Sex differences in adrenal function in the lizard Cnemidophorus sexlineatus: II. Responses to acute stress in the laboratory.

Circulating concentrations of plasma corticosterone and gonadal steroids were measured in intact and gonadectomized male and female lizards (Cnemidophorus sexlineatus) following acute stress (handling) in the laboratory. There was a significant increase in plasma corticosterone after stress. Whereas intact females exhibited greater concentrations of corticosterone relative to intact males, ovariectomized females exhibited lower concentrations of corticosterone relative to castrated males. In addition to sex differences in corticosterone responses to gonadectomy, progesterone was elevated by stress in both intact and ovariectomized females but not in males. Corticosterone adjusted for castration and handling in males was negatively correlated with the plasma androgen level. The adrenal responsiveness of males to acute stress may be attenuated by androgens presumably secreted by the testis. Not only does adrenal function influence reproduction, but adrenal responses differ between males and females, and appear to be influenced by the gonadal axis. The sex differences in adrenal responses to stress likely reflect different reproductive strategies and nutritional requirements of males and females during the breeding season.     

NMDA receptor antagonism disrupts the development of morphine analgesic tolerance in male, but not female C57BL/6J mice

Multiple studies demonstrate that coadministration of N-methyl-D-aspartate (NMDA) receptor antagonists with the opioid agonist morphine attenuates the development of analgesic tolerance. Sex differences in the effects of noncompetitive, but not competitive NMDA receptor antagonists on acute morphine analgesia, have been reported in mice, yet the role of sex in modulation of morphine tolerance by NMDA receptor antagonists has yet to be addressed. Therefore, we tested whether there is a sex difference in the effect of NMDA receptor antagonists on the development of morphine analgesic tolerance in C57BL/6J mice. Acutely, at a dose required to affect morphine tolerance in male mice, the noncompetitive NMDA receptor antagonist dizocilpine (MK-801) prolonged morphine analgesia similarly in both sexes in the hot plate and tail withdrawal assays. In the hot plate assay, coadministration of MK-801 or the competitive antagonist 3-(2-carboxpiperazin-4-yl)propyl-1-phosphanoic acid (CPP) with morphine attenuated the development of tolerance in male mice, while having no effect in females. Like normal and sham females, ovariectomized mice were similarly insensitive to the attenuation of morphine tolerance by MK-801 in the hot plate assay. Surprisingly, in the tail withdrawal assay, MK-801 facilitated the development of morphine-induced hyperalgesia and tolerance in males but not females. The results demonstrate that male mice are more sensitive to modulation of nociception and morphine analgesia after repeated coadministration of NMDA receptor antagonists. Furthermore, the underlying mechanisms are likely to be different from those mediating the sex difference in the modulation of acute morphine analgesia that has previously been reported.     

Sex Differences in Acute Swim Stress-Induced Changes in the Binding of MK-801 to the NMDA Subclass of Glutamate Receptors in Mouse Forebrain

Acute swim stress (3 min at 32°C) in mice produces increases in the binding of MK-801 to the NMDA subclass of glutamate receptors to forebrain membranes prepared from male mice. Scatchard analyses indicate that the observed increases in the binding of MK-801 in membranes from male mice are the result of changes in the affinity and density of low-affinity binding sites and in the density of high-affinity binding sites. In female mice, any changes in the binding of MK-801 appear to be much less pronounced and restricted to the low-affinity binding sites. These results are in contrast to the situation with binding to GABA receptors where acute swim stress increases GABA binding in forebrain membranes much more in female than in male mice. This indicates significant sex differences in the responses of receptors for the major excitatory and inhibitory transmitters to acute swim stress. These rapid changes in MK-801 binding may result from changes in endogenous modulators as appears to be the case in the acute swim stress-induced changes in GABA binding. As with GABA binding, the endogenous modulators are likely to include steroids, the sex differences reflecting differences in modulation by gonadal steroids and the stress-induced changes reflecting differences in modulation by adrenal steroids. Estradiol, progesterone, and corticosterone treatments have been reported by other workers to influence the properties of glutamate receptors.     

Members of opposite sex mutually regulate gonadal recrudescence in the lizard Calotes versicolor Agamidae)

Adult males and females of the seasonally breeding lizardCalotes versicolor were subjected to various social situations under semi-natural conditions to explain the role of socio-sexual factors in gonadal recrudescence. They were grouped as: (i) males and females, (ii) males and females separated by a wire mesh, (iii) same sex groups of males or females, (iv) castrated males with intact females and (v) ovariectomized (OvX) females with intact males from postbreeding to breeding phase. Specimens collected from the wild during breeding season served as the control group. Plasma sex steroid levels (testosterone in male and 17β-estradiol in female), spermatogenetic activity and vitellogenesis were the criteria to judge gonadal recrudescence. In intact males and females that were kept together, gonadal recrudescence and plasma sex steroids levels were comparable to those in wild-caught individuals. Gonadal recrudescence was at its least in all male and all female groups, and plasma sex steroids were at basal levels. Association with OvX females initiated testicular recrudescence but spermatogenetic activity progressed only up to the spermatid stage while males separated from females by wire mesh showed spermatogenetic activity for a shorter period. Females grouped with castrated males and those separated from males by wire mesh produced vitellogenic follicles. However, the total number and diameter of vitellogenic follicles, and plasma estradiol levels were lower than in the females grouped with intact males. The findings indicate that association with members of the opposite sex with progressively rising titers of sex steroids is crucial in both initiating and sustaining gonadal recrudescence in the lizard. Thus, members of the opposite sex mutually regulate gonadal recrudescence in theC. versicolor.     

Independent influences of sex steroids of systemic and central origin in a rat model of Parkinson's disease: A contribution to sex-specific neuroprotection by estrogens

This review considers evidence which reveals considerable complexity and sex differences in the response of the nigrostriatal dopaminergic (NSDA) system to hormonal influences. This pathway degenerates in Parkinson's disease (PD) and sex hormones contribute to sex differences in PD, where men fare worse than women. Here we discuss evidence from animal studies which allows us to hypothesize that, contrary to expectations, the acclaimed neuroprotective property of physiological concentrations of estradiol arises not by promoting NSDA neuron survival, but by targeting powerful adaptive responses in the surviving neurons, which restore striatal DA functionality until over 60% of neurons are lost. Estrogen generated locally in the NSDA region appears to promote these adaptive mechanisms in females and males to preserve striatal DA levels in the partially injured NSDA pathway. However, responses to systemic steroids differ between the sexes. In females there is general agreement that gonadal steroids and exogenous estradiol promote striatal adaptation in the partially injured NSDA pathway to protect against striatal DA loss. In contrast, the balance of evidence suggests that in males gonadal factors and exogenous estradiol have negligible or even harmful effects. Sex differences in the organization of NSDA-related circuitry may well account for these differences. Compensatory mechanisms and sexually dimorphic hard-wiring are therefore likely to represent important biological substrates for sex dimorphisms. As these processes may be targeted differentially by systemic steroids in males and females, further understanding of the underlying processes would provide valuable insights into the potential for hormone-based therapies in PD, which would need to be sex-specific. Alternatively, evidence that estrogen generated locally is protective in the injured male NSDA pathway indicates the great therapeutic potential of harnessing central steroid synthesis to ameliorate neurodegenerative disorders. A clearer understanding of the relative contributions and inter-relationships of central and systemic steroids within the NSDA system is an important goal for future studies.     

Sex differences in cortisol secretion after administration of an ACTH analogue in sheep during the breeding and non-breeding season

The aim of this study was to compare the response of cortisol in sheep of different sex and gonadal status to adrenal cortex stimulation by an ACTH analogue in the breeding and non-breeding season. Twenty-four adult Corriedale sheep were used in the non-breeding season, and 19 in the breeding season. Three weeks prior to the first trial (non-breeding season), six rams and six ewes were gonadectomised. In each trial, blood was obtained every 15min for 9h and the animals received 0.5mg of ACTH (Tetracosactid, Synacthen Depot i.m., after 1.5h of sampling. Sampling began at 10:00a.m. in the non-breeding season and at 9:00a.m. in the breeding season. Three main effects (sex, gonadal status and season) were evaluated, each with two levels (male and female, intact and gonadectomised, breeding and non-breeding season, respectively). In both seasons, the females showed higher cortisol levels after ACTH than males (P<0.001), though the difference seemed less marked in the non-breeding season. The cortisol response in the ewes was not affected by season. The rams, however, showed a lower response in the breeding season (P<0.03). Gonadectomy reduced the response in the ewes (P<0.001) but had no effect in the rams. Nevertheless, gonadectomy also eliminated the differences between the ewes and the rams, such that the intact rams had lower levels of cortisol compared to the intact females, with those of the gonadectomised animals of both sexes being intermediate between the gonad-intact groups. The results of this study confirm sex differences in ACTH induced cortisol secretion in intact sheep in vivo. Furthermore, by applying exogenous ACTH we have directly stimulated the adrenal cortex, indicating the existence of sex differences also at this level. The circulating gonadal steroids, which are responsible at least in part for the sex differences in the responses to stress, may influence cortisol secretion from the adrenal gland by direct action at the cortex.     

Gender differences in murine airway responsiveness and lipopolysaccharide-induced inflammation

The roles of gender and sex hormones in lung function and disease are complex and not completely understood. The present study examined the influence of gender on lung function and respiratory mechanics in naive mice and on acute airway inflammation and hyperresponsiveness induced by intratracheal LPS administration. Basal lung function characteristics did not differ between naive males and females, but males demonstrated significantly greater airway responsiveness than females following aerosolized methacholine challenge as evidenced by increased respiratory system resistance and elastance (p < 0.05). Following LPS administration, males developed more severe hypothermia and greater airway hyperresponsiveness than females (p < 0.05). Inflammatory indices including bronchoalveolar lavage fluid total cells, neutrophils, and TNF-alpha content were greater in males than in females 6 h following LPS administration (p < 0.05), whereas whole-lung TLR-4 protein levels did not differ among treatment groups, suggesting that differential expression of TLR-4 before or after LPS exposure did not underlie the observed inflammatory outcomes. Gonadectomy decreased airway inflammation in males but did not alter inflammation in females, whereas administration of exogenous testosterone to intact females increased their inflammatory responses to levels observed in intact males. LPS-induced airway hyperresponsiveness was also decreased in castrated males and was increased in females administered exogenous testosterone. Collectively, these data indicate that airway responsiveness in naive mice is influenced by gender, and that male mice have exaggerated airway inflammatory and functional responses to LPS compared with females. These gender differences are mediated, at least in part, by effects of androgens.     

Sex differences and hormone influences on tyrosine hydroxylase immunoreactive cells in the leopard frog

We examined sex differences in tyrosine hydroxylase immunoreactive (TH-ir) cell populations in the preoptic area (POA), suprachiasmatic nucleus (SCN), posterior tuberculum (TP), and caudal hypothalamus (Hy) in the leopard frog (Rana pipiens), in addition to the effects of natural variation in sex steroid hormones on these same populations in both sexes. All four of these populations have been shown to be dopaminergic. Gonadal sex, androgens, and estrogen all influenced TH-ir cell numbers, but in a complicated pattern of interactions. After factoring out the effects of sex steroids by multiple regression, TH-ir cell numbers in all four areas differed between the sexes, with males having a greater number of TH-ir cells. The influence of androgens and estrogen differed by region and sex of the animals. Androgens were the main influence on TH-ir cell numbers in the POA and SCN. Plasma androgen concentrations were positively correlated with TH-ir cell numbers in both areas in males. In females, androgen concentration was negatively correlated with TH-ir cell numbers in the POA; there was no significant relationship in the SCN in females. In the more caudal populations, estrogen (E2) levels were positively correlated with TH-ir cell numbers in the TP of both males and females. In the caudal hypothalamus, E2 levels were positively correlated with TH-ir cell numbers in females, but there was no significant correlation in males. The results indicate that gonadal sex imposes a baseline sex difference in the four TH-ir (dopamine) populations, resulting in a higher number of such cells in males. Individual and sex-linked differences in gonadal steroid hormones lead to variation around this baseline condition, with androgens having a greater influence on rostral populations and estrogen on caudal populations. Last, an individual's gonadal sex determines the effect that androgens and estrogen have on each population.     

Endocrine influences on the actions of morphine: IV. Effects of sex and strain

The antinociceptive and temperature responses to morphine were compared in male and female rats from two different strains. Males of both the Sprague-Dawley and Wistar-Furth strains were slightly more responsive to the acute actions of morphine than were females of the same strain. However, Wistar-Furth animals required approximately twice the dose of morphine to display equivalent antinociceptive responses and four times the dose of display equivalent hypothermic responses when compared with Sprague-Dawley animals. During chronic morphine treatment, the development of tolerance was slightly more rapid in males than in females and in Sprague-Dawley animals than in Wistar-Furth animals. Gonadal hormones also influenced morphine responses. Ovariectomized rats were significantly more responsive acutely to morphine and developed tolerance less rapidly than estradiol-treated females. However, alterations of gonadal hormones in males did not affect morphine responses. These results indicate that morphine responses vary considerably between strains of animals and are influenced by gonadal hormones of females, but not of males.     

Sex chromosome complement contributes to sex differences in coxsackievirus B3 but not influenza A virus pathogenesis

Background

Both coxsackievirus B3 (CVB3) and influenza A virus (IAV; H1N1) produce sexually dimorphic infections in C57BL/6 mice. Gonadal steroids can modulate sex differences in response to both viruses. Here, the effect of sex chromosomal complement in response to viral infection was evaluated using four core genotypes (FCG) mice, where the Sry gene is deleted from the Y chromosome, and in some mice is inserted into an autosomal chromosome. This results in four genotypes: XX or XY gonadal females (XXF and XYF), and XX or XY gonadal males (XXM and XYM). The FCG model permits evaluation of the impact of the sex chromosome complement independent of the gonadal phenotype.

Methods

Wild-type (WT) male and female C57BL/6 mice were assigned to remain intact or be gonadectomized (Gdx) and all FCG mice on a C57BL/6 background were Gdx. Mice were infected with either CVB3 or mouse-adapted IAV, A/Puerto Rico/8/1934 (PR8), and monitored for changes in immunity, virus titers, morbidity, or mortality.

Results

In CVB3 infection, mortality was increased in WT males compared to females and males developed more severe cardiac inflammation. Gonadectomy suppressed male, but increased female, susceptibility to CVB3. Infection with IAV resulted in greater morbidity and mortality in WT females compared with males and this sex difference was significantly reduced by gonadectomy of male and female mice. In Gdx FCG mice infected with CVB3, XY mice were less susceptible than XX mice. Protection correlated with increased CD4+ forkhead box P3 (FoxP3)+ T regulatory (Treg) cell activation in these animals. Neither CD4+ interferon (IFN)γ (T helper 1 (Th1)) nor CD4+ interleukin (IL)-4+ (Th2) responses differed among the FCG mice during CVB3 infection. Infection of Gdx FCG mice revealed no effect of sex chromosome complement on morbidity or mortality following IAV infection.

Conclusions

These studies indicate that sex chromosome complement can influence pathogenicity of some, but not all, viruses.     

Influence of sex on the interaction between dizocilpine (MK-801) pretreatment and acute cold-restraint stress in epilepsy susceptibility in an animal study

Background: Stress is a part of our daily life, inducing neurochemical and neurophysiological changes in the central nervous system.Objective: The present study was designed to investigate the importance of sex differences in the interaction between dizocilpine (MK-801) pretreatment and acute cold-restraint stress (CRS) in pentylenetetrazole (PTZ)-induced seizures in Swiss albino mice.Methods: A CRS protocol was applied to mice to investigate the interaction between MK-801 pretreatment (30 min before CRS) and stress (followed by PTZ injection) in epilepsy susceptibility. For this purpose, 6 groups were designated: (1) PTZ control group (received only PTZ); (2) stress group (received stress and PTZ); (3) saline group (received saline and PTZ); (4) MK-801 group (received MK-801 and PTZ); (5) saline + stress group (received saline, stress, and PTZ); and (6) MK-801 + stress group (received MK-801, stress, and PTZ).Results: Pretreatment with MK-801 (0.125, 0.25, 0.50 mg/kg) significantly potentiated the protective effect of stress in PTZ-induced (65 mg/kg) seizures in both sexes by prolonging the onset of myoclonic jerks and clonic convulsions. Male mice had a significantly greater delay in the onset of myoclonic jerks (males, 66.7–295.5 sec; females, 54.0–247.5 sec; P < 0.05) and clonic convulsions (males, 123.5–789.8 sec; females, 94.5–757.2 sec; P < 0.05) compared with female mice in all groups (ie, PTZ control, stress, saline, MK-801, saline + stress, and MK-801 + stress groups).Conclusion: The findings of this study in mice suggest the involvement of sex hormones in the interaction between MK-801 pretreatment and acute CRS in PTZ-induced seizures.     

Sex differences to myocardial ischemia and beta-adrenergic receptor blockade in conscious rats

We recently documented sex differences in the susceptibility to reperfusion-induced sustained ventricular tachycardia and beta-adrenergic receptor blockade in conscious rats. However, the effect of sex on ischemia-induced ventricular arrhythmias and beta-adrenergic receptor blockade is under-investigated. Therefore, we tested the hypothesis that gonadal hormones influence the ventricular arrhythmia threshold (VAT) induced by coronary artery occlusion as well as the response to beta-adrenergic receptor blockade. The VAT was defined as the time from coronary occlusion to sustained ventricular tachycardia resulting in a reduction in arterial pressure. Male and female intact and gonadectomized (GnX) rats were instrumented with a radiotelemetry device for recording arterial pressure, temperature, and ECG, as well as a Doppler ultrasonic flow probe to measure cardiac output and a snare around the left main coronary artery. The VAT was determined in conscious rats by pulling on the snare. The VAT was significantly longer in intact females (5.56 +/- 0.19) vs. intact males (4.31 +/- 0.14 min). This sex difference was abolished by GnX. Specifically, GnX decreased the VAT in females (4.55 +/- 0.22) and increased the VAT in males (5.14 +/- 0.30 min). Thus male sex hormones increase and female sex hormones decrease the susceptibility to ischemia-induced sustained ventricular tachycardia. beta-Adrenergic receptor blockade increased the VAT in intact males and GnX females only. Thus gonadal hormones influence the response to beta-adrenergic receptor blockade. Uncovering major differences between males and females in the pathophysiology of the cardiovascular system may result in sex-specific optimization of patient treatments.     

Estradiol deficiency during development modulates the expression of circadian and daily rhythms in male and female aromatase knockout mice

Gonadal steroids modify the phase, amplitude and period of circadian rhythms. To further resolve the role of estradiol, we examined daily patterns of activity, circadian free running period and behavioral responses to light pulses using aromatase deficient (ArKO) mice. These animals lack the enzyme necessary to produce estradiol. We hypothesized that circulating estrogens during development and adulthood modulate the amount of activity, the temporal relationship of activity patterns relative to a light:dark cycle, and the free running period. Intact and gonadectomized male and female ArKO and wildtype (WT) littermates were used. WT males, but not ArKO males, retained the ability to respond to steroid hormones; the time of activity onset, free running period in constant darkness, and total daily activity were significantly different in gonadectomized compared to intact males. In contrast, gonadectomy did not alter the expression of these variables in ArKO males. ArKO females had a longer free running period in constant darkness compared to WT females regardless of gonadal state. Ovariectomized ArKO females had a significantly delayed activity onset when compared to intact ArKO females and ovariectomized WT females, despite all 3 groups being estrogen deficient. Phase shifts in response to light pulses given at different times of the day revealed an interaction between genotype, sex, and circulating steroids. These results from ArKO animals strongly suggest an organizational effect of estradiol during a critical period of development on the expression of biological rhythms.     

Sex chromosome complement affects nociception in tests of acute and chronic exposure to morphine in mice

We tested the role of sex chromosome complement and gonadal hormones in sex differences in several different paradigms measuring nociception and opioid analgesia using "four core genotypes" C57BL/6J mice. The genotypes include XX and XY gonadal males, and XX and XY gonadal females. Adult mice were gonadectomized and tested 3-4 weeks later, so that differences between sexes (mice with testes vs. ovaries) were attributable mainly to organizational effects of gonadal hormones, whereas differences between XX and XY mice were attributable to their complement of sex chromosomes. In Experiment 1 (hotplate test of acute morphine analgesia), XX mice of both gonadal sexes had significantly shorter hotplate baseline latencies prior to morphine than XY mice. In Experiment 2 (test of development of tolerance to morphine), mice were injected twice daily with 10 mg/kg morphine or saline for 6 days. Saline or the competitive NMDA antagonist CPP (3-(2-carboxypiperazin-4yl) propyl-1-phosphonic acid) (10 mg/kg) was co-injected. On day 7, mice were tested for hotplate latencies before and after administration of a challenge dose of morphine (10 mg/kg). XX mice showed shorter hotplate latencies than XY mice at baseline, and the XX-XY difference was greater following morphine. In Experiment 3, mice were injected with morphine (10 mg/kg) or saline, 15 min before intraplantar injection of formalin (5%/25 microl). XX mice licked their hindpaw more than XY mice within 5 min of formalin injection. The results indicate that X- or Y-linked genes have direct effects, not mediated by gonadal secretions, on sex differences in two different types of acute nociception.     

Apoptosis during sexual differentiation of the bed nucleus of the stria terminalis in the rat brain

The bed nucleus of the stria terminalis (BST) in the rat forebrain differs between males and females. To test whether apoptosis may contribute to the development of sex differences in the BST, the incidence of apoptosis was determined in sham-treated males and sham-treated females sacrificed on postnatal days (PN) 2, 4, 6, 8, 10, and 12 (PN 1 being day of birth). More apoptotic nuclei were found in the principal nucleus of the BST (BSTpr) in females than in males, whereas the reverse was true for the lateral division of the BST (BSTl). Moreover, the volume of the BSTpr was larger in males than in females, whereas there was no sex difference in the volume of the BSTl. Our results also confirmed earlier reports indicating that the incidence of apoptosis in the central part of the medial preoptic nucleus (MPNc) is higher in females than in males. No sex difference in apoptosis was found in the ventromedial hypothalamus (VMH) and paraventricular nucleus (PVN). The volume of the MPNc and VMH was larger in males than in females, whereas the PVN volume did not differ between males and females. To test whether sex differences in neonatal levels of gonadal steroids may cause sex differences in the incidence of apoptosis in the BSTpr, the incidence of apoptosis was compared between castrated males and females that were treated with testosterone propionate or vehicle on the day of birth. In the BSTpr of gonadal steroid-treated animals, the incidence of apoptosis was lower when compared to animals treated with vehicle, which was also true for the MPNc. These results are consistent with the hypothesis that gonadal steroids contribute to the sexually dimorphic differentiation of the BST by controlling the incidence of apoptosis.     

Gender-dependent modulation of alpha 1-adrenergic responses in rat mesenteric arteries

The purpose of this study was to test the hypothesis that pathways modulating vasoconstriction in rat mesenteric resistance arteries are gender dependent. Net contractile responses to phenylephrine were significantly increased by endothelium disruption in arteries from males but not females. This gender-dependent effect was stimulus specific, because disruption of endothelium increased reactivity to serotonin comparably in arteries from both genders. Ovariectomy unmasked an increase in net alpha(1)-adrenergic contractile responsiveness after endothelium disruption, suggesting alpha(1)-adrenergic-stimulated production of endothelial vasodilators is suppressed in control females by gonadal sex steroids. Production of modulatory endothelium-derived vasodilators in males is balanced by production of vasoconstricting arachidonic acid metabolites. This was revealed by decreased alpha(1)-adrenergic contractile responses in arteries from males after pretreatment with indomethacin or the cyclooxygenase-1 selective inhibitor SC-560. The indomethacin-induced effect persisted after endothelium disruption, indicating smooth muscle as the source of cyclooxygenase-1-derived vasoconstrictors and was attenuated after orchiectomy. This study indicates gender differences in the expression of two pathways modulating alpha(1)-adrenergic sensitivity in mesenteric arteries: an endothelium-dependent vasodilator pathway and a balancing smooth muscle cyclooxygenase-1-dependent vasoconstrictor pathway. One consequence of these differences is that endothelial damage produces a selective increase in alpha(1)-adrenergic agonist reactivity in arteries from males.     

Sex differences in morphine-induced analgesia of visceral pain are supraspinally and peripherally mediated

Increasing evidence suggests there is a sex difference in opioid analgesia of pain arising from somatic tissue. However, the existence of a sex difference in visceral pain and opioid analgesia is unclear. This was examined in the colorectal distention (CRD) model of visceral pain in the current study. The visceromotor response (vmr) to noxious CRD was recorded in gonadally intact male and female rats. Subcutaneous injection of morphine dose-dependently decreased the vmr in both groups without affecting colonic compliance. However, morphine was significantly more potent in male rats than females. Because systemic morphine can act at peripheral tissue and in the central nervous system (CNS), the source of the sex difference in morphine analgesia was determined. The peripherally restricted mu-opioid receptor (MOR) antagonist naloxone methiodide dose-dependently attenuated the effects of systemic morphine. Systemic administration of the peripherally restricted MOR agonist loperamide confirmed peripherally mediated morphine analgesia and revealed greater potency in males compared with females. Spinal administration of morphine dose-dependently attenuated the vmr, but there was no sex difference. Intracerebroventricular administration of morphine also dose-dependently attenuated the vmr with significantly greater potency in male rats. The present study documents a sex difference in morphine analgesia of visceral pain that is both peripherally and supraspinally mediated.     

Sex differences following gonadectomy in basal gonadotropin secretion rate of rat pituitary fragments in vitro

Sex differences in the acute response of circulating luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to withdrawal from gonadal negative feedback in the rat are well established. To investigate postgonadectomy changes at the anterior pituitary level that may underlie dramatic in vivo sex differences, we used a computer-controlled pituitary perifusion system to measure in vitro basal secretion rates (BSRs) of LH and FSH following gonadectomy in the absence of exogenous gonadotropin-releasing hormone (GnRH). We compared BSRs of pituitaries removed from intact rats and from males and females 2 and 6 days post-gonadectomy. Glands were cut into quarters, placed into individual chambers, and perifused in Medium 199 at 10 ml/h for 4 h. In females (n = 12/gp), BSR of LH was not significantly elevated above intact levels by 2 days but had tripled by 6 days post-ovariectomy, while BSR of FSH had already doubled by 2 days and doubled again by 6 days. These changes in BSR in females paralleled changes in serum levels of both hormones. In males (n = 14/gp), although serum LH and FSH had increased 7-fold by 2 days post-orchidectomy, BSRs of LH and FSH had decreased to 75% and 64% of intact levels, respectively, by 6 days. These findings suggest important sex differences at the pituitary level in the responses to withdrawal from gonadal feedback that persist in culture in the absence of direct hypothalamic (GnRH) input.     

Hormone responses to clomiphene citrate in young chimpanzees

The responses of gonadotropin and gonadal steroids to the administration of clomiphene citrate were studied in male and female chimpanzees, aged 3.6 to 9.9 years. Follicle-stimulating hormone (FSH) was significantly reduced after treatment in the prepubertal females (n = 4) and in early pubertal males (n = 2) but not in prepubertal males (n = 5). FSH was unchanged or increased in early pubertal females (n = 2) and late pubertal males (n = 2). There was no consistent response to treatment with clomiphene citrate by luteinizing hormone (LH) in either males or females, nor by 17 beta-estradiol in the females. Testosterone levels were reduced in the early pubertal males only. These results support the hypothesis that negative feedback by gonadal steroids is operative in prepubertal chimpanzees and that puberty is accompanied by a reduction in the sensitivity to such feedback.     

Adrenal function in female rats before puberty: the effects of gonadectomy

The following study was designed to test whether the change in the amplitude of the adrenal rhythm and the response to stress seen at puberty in female rats is dependent upon stimulation of the adrenal system by gonadal steroids. Rats were gonadectomized either at two days of age or at 21 days of age and periodic blood samples were taken by cardiac puncture and assayed for corticosterone (B) by a fluorometric procedure. Ovariectomy at weaning age (21 days) had no effect on adrenal function until the time of normal puberty onset. In intact animals, a rise in resting levels of corticosterone and an increase in the incremental response to ether stress was noted at 35 days of age. (Puberty in females was 35.3 ± 1.2 days as indicated by vaginal opening). Ovulation occurred the following day in 9/10 rats. Gonadectomy at two days of age had essentially the same effect as later gonadectomy in females. By 70 days of age, resting corticosterone values and stress responses in gonadectomized females reached levels similar to intact females. It is concluded that an independent adrenarche can occur in females but that gonadal steroids present at the time of puberty modulate the timing of this process.