significant in females, as reflected by higher inflammatory markers. Given that estrogens or androgens are known to modulate inflammation, their different levels in males and females cannot account for the sexual dimorphism observed in humans and animals from birth to death with regard to inflammation. Numerous studies evaluated receptors, cytokine production, and clinical outcomes in both animals and humans, revealing that estrogens clearly modulate the immune response, but the results are contradictory and difficult to link to hormone concentrations. Even in prepubescent children, the presentation of acute pneumonia or chronic diseases mimics the adult pattern. Several genes located on the X chromosome have been shown to encode molecules involved in inflammation. Moreover, 10% to 15% of the genes from silenced X chromosome may escape inhibition. Females are also a mosaic of cells with genes from either paternal or maternal X chromosome. Therefore, polymorphism of X-linked genes would result in the presence of two cell populations with distinct regulatory arsenals, providing females with greater diversity to fight against infectious challenges, in comparison with the uniform cell populations in hemizygous males. The similarities observed between males and Turner syndrome patients using an endotoxin stimulation model support the difference in gene expression between monosomy and disomy for the X chromosome. Considering the enhanced inflammation in females, cytokine production may be assumed to be higher in females than males. Even if all results are not clear-cut, nonetheless, many studies have reported higher cytokine levels in both male humans and animals than in females. High IL-6 levels in males correlated with poorer prognosis and shorter longevity. A sound understanding of the basic regulatory mechanisms responsible for these gender differences may lead to new therapeutic targets.
PMCID: PMC3765878  PMID: 24128344
Sex; Respiratory inflammation; X chromosome; Hormones; Cytokines
19.  Social and emotional predictors of the tempo of puberty in female rhesus monkeys 
Psychoneuroendocrinology  2012;38(1):67-83.
A cascade of neuroendocrine events regulates the initiation and progression of female puberty. However, the factors that determine the timing of these events across individuals are still uncertain. While the consequences of puberty on subsequent emotional development and adult behavior have received significant attention, what is less understood are the social and environmental factors that actually alter the initiation and progression of puberty. In order to more fully understand what factors influence pubertal timing in females, the present study quantified social and emotional behavior; stress physiology; and growth and activity measures in juvenile female rhesus monkeys to determine what best predicts eventual puberty. Based on previous reports, we hypothesized that increased agonistic behavior resulting from subordinate status in their natal group, in combination with slowed growth, reduced prosocial behavior, and increased emotional reactivity would predict delayed puberty. The analyses were restricted to behavioral and physiological measures obtained prior to the onset of puberty, defined as menarche. Together, our findings indicate that higher rates of aggression but lower rates of submission received from group mates; slower weight gain; and greater emotional reactivity, evidenced by higher anxiety, distress and appeasing behaviors, and lower cortisol responsivity in response to a potentially threatening situation, predicts delayed puberty. Together the combination of these variables accounted for 58% of the variance in the age of menarche, 71% in age at first ovulation, and 45% in the duration of adolescent sterility. While early puberty may be more advantageous for the individual from a fertility standpoint, it presents significant health risks, including increased risk for a number of estrogen dependent cancers and as well as the emergence of mood disorders during adulthood. On the other hand, it is possible that increased emotional reactivity associated with delayed puberty could persist, increasing the risk for emotional dysregulation to socially challenging situations. The data argue for prospective studies that will determine how emotional reactivity shown to be important for pubertal timing is affected by early social experience and temperament, and how these stress-related variables contribute to body weight accumulation, affecting the neuroendocrine regulation of puberty.
PMCID: PMC3442129  PMID: 22658962
menarche; first ovulation; puberty; emotionality; and social stress
20.  Gene Expression in Peripheral Immune Cells following Cardioembolic Stroke Is Sexually Dimorphic 
PLoS ONE  2014;9(7):e102550.
Epidemiological studies suggest that sex has a role in the pathogenesis of cardioembolic stroke. Since stroke is a vascular disease, identifying sexually dimorphic gene expression changes in blood leukocytes can inform on sex-specific risk factors, response and outcome biology. We aimed to examine the sexually dimorphic immune response following cardioembolic stroke by studying the differential gene expression in peripheral white blood cells.
Methods and Results
Blood samples from patients with cardioembolic stroke were obtained at ≤3 hours (prior to treatment), 5 hours and 24 hours (after treatment) after stroke onset (n = 23; 69 samples) and compared with vascular risk factor controls without symptomatic vascular diseases (n = 23, 23 samples) (ANCOVA, false discovery rate p≤0.05, |fold change| ≥1.2). mRNA levels were measured on whole-genome Affymetrix microarrays. There were more up-regulated than down-regulated genes in both sexes, and females had more differentially expressed genes than males following cardioembolic stroke. Female gene expression was associated with cell death and survival, cell-cell signaling and inflammation. Male gene expression was associated with cellular assembly, organization and compromise. Immune response pathways were over represented at ≤3, 5 and 24 h after stroke in female subjects but only at 24 h in males. Neutrophil-specific genes were differentially expressed at 3, 5 and 24 h in females but only at 5 h and 24 h in males.
There are sexually dimorphic immune cell expression profiles following cardioembolic stroke. Future studies are needed to confirm the findings using qRT-PCR in an independent cohort, to determine how they relate to risk and outcome, and to compare to other causes of ischemic stroke.
PMCID: PMC4103830  PMID: 25036109
21.  Pubertal immune challenge blocks the ability of estradiol to enhance performance on cognitive tasks in adult female mice 
Psychoneuroendocrinology  2012;38(7):1170-1177.
Puberty is a period characterized by brain reorganization that contributes to the development of neural and behavioral responses to gonadal steroids. Previously, we have shown that a single injection of the bacterial endotoxin, lipopolysaccharide (LPS; 1.5mg/kg IP), during the pubertal period (around 6 weeks old) in mice decreases sexual receptivity in response to estradiol and progesterone in adulthood. These findings suggest that pubertal immune challenge has an enduring effect of decreasing the behavioral responsiveness to gonadal steroid hormones. Since estradiol improves cognitive function in certain tasks in mice, we investigated the effect of pubertal immune challenge on the ability of estradiol to enhance cognitive function. We hypothesized that estradiol would be less effective at enhancing performance on particular cognitive tasks in female mice treated with LPS during puberty. Six-week old (pubertal) and ten-week old (adult) female CD1 mice were injected with either saline or LPS. Five weeks later, they were ovariectomized and implanted subcutaneously with either an estradiol- or oil-filled Silastic© capsule followed one week later with testing for cognitive function. The duration of juvenile investigation during social discrimination and recognition tests was used as a measure of social memory, and the duration of object investigation during object recognition and placement tests was used as a measure of object memory. Chronic estradiol treatment enhanced social and object memory in saline-treated females and in females treated with LPS in adulthood. In contrast, in females treated with LPS at 6 weeks old, estradiol failed to improve social and object memories. These results support the hypothesis that exposure to an immune challenge during puberty reduces at least some of the cognitive effects of estradiol. Moreover, these results support the idea that pubertal immune challenge compromises a wide variety of behavioral influences of ovarian hormones.
PMCID: PMC3604046  PMID: 23218519
Estradiol; hippocampus-dependent tasks; immune challenge; puberty
22.  Peripheral vs. Central Sex Steroid Hormones in Experimental Parkinson’s Disease 
The nigrostriatal dopaminergic (NSDA) pathway degenerates in Parkinson’s disease (PD), which occurs with approximately twice the incidence in men than women. Studies of the influence of systemic estrogens in females suggest sex hormones contribute to these differences. In this review we analyze the evidence revealing great complexity in the response of the healthy and injured NSDA system to hormonal influences, and emphasize the importance of centrally generated estrogens. At physiological levels, circulating estrogen (in females) or estrogen precursors (testosterone in males, aromatized to estrogen centrally) have negligible effects on dopaminergic neuron survival in experimental PD, but can modify striatal dopamine levels via actions on the activity or adaptive responses of surviving cells. However, these effects are sexually dimorphic. In females, estradiol promotes adaptive responses in the partially injured NSDA pathway, preserving striatal dopamine, whereas in males gonadal steroids and exogenous estradiol have a negligible or even suppressive effect, effectively exacerbating dopamine loss. On balance, the different effects of gonadal factors in males and females contribute to sex differences in experimental PD. Fundamental sex differences in brain organization, including the sexually dimorphic networks regulating NSDA activity are likely to underpin these responses. In contrast, estrogen generated locally appears to preserve striatal dopamine in both sexes. The available data therefore highlight the need to understand the biological basis of sex-specific responses of the NSDA system to peripheral hormones, so as to realize the potential for sex-specific, hormone-based therapies in PD. Furthermore, they suggest that targeting central steroid generation could be equally effective in preserving striatal dopamine in both sexes. Clarification of the relative roles of peripheral and central sex steroid hormones is thus an important challenge for future studies.
PMCID: PMC3355917  PMID: 22649388
nigrostriatal pathway; estrogen; Parkinson’s disease; central vs. gonadal steroids; sex
23.  Sex-specific control of CNS autoimmunity by p38 MAPK signaling in myeloid cells 
Annals of neurology  2014;75(1):50-66.
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), characterized by a global increasing incidence driven by relapsing-remitting disease in females. p38 MAP kinase (MAPK) has been described as a key regulator of inflammatory responses in autoimmunity, but its role in the sexual dimorphism in MS or MS models remains unexplored.
Toward this end, we used experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS, combined with pharmacologic and genetic inhibition of p38 MAPK activity and transcriptomic analyses.
Pharmacologic inhibition of p38 MAPK selectively ameliorated EAE in female mice. Conditional deletion studies demonstrated that p38α signaling in macrophages/myeloid cells, but not T cells or dendritic cells, recapitulated this sexual dimorphism. Analysis of CNS inflammatory infiltrates showed that female, but not male mice lacking p38α in myeloid cells exhibited reduced immune cell activation compared with controls, while peripheral T cell priming was unaffected in both sexes. Transcriptomic analyses of myeloid cells revealed differences in p38α-controlled transcripts comprising female- and male-specific gene modules, with greater p38α dependence of pro-inflammatory gene expression in females.
Our findings demonstrate a key role for p38α in myeloid cells in CNS autoimmunity and uncover important molecular mechanisms underlying sex differences in disease pathogenesis. Taken together, our results suggest that the p38 MAPK signaling pathway represents a novel target for much needed disease modifying therapies for MS.
PMCID: PMC3945470  PMID: 24027119
24.  Role of STAT5a in Regulation of Sex-specific Gene Expression in Female but not Male Mouse Liver Revealed by Microarray Analysis* 
Physiological genomics  2007;31(1):63-74.
Sexual dimorphism in mammalian liver impacts genes affecting hepatic physiology, including inflammatory responses, diseased states and the metabolism of steroids and foreign compounds. Liver sex-specificity is dictated by sex differences in pituitary growth hormone (GH) secretion, with the transcription factor STAT5b required for intracellular signaling initiated by the pulsatile, male plasma GH profile. STAT5a, a highly homologous but minor liver STAT5 form, also responds to sexually dimorphic plasma GH stimulation, but is unable to compensate for the loss of STAT5b and the associated loss of sex-specific liver gene expression. A large-scale gene expression study was conducted using 23,574-feature oligonucleotide microarrays and livers of male and female mice, both wild-type and Stat5a-inactivated, to elucidate any dependence of liver gene expression on STAT5a. Significant sex differences in expression were found for 2482 mouse genes, 1045 showing higher expression in males and 1437 showing higher expression in females. In contrast to the widespread effects of the loss of STAT5b, STAT5a deficiency had a limited but well defined impact on liver sex-specificity, with 219 of 1437 female-predominant genes (15%) specifically decreased in expression in STAT5a-deficient female liver. Analysis of liver RNAs from wild-type mice representing three mixed or outbred strains identified 1028 sexually dimorphic genes across the strains, including 405 female-predominant genes, of which 91 (23%) required STAT5a for normal expression in female liver. These findings highlight the importance of STAT5a for regulation of sex-specific hepatic genes specifically in female liver, in striking contrast to STAT5b, whose major effects are restricted to male liver.
PMCID: PMC2586676  PMID: 17536022
STAT5a; microarray; liver sexual dimorphism; growth hormone action; strain-dependent gene expression
25.  Experimental pediatric arterial ischemic stroke model reveals sex-specific estrogen signaling 
Background and Purpose
Pediatric stroke, birth-18 years, is a significant cause of long-term disability in the United States, however there is currently little experimental data on the pathophysiology of childhood stroke due to lack of animal models. We developed a novel mouse model of experimental childhood-onset arterial ischemic stroke (AIS) in order to characterize the sex-specific response of the adolescent brain to cerebral ischemia and assess the neuroprotective effect of estrogen at this developmental stage.
Postnatal day 20–25 (P20-25) mice were subjected to 90 minutes experimental stroke via the intraluminal filament middle cerebral artery occlusion (MCAO) model and ischemic damage assessed 22 hr after reperfusion. Real-time quantitative RT-PCR (qPCR) was performed 22 hr after MCAO to determine the effects of ischemia and estrogen treatment on the pro-apoptotic gene Bax.
Ischemic injury did not differ between male and female juvenile (P20-25) mice following MCAO. However, estrogen reduced ischemic injury in female mice, while having no effect in juvenile males. No differences in estrogen receptor expression was observed between P20 males and females. In contrast, estrogen minimized the ischemia-induced increase in the pro-apoptotic gene Bax in female mice, while having no effect on Bax induction in the male brain.
Focal ischemia has fundamentally different effects in the juvenile brain compared to the adult, as evidenced by the lack of gender difference in ischemic injury in the murine P20-25 MCAO model and the sexually dimorphic response to estrogen neuroprotection.
PMCID: PMC3930081  PMID: 23349190
childhood stroke; estrogen; cerebral ischemia; Bax, Bcl-2

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