Hormone-dependent sexual responses of female mice in response to manual genital stimulation.

Although copulatory behavior is thought to have a strong innate basis in mice, there is also clear evidence that sexual experience shapes its expression. Reinforcement of behavior through rewarding genital tactile stimulation is a primary candidate mechanism for this modification. In rats, manual tactile clitoral stimulation is rewarding only when it is temporally distributed, which is hypothesized to result from an innate preference for species-typical copulatory patterning. Here we test this hypothesis using mice, which have a temporal copulatory pattern which is distinctly less temporally distributed than that of rats. Female mice received manual clitoral stimulation which was either temporally continuous every second, or stimulation which was temporally distributed, occurring every 5 s, This pattern of stimulation was paired with environmental cues in a conditioned place preference apparatus to assess reward. Neural activation in response to this stimulation was evaluated by measuring FOS immunoreactivity. Results indicated that both temporal patterns of clitoral stimulation were rewarding, but that continuous stimulation better reproduced brain activation associated with sexual reward. Furthermore, continuous, but not distributed stimulation elicited a lordosis response in some females, and this response increased within and across days. Sexual reward, neural activation and lordosis resulting from tactile genital stimulation were eliminated by ovariectomy and restored with combined 17ß-estradiol and progesterone treatment but not 17ß-estradiol treatment alone. These observations are consistent with the hypothesis that sexual reward resulting from species-typical genital tactile stimulation has a permissive effect on copulatory behavior of female mice.

A study of the pharmacokinetics and pharmacodynamics of oxytocin at elective caesarean delivery.

Oxytocin is widely used to prevent atonic postpartum haemorrhage after caesarean delivery. Initial treatment failure rates are high and inadequate dosing may contribute. Excessive doses, however, are associated with serious adverse effects. The pharmacokinetic data from this context are sparse and there is a lack of data in the immediate postpartum minutes after an initiating bolus. The pharmacodynamic data from this context are exclusively from dose-effect studies, with some suggesting that higher doses of oxytocin are required to provide adequate uterine tone in obese compared with non-obese women. We aimed to perform a pharmacokinetic and pharmacodynamic study that would facilitate more precise weight-based oxytocin dosing. We measured arterial oxytocin concentration, uterine tone and haemodynamic parameters in 25 women in the first 40 min after exogenous oxytocin administration at elective caesarean delivery. Serum oxytocin concentrations varied considerably between individuals. We constructed a one-compartment pharmacokinetic model of exogenous oxytocin deposition, after its administration with an initiating bolus and a maintenance infusion, at elective caesarean delivery. Body weight was evaluated as a potential covariate but was not included in the model due to lack of statistically significant reduction in the objective function. We calculated the volume of distribution and clearance (mean [coefficient of variation]) as 156.1 l [18%] and 83 ml.s-1 [32%] but found no within-individual correlation between serum oxytocin concentration and uterine tone or haemodynamic parameters. In conclusion, we observed a large variation in serum oxytocin concentrations between individuals receiving similar doses of oxytocin and were unable to establish weight-based dosing of exogenous oxytocin at caesarean delivery. Our findings suggest that future studies on oxytocin pharmacokinetics would need large sample sizes. In the absence of such data, oxytocin dosing should continue to be guided by uterine tone assessments and adjusted according to a strategy based on the best evidence from dose-effect studies.

Efficacy of regional blocks or local anaesthetic infiltration for analgesia after caesarean delivery: a network meta-analysis of randomised controlled trials.

Caesarean delivery is common and can cause severe postoperative pain but injection of local anaesthetic at various sites for regional blocks or local anaesthetic infiltration may reduce this. We aimed to compare and rank these sites. We searched PubMed, Google Scholar, EMBASE and CENTRAL to June 2021 for randomised controlled trials and performed a random-effects Bayesian model network meta-analysis. The primary outcome was dose of parenteral morphine equivalents in the first 24 postoperative hours. We used surface under cumulative ranking probabilities to order techniques. We analysed 114 trials (8730 participants). The ordered mean (95% credible interval) reduction in morphine equivalents, from 34 mg with placebo, were as follows: ilio-inguinal 15 (1-32) mg; ilio-inguinal-iliohypogastric 13 (6-19) mg; transversalis fascia 11 (4-26) mg; erector spinae 11 (10-32); transverse abdominis 9 (4-13) mg; wound catheter infusion 8 (2-15) mg; quadratus lumborum 8 (1-15) mg; wound infiltration 8 (2-13) mg; and no intervention -4 (-10 to 2) mg. Ordered efficacies for injection sites were different for other relevant outcomes, including pain (to 4-6 h and to 24 h) and time to rescue analgesia: there was no single preferred route of injection. The ordered mean (95% credible interval) reduction in dynamic pain scores (0-10 scale) at 24 h compared with placebo were as follows: wound infusion 1.2 (0.2-2.1); erector spinae 1.3 (-0.5 to 3.1); quadratus lumborum 1.0 (0.1-1.8); ilio-inguinal-iliohypogastric 0.6 (-0.5 to 1.8); transverse abdominis 0.6 (-0.1 to 1.2); wound infiltration 0.5 (-0.3 to 1.3); transversalis fascia -0.8 (-3.4 to 1.9); ilio-inguinal -0.9 (-3.6 to 1.7); and no intervention -0.8 (-1.8 to 0.2). We categorised our confidence in effect sizes as low or very low.

Evidence for distinct biodevelopmental influences on male sexual orientation.

Several biological mechanisms have been proposed to influence male sexual orientation, but the extent to which these mechanisms cooccur is unclear. Putative markers of biological processes are often used to evaluate the biological basis of male sexual orientation, including fraternal birth order, handedness, and familiality of same-sex sexual orientation; these biomarkers are proxies for immunological, endocrine, and genetic mechanisms. Here, we used latent profile analysis (LPA) to assess whether these biomarkers cluster within the same individuals or are present in different subgroups of nonheterosexual men. LPA defined four profiles of men based on these biomarkers: 1) A subgroup who did not have these biomarkers, 2) fraternal birth order, 3) handedness, and 4) familiality. While the majority of both heterosexual and nonheterosexual men were grouped in the profile that did not have any biomarker, the three profiles associated with a biomarker were composed primarily of nonheterosexual men. We then evaluated whether these subgroups differed on measures of gender nonconformity and personality that reliably show male sexual orientation differences. The subgroup without biomarkers was the most gender-conforming whereas the fraternal birth order subgroup was the most female-typical and agreeable, compared with the other profiles. Together, these findings suggest there are multiple distinct biodevelopmental pathways influencing same-sex sexual orientation in men.

Overexpression of Androgen Receptors Masculinizes 2D:4D Digit Ratios in Mice.

Studying the role of the prenatal endocrine environment in humans is challenging due to the ethical and practical considerations of measuring hormone levels of the developing fetus. Because it has been difficult to ascertain whether prenatal androgens contribute to the brain and behavior in humans as it does in non-human species, retrospective markers of prenatal androgens, such as the second-to-fourth finger digit ratio (2D:4D), are of interest to the studying of human behavioral endocrinology. To assess the validity of such markers, laboratory animals have been studied. Some strains of mice have been reported to show a sex difference in 2D:4D, and pharmacological and genetic manipulation of the androgen and estrogen receptors (AR and ER) has implicated a role for prenatal androgens in mediating this sex difference, although there have been conflicting reports. Here, we compared mice with global AR overexpression to mice with wildtype (WT) littermates and mice with neural-specific AR overexpression. We found a sex difference in the right hind paw, such that males had larger digit ratios than females. Regardless of sex, mice with global AR overexpression showed an increase in the right hind 2D:4D ratio compared with both WT and neural-specific AR overexpression mice. These results support a role for non-neural AR in the development of 2D:4D and suggest that increased sensitivity to androgens via increased AR is sufficient to increase the masculinization of digit ratios. Future directions for confirming the validity of 2D:4D as a marker for prenatal androgen exposure are discussed.

Oxytocin: at birth and beyond. A systematic review of the long-term effects of peripartum oxytocin.

Oxytocin is one of the most commonly used medications during labour and delivery. Recent insights from basic neuroscience research suggest that the uterotonic effects of oxytocin may arguably be trivial when compared with its profound effects on higher-order human behaviour. The purpose of this review is to highlight the potential consequences of manipulating oxytocinergic signalling during the peripartum period and its long-term impact on the maternal-infant dyad. We identified four domains where modulation of oxytocinergic signalling might be consequential: postpartum depression; breastfeeding; neurodevelopment; and chronic pain, and performed a literature search to address the impact of peripartum oxytocin administration. We have shown modest, but inconsistent, evidence linking peripartum oxytocin administration with postpartum depression. Breastfeeding success appeared to be negatively correlated with peripartum oxytocin exposure, perhaps secondary to impaired primitive neonatal reflexes and maternal-infant bonding. The association between perinatal oxytocin exposure and subsequent development of neurodevelopmental disorders such as autism in the offspring was weak, but these studies were limited by the lack of information on the cumulative dose. Finally, we identified substantial evidence for analgesic and anti-hypersensitivity effects of oxytocin which might partly explain the low incidence of chronic pain after caesarean birth. Although most data presented here are observational, our review points to a compelling need for robust clinical studies to better dissect the impact of peripartum oxytocin administration, and as stewards of its use, increase the precision with which we administer oxytocin to prevent overuse of the drug.

The association between post-dural puncture headache and needle type during spinal anaesthesia: a systematic review and network meta-analysis.

Post-dural puncture headache is one of the most undesirable complications of spinal anaesthesia. Previous pairwise meta-analyses have either compared groups of needles or ranked individual needles based on the pooled incidence of post-dural puncture headache. These analyses have suggested both the gauge and needle tip design as risk-factors, but failed to provide an unbiased comparison of individual needles. This network meta-analysis compared the odds of post-dural puncture headache with needles of varying gauge and tip design. We searched randomised controlled trials in medical databases. The primary outcome measure of the network meta-analysis was the incidence of post-dural puncture headache. Secondary outcomes were procedural failure, backache and non-specific headache. Overall, we compared 11 different needles in 61 randomised controlled trials including a total of 14,961 participants. The probability of post-dural puncture headache and procedural failure was lowest with 26-G atraumatic needles. The 29-G cutting needle was more likely than three atraumatic needles to have the lowest odds of post-dural puncture headache, although with increased risk of procedural failure. The probability rankings were: 26 atraumatic > 27 atraumatic > 29 cutting > 24 atraumatic > 22 atraumatic > 25 atraumatic > 23 cutting > 22 cutting > 25 cutting > 27 cutting = 26 cutting for post-dural puncture headache; and 26 atraumatic > 25 cutting > 22 cutting > 24 atraumatic > 22 atraumatic > 25 atraumatic > 26 cutting > 29 cutting > 27 atraumatic = 27 cutting for procedural success. Meta-regression by type of surgical population (obstetric/non-obstetric) and participant position (sitting/lateral) did not alter these rank orders. This analysis provides an unbiased comparison of individual needles that does not support the use of simple rules when selecting the optimal needle. The 26-G atraumatic needle is most likely to enable successful insertion while avoiding post-dural puncture headache but, where this is not available, our probability rankings can help clinicians select the best of available options.

Choice of local anaesthetic for epidural caesarean section: a Bayesian network meta-analysis.

Rapid-onset epidural local anaesthesia can avoid general anaesthesia for caesarean delivery. We performed a Bayesian network meta-analysis of direct and indirect comparisons to rank speed of onset of the six local anaesthetics most often used epidurally for surgical anaesthesia for caesarean delivery. We searched Google Scholar, PubMed, EMBASE, Ovid, CINAHL and CENTRAL to June 2019. We analysed 24 randomised controlled trials with 1280 women. The mean (95%CrI) onset after bupivacaine 0.5% was 19.8 (17.3-22.4) min, compared with which the mean (95%CrI) speed of onset after lidocaine 2% with bicarbonate, 2-chloroprocaine 3% and lidocaine 2% was 6.4 (3.3-9.6) min faster, 5.7 (3.0-8.3) min faster and 3.9 (1.8-6.0) min faster, respectively. Speed of onset was similar to bupivacaine 0.5% after ropivacaine 0.75% and l-bupivacaine 0.5%: 1.6 (-1.4 to 4.8) min faster and 0.4 (-2.2 to 3.0) min faster, respectively. The rate (95%CrI) of intra-operative hypotension was least after l-bupivacaine 0.5%, 315 (236-407) per 1000, and highest after 2-chloroprocaine 3%, 516 (438-594) per 1000. The rate (CrI) of intra-operative supplementation of analgesia was least after ropivacaine 0.75% 48 (19-118) per 1000 and highest after 2-chloroprocaine 3%, 250 (112-569) per 1000.

Androgenic mechanisms of sexual differentiation of the nervous system and behavior.

Testicular androgens are the major endocrine factor promoting masculine phenotypes in vertebrates, but androgen signaling is complex and operates via multiple signaling pathways and sites of action. Recently, selective androgen receptor mutants have been engineered to study androgenic mechanisms of sexual differentiation of the nervous system and behavior. The focus of these studies has been to evaluate androgenic mechanisms within the nervous system by manipulating androgen receptor conditionally in neural tissues. Here we review both the effects of neural loss of AR function as well as the effects of neural overexpression of AR in relation to global AR mutants. Although some studies have conformed to our expectations, others have proved challenging to assumptions underlying the dominant hypotheses. Notably, these studies have called into question both the primacy of direct, neural mechanisms and also the linearity of the relationship between androgenic dose and sexual differentiation of brain and behavior.

Androgen receptors and muscle: a key mechanism underlying life history trade-offs.

Sexual dimorphism in skeletal muscle is prominent in mammals, with males typically having larger and stronger muscles than females. Furthermore, neuromuscular systems with sexual functions are remarkably sexually dimorphic in a wide variety of vertebrates. Endocrine mechanisms are of central importance for sexual differentiation of these traits, and anabolic actions of gonadal testosterone have been intensively studied. Here we review the relationship between androgen receptor (AR) and sexual differentiation of neuromuscular systems. We focus our review on the hypotheses that sexual dimorphism and androgen responsiveness of neuromuscular systems is a function of the amount of AR expressed by muscle and that AR in muscle is a key mechanism on which evolution acts to shape individual and species differences in reproductive behavior.

Muscle, a conduit to brain for hormonal control of behavior.

SBN Elsevier Lecture Investigation into mechanisms whereby hormones control behavior often starts with actions on central nervous system (CNS) motivation and motor systems and is followed by assessment of CNS drive of coordinated striated muscle contractions. Here we turn this perspective on its head by discussing ways in which hormones might first act on muscle that then secondarily drive upstream the evolution and function of the CNS. While there is a lengthy history for consideration of this perspective, newly discovered properties of muscle signaling reveal novel mechanisms that may well be captured by endocrine systems and thus of interest to behavioral endocrinologists.

Androgen receptor is a negative regulator of contextual fear memory in male mice.

Although sex-hormones have a well-documented role in memory formation, most literature has focused on estrogens, whereas the role of androgens and their receptor (the androgen receptor; AR) in fear memory is relatively unexplored. To address this gap, we used a transgenic mouse model of AR overexpression (CMV-AR) to determine if AR regulates fear memory, and if this effect can be reversed either by the removal of circulating androgens via gonadectomy, or by antagonising AR activity with flutamide. We found that AR overexpression results in reduced freezing in response to foot shock, and that this difference is reversed with both gonadectomy and flutamide treatment. Differences between genotypes were reinstated by testosterone replacement in gonadectomized mice, suggesting that reduced fear memory in mutants results from AR activation by testosterone and is not secondary to group differences in circulating testosterone. Potential transcriptional mechanisms by which CMV-AR exerts its effects on fear memory were assessed by quantitating the expression of memory-related genes in area CA1 of the hippocampus. Several genes that are altered with AR inhibition and activation, including genes that encode for the histone variant H2A.Z, cholinergic receptors, glutamate receptors, and brain-derived neurotrophic factor. Overall, our findings suggest that AR is a negative regulator of fear memory and identify potential gene targets through which AR may mediate this effect.

Gender Nonconformity and Birth Order in Relation to Anal Sex Role Among Gay Men.

Androphilia is associated with an elevated number of older brothers among natal males. This association, termed the fraternal birth order effect, has been observed among gay men who exhibit marked gender nonconformity. Gender nonconformity has been linked to gay men's preferred anal sex role. The present study investigated whether these two lines of research intersect by addressing whether the fraternal birth order effect was associated with both gender nonconformity and a receptive anal sex role (243 gay men, 91 heterosexual men). Consistent with previous research, we identified the fraternal birth order effect in our sample of gay men. Also, gay men were significantly more gender-nonconforming on adulthood and recalled childhood measures compared to heterosexual men. When gay men were compared based on anal sex role (i.e., top, versatile, bottom), all groups showed significantly greater recalled childhood and adult male gender nonconformity than heterosexual men, but bottoms were most nonconforming. Only gay men with a bottom anal sex role showed evidence of a fraternal birth order effect. A sororal birth order effect was found in our sample of gay men, driven by versatiles. No significant associations were found between fraternal birth order and gender nonconformity measures. These results suggest that the fraternal birth order effect may apply to a subset of gay men who have a bottom anal sex role preference and that this subgroup is more gender-nonconforming. However, there were no significant associations between fraternal birth order and gender nonconformity at the individual level. As such, based on the present study, whether processes underpinning the fraternal birth order effect influence gender nonconformity is equivocal.

Age Adjusted D-Dimer for exclusion of Pulmonary Embolism: a retrospective cohort study.

D-Dimer (DD) will increase with age and recent studies have shown the upper limit of normal can be raised in those who are low risk and over 50. We studied age adjusted D-dimer (AADD) levels to assess whether pulmonary embolism (PE) could be safely excluded. This study analysed the Emergency Department (ED) Computed Tomographic Pulmonary Angiography (CTPA) requests. There were 756 requests. The parameters studied were; age, DD value, calculated AADD, CT result and Simplified Geneva Score (SGS). The primary outcome was the diagnostic performance of AADD. One hundred and eighty-five patients were included in the final cohort. Twenty-one patients had a negative DD after age adjustment. Of these one had a PE, corresponding to a failure rate of 4.76% (1 in 22). The sensitivity of AADD was 0.96 (95% CI 0.76 to 0.99) and its specificity was 0.12 (95% CI 0.08- 0.19). AADD demonstrated a reduction in false positives with one false negative, giving rise to a failure rate higher than that of other larger studies. Further study is indicated to accurately define the diagnostic characteristics for the Irish context.

Distinct Etiological Roles for Myocytes and Motor Neurons in a Mouse Model of Kennedy's Disease/Spinobulbar Muscular Atrophy.

Polyglutamine (polyQ) expansion of the androgen receptor (AR) causes Kennedy's disease/spinobulbar muscular atrophy (KD/SBMA) through poorly defined cellular mechanisms. Although KD/SBMA has been thought of as a motor neuron disease, recent evidence indicates a key role for skeletal muscle. To resolve which early aspects of the disease can be caused by neurogenic or myogenic mechanisms, we made use of the tet-On and Cre-loxP genetic systems to selectively and acutely express polyQ AR in either motor neurons (NeuroAR) or myocytes (MyoAR) of transgenic mice. After 4 weeks of transgene induction in adulthood, deficits in gross motor function were seen in NeuroAR mice, but not MyoAR mice. Conversely, reduced size of fast glycolytic fibers and alterations in expression of candidate genes were observed only in MyoAR mice. Both NeuroAR and MyoAR mice exhibited reduced oxidative capacity in skeletal muscles, as well as a shift in fast fibers from oxidative to glycolytic. Markers of oxidative stress were increased in the muscle of NeuroAR mice and were reduced in motor neurons of both NeuroAR and MyoAR mice. Despite secondary pathology in skeletal muscle and behavioral deficits, no pathological signs were observed in motor neurons of NeuroAR mice, possibly due to relatively low levels of polyQ AR expression. These results indicate that polyQ AR in motor neurons can produce secondary pathology in muscle. Results also support both neurogenic and myogenic contributions of polyQ AR to several acute aspects of pathology and provide further evidence for disordered cellular respiration in KD/SBMA skeletal muscle.

Non-neural androgen receptor promotes androphilic odor preference in mice.

In mice, male-typical preference for female olfactory cues results largely from sexually differentiated testosterone production. It is currently unclear on which cells and tissues testosterone acts to produce male-typical preference for female olfactory cues. To further address the site of androgen action on olfactory preference, we have developed a loxP-based transgenic mouse that overexpresses androgen receptors (AR) only when activated by Cre. We used this transgene to overexpress AR globally in all tissues using a CMV-Cre driver and a Nestin-Cre driver to overexpress AR selectively in neural tissue. We then examined olfactory preference in transgenic and wildtype (Wt) littermates by simultaneously exposing animals to female-soiled, male-soiled and clean bedding. Ubiquitous overexpression of AR in CMV-AR mice increased preference for male bedding, whereas neural-specific AR overexpression in Nestin-AR transgenic mice did not differ from wildtype siblings in olfactory preference. Neural activation of olfactory brain areas in response to female-soiled bedding was also evaluated in these mice by measuring FOS immunoreactivity. This revealed a decrease in neural activity along the accessory olfactory pathway that accompanied the decrease in preference for female odors in CMV-AR males, compared to both Nestin-AR and Wt male siblings. Together, results indicate that androgens act via non-neural AR to mediate olfactory preference and neural responses to olfactory stimuli, and further suggest that AR in non-neural tissues can promote androphilic odor preferences in male mice.In mice, male-typical preference for female olfactory cues results largely from sexually differentiated testosterone production. It is currently unclear on which cells and tissues testosterone acts to produce male-typical preference for female olfactory cues. To further address the site of androgen action on olfactory preference, we have developed a loxP-based transgenic mouse that overexpresses androgen receptors (AR) only when activated by Cre. We used this transgene to overexpress AR globally in all tissues using a CMV-Cre driver and a Nestin-Cre driver to overexpress AR selectively in neural tissue. We then examined olfactory preference in transgenic and wildtype (Wt) littermates by simultaneously exposing animals to female-soiled, male-soiled and clean bedding. Ubiquitous overexpression of AR in CMV-AR mice increased preference for male bedding, whereas neural-specific AR overexpression in Nestin-AR transgenic mice did not differ from wildtype siblings in olfactory preference. Neural activation of olfactory brain areas in response to female-soiled bedding was also evaluated in these mice by measuring FOS immunoreactivity. This revealed a decrease in neural activity along the accessory olfactory pathway that accompanied the decrease in preference for female odors in CMV-AR males, compared to both Nestin-AR and Wt male siblings. Together, results indicate that androgens act via non-neural AR to mediate olfactory preference and neural responses to olfactory stimuli, and further suggest that AR in non-neural tissues can promote androphilic odor preferences in male mice.

Using morphometrics to identify sex in the eastern blue-tongued skink (Tiliqua scincoides).

INTRODUCTION: Tiliqua scincoides coexists with human activity and is frequently presented for rehabilitation due to injury. The correct identification of sex is important as animals identified as female should be subject to a different decision-making matrix for rehabilitation. However, identification of sex is notoriously difficult in Tiliqua scincoides. We describe a reliable, safe and cost-effective morphometry-based method. MATERIALS AND METHODS: Adult and sub-adult, wild Tiliqua scincoides dead on presentation or euthanased due to their presenting injuries were collected in South-East Queensland (SE Qld). Head-width to snout-vent length ratio (H:SV) and head-width to trunk length ratio (H:T) were measured and sex was defined at necropsy. Similar data were obtained from a previous study in Sydney, New South Wales (NSW). H:SV and H:T were assessed for accuracy of sex prediction by the area under the receiver operating characteristic curve (AUC-ROC). Optimal cut-points were identified. RESULTS: The AUC-ROC for the H:T test was for NSW adults, 0.99 (n = 29), NSW sub-adults, 0.95 (n = 10), Qld adults, 0.90 (n = 35) and Qld sub-adults, 0.79 (n = 25). In all cases, H:T was as good or superior to H:SV. H:T cut-points optimized for female sexing or both sexes ranged from 0.20 to 0.23 depending on State and adult status. Sensitivities and specificities of the test at suggested optimal cut-points ranged from 0.54 to 1.0. CONCLUSION: We describe how H:T can be used as an accurate method to determine sex in Tiliqua scincoides. However, it is more accurate in adults than sub-adults and more accurate in NSW skinks than in SE Qld skinks.