Adult Gonadal Hormones Research Articles

Sex differences in cognition following variations in endocrine status.

Spatial memory, mediated primarily by the hippocampus, is responsible for orientation in space and retrieval of information regarding location of objects and places in an animal's environment. Since the hippocampus is dense with steroid hormone receptors and is capable of robust neuroplasticity, it is not surprising that changes in spatial memory performance occur following a variety of endocrine alterations. Here, we review cognitive changes in both spatial and nonspatial memory tasks following manipulations of the hypothalamic-pituitary-adrenal and gonadal axes and after exposure to endocrine disruptors in rodents. Chronic stress impairs male performance on numerous behavioral cognitive tasks and enhances or does not impact female cognitive function. Sex-dependent changes in cognition following stress are influenced by both organizational and activational effects of estrogen and vary depending on the developmental age of the stress exposure, but responses to gonadal hormones in adulthood are more similar than different in the sexes. Also discussed are possible underlying neural mechanisms for these steroid hormone-dependent, cognitive effects. Bisphenol A (BPA), an endocrine disruptor, given at low levels during adolescent development, impairs spatial memory in adolescent male and female rats and object recognition memory in adulthood. BPA's negative effects on memory may be mediated through alterations in dendritic spine density in areas that mediate these cognitive tasks. In summary, this review discusses the evidence that endocrine status of an animal (presence or absence of stress hormones, gonadal hormones, or endocrine disruptors) impacts cognitive function and, at times, in a sex-specific manner.

Sex Differences in Mast Cell-Associated Disorders: A Life Span Perspective.

Mast cells are critical innate immune effectors located throughout the body that are crucial for host defense mechanisms via orchestrating immune responses to a variety of host and environmental stimuli necessary for survival. The role of mast cells in brain development and behavior, meningeal function, and stress-related disorders has also been increasingly recognized. While critical for survival and development, excessive mast cell activation has been linked with an increasing number of inflammatory, stress-associated, and neuroimmune disorders including allergy/anaphylaxis, autoimmune diseases, migraine headache, and chronic pain disorders. Further, a strong sex bias exists for mast cell-associated diseases with females often at increased risk. Here we review sex differences in human mast cell-associated diseases and animal models, and the underlying biological mechanisms driving these sex differences, which include adult gonadal sex hormones as well the emerging organizational role of perinatal gonadal hormones on mast cell activity and development.

Non-androgenic testicular mediation of androphilia in male mice with global overexpression of androgen receptors

Sexual attraction is robustly sexually differentiated among mammalian species. Gonadal androgens acting perinatally and in adulthood are required for male-typical preference for female sexual cues. Recent evidence suggests that at the high extent of AR signaling, male mice show an increased preference for same-sex odor cues. These findings were found only in mice that overexpress AR globally in all tissues (CMV-AR), whereas neural AR overexpression (Nestin-AR) did not affect sexual preference. The present studies investigated the endocrine basis of this phenotype and examined whether preference for male or female stimulus animals (partner preference) was also affected in these transgenic animals. We manipulated adult gonadal hormones in male mice that overexpress AR globally and males that overexpress AR only in neural tissue. We replicate the finding that androphilia is increased in gonadally intact CMV-AR males, and these males exhibited reduced neural activation in response to estrus female odors. Testosterone treatment of gonadectomized CMV-AR males was sufficient to induce a gynephilic olfactory preference, while a gynephilic partner preference was induced with gonadectomy alone. These findings suggest that altered sexual preference of CMV-AR male mice is mediated by inhibitory activational functions of the testes. Together, these results suggest that at the high extent of AR signaling, non-neural AR via the gonads, can promote androphilia.

In vivo magnetic resonance imaging reveals the effect of gonadal hormones on morphological and functional brain sexual dimorphisms in adult sheep

Sex differences in the brain and behavior are produced by the perinatal action of testosterone, which is converted into estradiol by the enzyme aromatase in the brain. Although magnetic resonance imaging (MRI) has been widely used in humans to study these differences, the use of animal models, where hormonal status can be properly manipulated, is necessary to explore the mechanisms involved. We used sheep, a recognized model in the field of neuroendocrinology, to assess brain morphological and functional sex differences and their regulation by adult gonadal hormones. To this end, we performed voxel-based morphometry and a resting-state functional MRI approach to assess sex differences in gonadally intact animals. We demonstrated significant sex differences in gray matter concentration (GMC) at the level of the gonadotropic axis, i.e., not only within the hypothalamus and pituitary but also within the hippocampus and the amygdala of intact animals. We then performed the same analysis one month after gonadectomy and found that some of these differences were reduced, especially in the hypothalamus and amygdala. By contrast, we found few differences in the organization of the functional connectome between males and females either before or after gonadectomy. As a whole, our study identifies brain regions that are sexually dimorphic in the sheep brain at the resolution of the MRI and highlights the role of gonadal hormones in the maintenance of these differences.

Characterization and gonadal hormone regulation of a sexually dimorphic corticotropin‐releasing factor receptor 1 cell group

Corticotropin-releasing factor binds with high affinity to CRF receptor 1 (CRFR1) and is implicated in stress-related mood disorders such as anxiety and depression. Using a validated CRFR1-green fluorescent protein (GFP) reporter mouse, our laboratory recently discovered a nucleus of CRFR1 expressing cells that is prominent in the female rostral anteroventral periventricular nucleus (AVPV/PeN), but largely absent in males. This sex difference is present in the early postnatal period and remains dimorphic into adulthood. The present investigation sought to characterize the chemical composition and gonadal hormone regulation of these sexually dimorphic CRFR1 cells using immunohistochemical procedures. We report that CRFR1-GFP-ir cells within the female AVPV/PeN are largely distinct from other dimorphic cell populations (kisspeptin, tyrosine hydroxylase). However, CRFR1-GFP-ir cells within the AVPV/PeN highly co-express estrogen receptor alpha as well as glucocorticoid receptor. A single injection of testosterone propionate or estradiol benzoate on the day of birth completely eliminates the AVPV/PeN sex difference, whereas adult gonadectomy has no effect on CRFR1-GFP cell number. These results indicate that the AVPV/PeN CRFR1 is regulated by perinatal but not adult gonadal hormones. Finally, female AVPV/PeN CRFR1-GFP-ir cells are activated following an acute 30-min restraint stress, as assessed by co-localization of CRFR1-GFP cells with phosphorylated (p) CREB. CRFR1-GFP/pCREB cells were largely absent in the male AVPV/PeN. Together, these data indicate a stress and gonadal hormone responsive nucleus that is unique to females and may contribute to sex-specific stress responses.

Sex differences in the traumatic stress response: the role of adult gonadal hormones

BackgroundOur previous study revealed that adult female rats respond differently to trauma than adult males, recapitulating sex differences in symptoms of post-traumatic stress disorder (PTSD) exhibited by women and men. Here, we asked two questions: does the female phenotype depend on (1) social housing condition and/or (2) circulating gonadal hormones?MethodsFor the first study, the effects of single prolonged stress (SPS) were compared for females singly or pair-housed. For the second study, adult male and female rats were gonadectomized or sham-gonadectomized 2 weeks prior to exposure to SPS, with half the gonadectomized rats given testosterone. In addition to the typical measures of the trauma response in rats, acoustic startle response (ASR), and the dexamethasone suppression test (DST), we also used two other measures typically used to assess depressive-like responses, social interaction and sucrose preference. Glucocorticoid receptor (GR) expression in the hypothalamus was also examined.ResultsWe now report that the distinct trauma response of female rats is not influenced by social housing condition. Moreover, sex differences in the response to SPS based on ASR and DST, replicated in the current study, are independent of adult gonadal hormones. Regardless of hormonal status, traumatized males show a hyper-responsive phenotype whereas traumatized females do not. Moreover, testosterone treatment in adulthood did not masculinize the response to trauma in females. Notably, both sucrose preference and social interaction tests revealed an effect of trauma in females but not in males, with the effects of SPS on sucrose preference dependent on ovarian hormones. Effects of SPS on GR expression in the hypothalamus also depended on gonadal hormones in females.ConclusionsWe propose that the trauma response for female rats is depressive in nature, recapitulating the female bias in PTSD for internalizing symptoms and major depression in contrast to the externalizing symptoms of males. Presumed core markers of PTSD (enhanced ASR and negative feedback control of corticosterone) are apparently relevant only to males and are independent of adult gonadal hormones. Such sex differences in trauma responding are likely determined earlier in life. We conclude that males and females show fundamentally different responses to trauma that do not simply reflect differences in resilience.

Dissociation of Puberty and Adolescent Social Development in a Seasonally Breeding Species

Alongside the development of sexual characteristics and reproductive competence, adolescents undergo marked cognitive, social, and emotional development [1]. A fundamental question is whether these changes are triggered by activation of the hypothalamic-pituitary-gonadal (HPG) axis at puberty (puberty dependent) or whether they occur independently of HPG activation (puberty independent). Disentangling puberty-dependent from puberty-independent mechanisms is difficult because puberty and adolescence typically proceed concurrently. Here, we test a new approach that leverages natural adaptations of a seasonally breeding species to dissociate pubertal status from chronological age. Siberian hamsters (Phodopus sungorus) reared in a long, summer-like day length (LD) exhibit rapid pubertal development, whereas those reared in a short, winter-like day length (SD) delay puberty by several months to synchronize breeding with the following spring [2, 3]. We tested whether the SD-induced delay in puberty delays the peri-adolescent decline in juvenile social play and the rise in aggression that characterizes adolescent social development in many species [4-6] and compared the results to those obtained after prepubertal gonadectomy. Neither SD rearing nor prepubertal gonadectomy altered the age at which hamsters transitioned from play to aggression; SD-reared hamsters completed this transition prior to puberty. SD rearing and prepubertal gonadectomy, however, increased levels of play in male and female juveniles, implicating a previously unknown role for prepubertal gonadal hormones in juvenile social behavior. Levels of aggression were also impacted (decreased) in SD-reared and gonadectomized males. These data demonstrate that puberty-independent mechanisms regulate the timing of adolescent social development, while prepubertal and adult gonadal hormones modulate levels of age-appropriate social behaviors.

Sex differences in stress-induced social withdrawal: Independence from adult gonadal hormones and inhibition of female phenotype by corncob bedding

There is compelling evidence for important sex differences in behavioral and hormonal responses to psychosocial stress. Here we examined the effects of gonadal hormones on behavioral responses to social defeat stress in monogamous California mice (Peromyscus californicus). Three episodes of social defeat induced social withdrawal in intact females but not males. Gonadectomy blocked corticosterone responses to defeat in females and sensitized male corticosterone responses. However, gonadectomy had no effects on social interaction behavior, suggesting that social withdrawal is not dependent on gonadal hormones in the adult California mouse. In contrast, defeat reduced exploratory behavior in the open field test for intact but not castrated males. We also examined the effects of social defeat on social interaction behavior when California mice were raised on corncob bedding, which has estrogenic properties. In this dataset of over 300 mice, we observed that social defeat did not induce social withdrawal when females were raised on corncob bedding. This finding suggests that the use of corncob in rodent studies could mask important sex differences in the effects of stress on brain and behavior. Although gonadal hormones do not affect social withdrawal behavior in adults, our data suggest that hormones may act earlier in development to induce a more resilient social phenotype.

Gonadal Steroids Regulate Neural Plasticity in the Sexually Dimorphic Nucleus of the Preoptic Area of Adult Male and Female Rats

Background: The densely staining sexually dimorphic nucleus of the preoptic area (SDNPOA) is profoundly affected by gonadal steroids during perinatal development. Methods: We tested whether the SDNPOA in rats also remains responsive to gonadal hormones in adulthood. Results: Castration of 60-day-old male rats led to a reduction of soma size in SDNPOA neurons 28 days later, but not 14 days later. In contrast, the SDNPOA volume in males was unaffected by adult castration, increasing somewhat between 60 and 88 days of age in both castrated males and sham controls. For female rats ovariectomized at 60 days of age, testosterone treatment resulted in a significantly larger SDNPOA soma size after either 14 or 28 days of treatment, compared to blank-treated controls. Testosterone-treated ovariectomized females also had a modestly larger SDNPOA volume after 28 days, but not 14 days, of treatment compared to blank-treated ovariectomized animals. A second experiment revealed that these effects in females were due to ovariectomy: both SDNPOA soma size and regional volume shrank in females that were ovariectomized compared to females subjected to sham surgery. The effects of ovariectomy were blocked by testosterone treatment. The cessation of testosterone treatment in females returned SDNPOA soma size and regional volume to that of control-treated ovariectomized females. Conclusion: These results indicate considerable plasticity of the adult rat SDNPOA, and that (1) circulating androgens are required to maintain soma size, but not regional volume in males, and (2) ovarian steroids maintain both soma size and regional volume of the SDNPOA in females, an effect that can be mimicked with testosterone treatment and is fully reversible in adulthood.

Females do not Express Learned Helplessness like Males do

Women are more likely than men to suffer from stress-related mental disorders, such as depression. In the present experiments, we identified sex differences in one of the most common animal models of depression, that of learned helplessness. Male and female rats were trained to escape a mild footshock each day for 7 days (controllable stress). Each rat was yoked to another rat that could not escape (uncontrollable stress), but was exposed to the same amount of shock. One day later, all stressed rats and unstressed controls were tested on a more difficult escape task in a different context. Most males exposed to uncontrollable stress did not learn to escape and were therefore helpless. In contrast, most females did learn to escape on the more difficult escape task, irrespective of whether they had been exposed to controllable or uncontrollable stress. The sex differences in helplessness behavior were not dependent on the presence of sex hormones in adulthood, because neither ovariectomy of females nor castration of males abolished them. The absence of helplessness in females was neither dependent on organizational effects of testosterone during the day of birth, because masculinized females did not express helplessness as adults. Thus, sex differences in helplessness behavior are independent of gonadal hormones in adulthood and testosterone exposure during perinatal development. Learned helplessness may not constitute a valid model for depressive behavior in women, at least as reflected by the response of female rats to operant conditioning procedures after stressful experience.

Odor-facilitated reentrainment in male and female juvenile Octodon degus

The social, diurnal rodent, Octodon degus, exhibits faster reentrainment rates of circadian activity when exposed to olfactory social cues from females already entrained to the new light cycle (donors) during reentrainment after a phase shift of the light:dark (LD) cycle. However, adult degus display sex differences in the use of olfactory stimuli to accelerate reentrainment, with intact males requiring odors from at least two females for accelerated reentrainment, while odors from a single female are sufficient for faster recovery for females. In addition, adult gonadal hormones modulate responsiveness to the rate-enhancing olfactory stimuli. The present study examines responsiveness to reentrainment-accelerating odors in juvenile animals just prior to puberty. We report that the sex difference in sensitivity observed in adults is not evident in juveniles; both males and females, when exposed to odors from one unfamiliar adult, accelerated reentrainment of circadian activity after a 6-h phase-advance of the LD cycle. In conjunction with adult data, these results suggest that the sensitivity-reducing role of testosterone does not change across the life span, while the sensitivity-enhancing role of ovarian hormones in females occurs only post-pubertally.

Sexually dimorphic expression of oxytocin binding sites in forebrain and spinal cord of the rat

The central actions of oxytocin on reproduction-related functions and behaviors are strongly steroid-dependent and gender specific. This study characterizes sexual differences in the oxytocin binding site expression in forebrain and spinal cord of the rat. Using film autoradiography, we quantified the density of oxytocin binding sites in the ventromedial hypothalamic nucleus, the medial and central nuclei of the amygdala, the medial bed nucleus of the stria terminalis and the spinal cord dorsal horns both in adult male and female rats, and during development. In addition, neonatal castrated males and intact neonatal females treated with a single injection of testosterone (1 mg) were examined. Data showed a sexual dimorphism in the expression of oxytocin binding sites in the spinal cord dorsal horns and in restricted areas of the forebrain that are sensitive to gonadal steroids such as the ventromedial hypothalamic nucleus, but not in gonadal steroid insensitive sites such as the central nucleus of the amygdala. Adult males had higher oxytocin binding site densities in the ventromedial hypothalamic nucleus and dorsal horns than females. In the forebrain, but not in the dorsal horn, this sexual difference required a perinatal exposure to testosterone. Neonatal castration only abolished the sexual difference in the ventromedial hypothalamic nucleus of adults, but not in the dorsal horn. Furthermore, females that received a single injection of testosterone 1 day after birth showed significant increases in the density of oxytocin binding sites in the ventromedial hypothalamic nucleus, medial nucleus of the amygdala and medial bed nucleus of the stria terminalis. In addition, the findings suggest that the sexual difference in the ventromedial hypothalamic nucleus also requires gonadal hormones in adulthood. Our data support the hypothesis that sexually dimorphic oxytocin binding sites may contribute to the regulatory central actions of oxytocin in gender specific functions and behaviors such as nociception and reproduction.

Adult Gonadal Hormones Selectively Regulate Sexually Dimorphic Quantitative Traits Observed in Experimental Allergic Encephalomyelitis

Experimental allergic encephalomyelitis (EAE) and multiple sclerosis (MS) are characterized by strong sexual dimorphisms, many of which may be due to genetically controlled sex hormone effects on the immune system, the central nervous system (CNS), or both. In the present study we used 487 gonadectomized and 376 intact age-matched F(2) mice generated through crosses of B10.S/SgMcdJ and SJL/J mice to assess the role of adult gonadal hormones in regulating clinical and histopathological quantitative traits (QT) associated with EAE in the context of genetic heterogeneity. We found that gonadectomy resulted in different effects, depending on the QT and the sex of the mouse. Ovariectomized mice on average had lower cumulative clinical disease scores, shorter duration of clinical signs, and increased peak disease scores. This trend was accompanied by a significant increase in the incidence of acute, progressive EAE which is more frequently seen in intact and orchiectomized males. Although spinal cord (SC) inflammation was the better predictor of clinical signs of EAE in both sexes, ovariectomized females had considerable reductions in nearly all histopathological QT in both the brain and SC. Orchiectomy resulted in modestly significant increases in disease severity and peak score and earlier onset of clinical signs. With the exception of SC demyelination and lesion scores, orchiectomy had no effect on histopathological QT. Importantly, gonadectomy reduced but did not completely abolish any of the sexually dimorphic clinical QT seen in intact mice. It did however, lead to a significant sexual dimorphism in incidence and severity not seen in intact mice. For histopathological QT, no sexual dimorphism was detected for brain lesions in either intact or gonadectomized mice. In contrast, SC histopathological QT exhibited significant sexual dimorphisms, which were impacted by gonadectomy. The results from this study indicate that within the context of genetic heterogeneity, circulating gonadal hormones influence both clinical and histopathological QT in this model of MS, but they do not solely account for the sexual dimorphisms seen in these traits. Thus, additional mechanisms must play a role in regulating gender differences in autoimmune disease of the CNS.

Male Japanese quails with female brains do not show male sexual behaviors.

During embryonic development, gonadal steroid hormones (androgens and estrogens) are thought to organize the sexual differentiation of the brain in the heterogametic sexes of higher vertebrates (males in mammals, females in birds). Brain differentiation of the homogametic sexes is thought to proceed by default, not requiring sex hormones for sex-specific organization. In gallinaceous birds such as the Japanese quail, female brain organization is thought to develop via estrogen-dependent demasculinization of a default male brain phenotype. We performed male donor-to-female host (MF), female-to-male (FM), male-to-male (MM), and female-to-female (FF) isotopic, isochronic transplantation of the forebrain primordium in Japanese quail embryos before gonadal differentiation had occurred; brain chimeras had a forebrain (including the hypothalamus) originating exclusively from donor cells. MM, FF, and MF chimeras all showed sexual behavior governed by the genetic sex of the host. In contrast, FM chimeras (genetically female forebrain, all other tissues genetically male) showed no mounting and only rudimentary crowing behavior. Although MM, FF, MF, and FM chimeras all showed host-typical production of steroid hormones during embryonic life, only FM chimeras were hypogonadal, had atypical low levels of circulating testosterone in adulthood, and showed reduction (crowing) or absence (mounting) of reproductive behaviors. Morphological features of the medial preoptic nucleus (a sexually dimorphic brain area) also were not male-like in FM males. These data demonstrate a brain-intrinsic, genetically determined component that organizes the sex-typical production of gonadal hormones in adulthood and call for a reevaluation of the mechanisms underlying brain sexual differentiation in other higher-vertebrate species.

Testicular Hormones Modulate Circadian Rhythms of the Diurnal Rodent, Octodon degus

Sex differences have been identified in a variety of circadian rhythms, including free-running rhythms, light-induced phase shifts, sleep patterns, hormonal fluctuations, and rates of reentrainment. In the precocial, diurnal rodent Octodon degus, sex differences have been found in length of free-running rhythm (τ), phase response curves, rates of reentrainment, and in the use of social cues to facilitate reentrainment. Although gonadal hormones primarily organize circadian rhythms during early development, adult gonadal hormones have activational properties on various aspects of circadian rhythms in a number of species examined. Gonadectomy of adult female O. degus did not influence τ, phase angle of entrainment, or activity patterns in previous experiments. The present experiment examined the role of gonadal hormones in adult male degus' circadian wheel-running rhythms. We predicted that male gonadal hormones would have an activational effect on some aspects of circadian rhythms, particularly those in which we see sex differences. Phase angles of entrainment, τ, length of the active period (α), maximum and mean activity levels, and activity amplitude were examined for intact and castrated males housed in LD 12:12. Responses to light pulses while housed in constant darkness (DD) were also compared. Castration had no significant effect on τ or light-induced phase shifts. However, castration significantly increased phase angle of entrainment and decreased activity levels. The data indicate that adult gonadal steroids are not responsible for the sex differences in endogenous circadian mechanisms of O. degus (τ, PRC), although they influence activity level and phase angle of entrainment. This is most likely due to masking properties of testosterone, similar to the activity-increasing effects of estrogen during estrus in O. degus females.

Prenatal exposure to morphine differentially alters gonadal hormone regulation of δ-opioid receptor binding in male and female rats

The present study tested the hypothesis that exposure to morphine on gestation days 11–18 differentially alters δ-opioid receptors in the brain of adult male and female rats. In Experiment 1, the binding characteristics of δ-opioid receptors were examined in membrane homogenates from six brain regions, including the hypothalamus (HYP), preoptic area, frontal cortex (CX), ventral tegmental area, striatum (STR) and cerebellum of adult male and female rats. In Experiment 2, the density of δ-opioid receptors was assessed in the CX and STR using receptor autoradiography. Prenatal morphine exposure has no effects on δ-opioid receptors in the brain of gonadally intact, adult male rats regardless of methodology. However, when male rats were gonadectomized in Experiment 2, morphine-exposed males have fewer δ-opioid receptors than controls in the CX but not in the STR. These reductions in cortical δ-opioid receptors are restored by testosterone replacement, demonstrating that prenatal morphine exposure alters testosterone regulation in the CX of male rats. In ovariectomized (OVX) female rats, prenatal morphine exposure increases the density of δ-opioid receptors in the frontal CX. Interestingly, this up-regulation of δ-opioid receptors is not present when the CX is investigated by autoradiography. Moreover, progesterone given alone or in combination with estrogen reduces the density of δ-opioid receptors in the CX and STR of both saline- and morphine-exposed, OVX females. Thus, mid to late gestational morphine exposure differentially alters the influence of adult gonadal hormones on δ-opioid receptors in the CX, decreasing the sensitivity in females and increasing it in males. This is also the first report to demonstrate that gonadal hormones regulate δ receptor densities in brain regions other than the HYP of OVX females.

Postnatal Testicular Secretions Partially Restore the Disturbances in Reproductive Activity Caused by Prenatal Hormonal Manipulation

Vega Matuszczyk, J., R. S. Appa and K. Larsson. Postnatal testicular secretions partially restore the disturbances in reproductive activity caused by prenatal hormonal manipulation. Physiol Behav 62(1) 137–143, 1997.—Male rats that prenatally had been exposed to an antiestrogen, nitromifene citrate (CI 628), showed evidence of impaired defeminization and masculinization in adulthood, suggesting a role of endogenous estrogen for the sexual differentiation of the male. The present study was undertaken to investigate a possible role of postnatal testicular secretions for the above behavioral effects. Male rats were exposed prenatally to CI 628 (l mg/rat) or saline, and castrated on Day 0, Day 10, or Day 90 after birth. After treatment with gonadal hormones in adulthood, the males were tested for feminine and masculine sexual behavior and for sexual orientation, both when sexually naive and after they had acquired sexual experience. The following conclusions were drawn: 1. Permanent deficits of lordotic behavior were observed in all experimental groups, suggesting the importance of prenatal estrogen for the defeminization process. 2. Hop/darting and ear wiggling behaviors were enhanced in Day-0 and Day-10 castrates, and blocked in the Day-90 castrates. The restitution of these behaviors to normal levels in Day-90 castrates suggests that, in addition to prenatal estrogen, postnatal testicular secretions also are involved in the behavioral defeminization process. 3. Prenatal estrogen contributes to masculinization as evidenced by the impaired ejaculatory behavior observed in all experimental groups. 4. Male-typical sexual orientation toward the female seems to be facilitated by prenatal estrogen. Both the masculinization and the defeminization of male-typical sexual orientation toward a female were impaired by castration at birth and at Day 10 in the experimental animals, but a full restoration of the sexual orientation toward females was seen in Day-90 castrates, suggesting the restorative role of postnatal testicular secretions for these processes.

A prenatal source for defeminization of female rats is the maternal ovary

Sexual behavior in laboratory rats is influenced by a variety of factors in the perinatal environment. Male rats are masculinized and defeminized in response to circulating testosterone perinatally. Females undergo a process of feminization but in some cases are exposed to testosterone. Previous work has shown that during prenatal development female rats normally undergo a partial masculinization and defeminization of sexual behavior as reflected by altered responsiveness to gonadal hormones in adulthood. In the present study we investigated whether the maternal ovary influences adult females' responsiveness to gonadal hormones. Pregnant rats were ovariectomized on Day 10 of pregnancy and their offspring tested for sexual behavior in adulthood. Following ovariectomy pregnancies were maintained by administration of systemic progesterone. In addition the ovariectomized pregnant rats were given one of three daily treatments (Days 10–21): 0.2 μg estradiol benzoate in sesame oil and 0.1 cc propylene glycol, 5 mg of the aromatase inhibitor 1,4,6-androstatriene-3,17-dione (ATD) in 0.1 cc propylene glycol, or 0.1 cc propylene glycol. A control group was generated from SHAM operated mothers given daily control injections of propylene glycol and sesame oil. Offspring were ovariectomized in adulthood and tested for display of feminine sexual behavior in response to estradiol benzoate and progesterone or estradiol benzoate alone. Masculine sexual behavior was measured in response to testosterone propionate (TP). Feminine sexual behavior was enhanced in offspring from ovariectomized mothers given only progesterone replacement during pregnancy. Offspring from mothers treated with ATD displayed the greatest elevations in feminine sexual behavior. Estradiol treatments of ovariectomized mothers prevented the increase in feminine potential seen in offspring in the other groups. Masculine sexual behavior in response to daily treatment with testosterone propionate did not differ between groups. The results indicated that the maternal ovary was associated with a defeminization to female offspring. It is suggested that normal female rats undergo a reduction in eventual responsiveness to ovarian hormones as a result of exposure to estrogens prenatally; the present study indicates that at least some of these estrogens originate in the maternal ovary.

Acetylcholinesterase activity in the sexually dimorphic area of the gerbil brain: sex differences and influences of adult gonadal steroids.

The morphology of the medial preoptic area-anterior hypothalamus (MPOA-AH) of gerbils is sexually dimorphic and influenced by adult gonadal hormones. This research shows that the distribution of (MPOA-AH) cells that synthesize acetylcholinesterase (AChE) and the activity of AChE within the MPOA-AH are also sexually dimorphic and hormone sensitive. Adult male and female gerbils were gonadectomized, gonadectomized and implanted subcutaneously with testosterone (T), or sham operated 4-8 weeks before sacrifice. Coronal sections through the sexually dimorphic area (SDA) of the MPOA-AH were stained for AChE. Planimeter measurements of camera lucida drawings showed that the total volume of the SDA is similar in the two sexes, but the proportion of the SDA that stains darkly and/or stands out clearly from the surround (dark volume) is larger in males. Optical density readings also indicated that AChE staining is darker in the male SDA. Gonadectomy decreases staining intensity in both sexes and reduces total SDA volume. Dark volume decreases more than 50%. Testosterone treatment reverses all effects of gonadectomy, although hormonal influences are smaller in females than in males. There were no sex differences or hormonal influences on AChE staining lateral to the SDA. The pars compacta of the male SDA was essentially devoid of AChE, indicating that this cell group is distinct from the rest of the SDA. It also shrinks after castration unless the males receive T. Histochemical changes in the SDA may be related to hormonal control of scent marking, a form of communication in this species.

Differentiation of coital behavior in mammals: A comparative analysis

The evidence reviewed suggests that in all mammalian species the adult male's ability to display masculine coital behavior depends in part on exposure of the developing brain to testicular testosterone or its metabolites. In many mammals, particularly rodents, ruminants, and some carnivores, perinatal exposure to androgen also causes behavioral defeminization, i.e., reduced capacity to display typically feminine coital behavior in response to gonadal hormones in adulthood. The data reviewed suggest that no such process occurs in certain other mammalian species, including ferret, rhesus monkey, marmoset, and man. Testicular androgen may cause behavioral defeminization only in those species in which expression of feminine sexual behavior normally depends on the neural action of progesterone, acting synergistically with estradiol; new data support this claim in the ferret. The possible contribution of estrogenic and 5α-reduced androgenic metabolites of testosterone to the occurrence of behavioral masculinization and defeminization is considered in those mammalian species for which data are available.