Disruptions in reproductive health, sex hormonal profiles, and hypothalamic hormone receptors content in females of the C58/J mouse model of autism.

Autism Spectrum Disorder (ASD) is characterized by differences in social communication and interaction, as well as areas of focused interests and/or repetitive behaviors. Recent studies have highlighted a higher prevalence of endocrine and reproductive disturbances among females on the autism spectrum, hinting at potential disruptions within the hypothalamus-pituitary-ovary (HPO) axis. This research aims to explore the reproductive health disparities in ASD using an animal model of autism, the C58/J inbred mouse strain, with a focus on reproductive performance and hormonal profiles compared to the C57BL/6J control strain. Our findings revealed that the estrous cycle in C58/J females is disrupted, as evidenced by a lower frequency of complete cycles and a lack of cyclical release of estradiol and progesterone compared to control mice. C58/J females also exhibited poor performance in several reproductive parameters, including reproductive lifespan and fertility index. Furthermore, estrogen receptor alpha content showed a marked decrease in the hypothalamus of C58/J mice. These alterations in the estrous cycle, hormonal imbalances, and reduced reproductive function imply dysregulation in the HPO axis. Additionally, our in-silico study identified a group of genes involved in infertility carrying single-nucleotide polymorphisms (SNPs) in the C58/J strain, which also have human orthologs associated with autism. These findings could offer valuable insights into the molecular underpinnings of neuroendocrine axis disruption and reproductive issues observed in ASD.

Negative correlation between testosterone and TNF-α in umbilical cord serum favors a weakened immune milieu in the human male fetoplacental unit.

Clinical and epidemiological evidence supports that pregnancies carrying a male fetus are more vulnerable to infections and preterm birth, probably due to testosterone immunosuppressive properties. In human placentas, testosterone lowers the expression of CYP27B1, the vitamin D (VD)-activating enzyme, diminishing cathelicidin synthesis, a potent VD-dependent antimicrobial peptide (AMP). VD also stimulates other AMPs, including defensins. To get insights into the increased male vulnerability mechanisms, we investigated the relationship between fetal sex and the immunoendocrine milieu at the fetoplacental unit. For this, umbilical vein serum and placental samples were collected from healthy newborns. In males' serum, testosterone levels were significantly higher and negatively associated with TNF-α, a cytokine that strengthens the immune response. Males showed lower serum TNF-α and increased levels and gene expression of the immunosuppressive cytokine IL-10. Only in female samples there was a positive association (P < 0.05) between AMPs and both TNF-α and CYP27B1 and between 25-hydroxyvitamin D3 and IL-1ß serum levels. Accordingly, VD-metabolites (25-hydroxyvitamin D3, calcitriol) significantly stimulated IL-1ß gene expression in cultured trophoblasts. Interestingly, IL-1ß mRNA correlated positively with defensins (P < 0.05) in males, but not with cathelicidin expression, which was significantly diminished in comparison to females. Our data suggest that high umbilical serum testosterone and IL-10 in males could explain reduced TNF-α levels and lack of association between VD-dependent innate immunity markers and proinflammatory cytokines expression in the fetoplacental unit. Altogether, our observations imply a restricted basal immune milieu in males compared to females, which may help understand the higher male susceptibility to adverse perinatal outcomes.

Testosterone, the progesterone/estradiol ratio, and female ratings of masculine facial fluctuating asymmetry for a long-term relationship.

Idiosyncratic variation within the normal range of androgens levels in women account for significant variations in personality and behavior. We studied if testosterone introduces significant biases in women's perception of fluctuating symmetry of male faces suitability for a long-term relationship. Participants were 145 female college students asked to rate in a two-choice forced paradigm the attractiveness, suitability as a long-term partner, and economic success, fatherliness and fidelity of an asymmetric and a symmetric male face. Since our sample consists of random women interested in participating, whether for personal reasons or because they were paid to participate, we controlled for menstrual phase. All participants provided salivary samples to determine testosterone (T), estradiol (E2) and progesterone (P4) levels. When the P4/E2 was low and T low-to-normal, the symmetric face was rated as more attractive, and a desirable long-term partner, but these preferences changed to the opposite when P4/E2 was high. In high T women, neither face was rated as more attractive, independently from the P4/E2 ratio, but the asymmetric face was preferred as a long-term partner when conception risk was high, changing to prefer the symmetric face as the P4/E2 increased. The overall perception of male faces was that the symmetric face was more economical successful but a poor parent and highly unfaithful compared to the asymmetric face. A significant interaction between T and P4/E2 for ratings success of the asymmetric face suggests that high levels of feminine T might be related to inter-sexual competition when conception risk is high.

Vinclozolin modulates hepatic cytochrome P450 isoforms during pregnancy.

Vinclozolin (V) is classified as a potent endocrine disruptor. The aim of the present study was to determine the effects of V on rat liver CYP regulation and on serum levels of testosterone and estradiol during pregnancy. Pregnancy decreased the liver total CYP content by 65%, enzyme activities of MROD, PROD, and PNPH, and testosterone hydroxylation activities, as well as the protein content of CYP2A and 3A. V exposure remarkably induced the protein content and enzyme activities of CYP1A, 2A, 2B and 3A subfamilies. Testosterone and estradiol were affected in an opposite manner, provoking a 3.5-fold increase in the estradiol/testosterone ratio. These results suggest that V could regulate the hepatic CYP expression through interaction with receptors and coactivators involved in its expression and may play an important role in hormonal balance during pregnancy. In addition, the results may also contribute to understanding the toxicity of V by in utero exposure.

Association between high serum estradiol levels and delirium among hospitalized elderly women.

BACKGROUND: Delirium is a common and serious disorder among hospitalized elderly individuals. We investigated the association between serum estradiol levels and incident delirium. METHODS: Longitudinal study of 141 women ≥ 70 years old admitted to a tertiary care hospital in Mexico City. All participants underwent a comprehensive geriatric assessment. Blood samples for cortisol and estradiol determination were obtained at hospital admission. Incident delirium was investigated until participants were discharged. Multivariate models were run to test the independent association between estradiol levels and incident delirium. RESULTS: Twenty-three (16.3%) participants developed delirium. Estradiol levels were higher among women with incident delirium compared with non-affected women. Multivariate logistic regression analysis showed that serum estradiol levels were associated with incident delirium even after adjusting for multiple confounding covariates, including cortisol levels (OR: 1.93; 95% CI: 1.28-2.92). CONCLUSIONS: Elderly women with high serum estradiol levels at hospital admission had an increased risk for incident delirium. Serum estradiol may be a biomarker for increased risk of delirium.

Effects of neurointermediate pituitary lobectomy and desmopressin on acute experimental autoimmune encephalomyelitis in Lewis rats.

OBJECTIVE: The role of arginine vasopressin (AVP) as a direct immune regulator has not yet been clarified, and more work is needed to assess its involvement in the immunoneuroendocrine network. In the present study, the effects of neurointermediate pituitary lobectomy (NIL) and desmopressin (DP), an agonist of AVP, on acute experimental autoimmune encephalomyelitis (EAE) in female Lewis rats were evaluated. The activity of the hypothalamic-pituitary-adrenocortical (HPA) axis was also assessed. METHODS: Five groups of rats were used, as follows: (1) sham-operated (SHAM) rats, (2) SHAM + DP rats, (3) NIL rats, (4) NIL + DP rats and (5) untreated normal control rats. DP treatment started 2 weeks after surgery, and immunization to induce EAE was carried out 1 week later. RESULTS: SHAM rats developed full-blown clinical and histological signs of EAE and activation of the HPA axis. SHAM + DP animals had mild clinical signs of EAE, inflammatory infiltrations in the spinal cord and an activated HPA axis. NIL animals developed minimal EAE, scanty spinal cord inflammation and no changes in HPA axis activity. NIL + DP rats developed severe clinical signs of EAE, extensive spinal cord inflammatory infiltrations and marked activation of the HPA axis. CONCLUSIONS: NIL decreased the cell-mediated immune response, while DP in NIL animals restored the immune response. AVP is directly involved in the maintenance of immune competence.