The secondary sex ratio (SSR), which reflects the proportion of male to female offspring at birth, is influenced by a complex interplay of multiple factors. This review delves into the current understanding of how infections and genetics contribute to variations in the SSR. The effects of infections on the SSR represent an intriguing intersection of biology and epidemiology. Research indicates that several infectious diseases, such as toxoplasmosis, coronavirus disease 2019, Spanish flu, acquired immunodeficiency syndrome and tuberculosis, can impact the SSR through mechanisms that are only partially understood. Genetics are also scrutinized in this review. Although their involvement in determining the SSR is debatable, various genetic factors have been studied. The influences of the Rhesus D heterozygous phenotype, major histocompatibility complex, corticosteroid-binding globulin deficiency, ethnicity, and consanguinity on SSR have been delineated. By amalgamating findings from diverse disciplines, this review aims to offer a comprehensive overview of the multifaceted impact of infections and genetics on SSR, pinpointing potential implications for reproductive biology and public health.

Corticosteroid binding globulin (CBG) deficiency is a rare disorder with poorly understood pathophysiology and variable presentations. We report on a pediatric patient presenting with poor growth and delayed puberty who was diagnosed initially with primary adrenal insufficiency following 2 failed ATCH stimulation tests with normal CBG and low stimulated salivary (free) cortisol. Genetic testing demonstrated a homozygous SERPINA6 variant known as CBG Lyon. The patient's 2 siblings were later diagnosed with the same homozygous variant but were asymptomatic with normal stimulated salivary cortisol. CBG deficiency or dysfunction should be considered in patients with unexplained adrenal insufficiency. Further research is needed to better understand CBG's role in cortisol physiology.

Produced by the liver, corticosteroid-binding globulin (CBG) regulates the plasma distribution and actions of glucocorticoids. A sex difference in pituitary growth hormone secretion patterns established during puberty in rats results in increased hepatic CBG production and 2-fold higher plasma corticosterone levels in females. Glucocorticoids control hepatic development and metabolic activities, and we have therefore examined how disrupting the SerpinA6 gene encoding CBG influences plasma corticosterone dynamics, as well as liver gene expression in male and female rats before and after puberty. Comparisons of corticosterone plasma clearance and hepatic uptake in adult rats, with or without CBG, indicated that CBG limits corticosterone clearance by reducing its hepatic uptake. Hepatic transcriptomic profiling revealed minor sex differences (207 differentially expressed genes) and minimal effect of CBG deficiency in 30-day-old rats before puberty. While liver transcriptomes in 60-day-old males lacking CBG remained essentially unchanged, 2710 genes were differentially expressed in wild-type female vs male livers at this age. Importantly, ∼10% of these genes lost their sexually dimorphic expression in adult females lacking CBG, including those related to cholesterol biosynthesis, inflammation, and lipid and amino acid catabolism. Another 203 genes were altered by the loss of CBG specifically in adult females, including those related to xenobiotic metabolism, circadian rhythm, and gluconeogenesis. Our findings reveal that CBG consolidates the sexual dimorphism of the rat liver initiated by sex differences in growth hormone secretion patterns and provide insight into how CBG deficiencies are linked to glucocorticoid-dependent diseases.

Hydrocortisone administration in septic shock remains controversial. Corticosteroid-binding globulin (CBG) transports cortisol to inflammatory sites and is depleted in septic shock. To determine whether severely deficient serum CBG < 200 nmol/L (reference range 269-641 nmol/L) independently predicts septic shock mortality. A prospective observational study in patients with septic shock. Patients were categorized into 2 groups: mean plasma CBG concentrations <200 nmol/L and ≥200 nmol/L (day 1/2), with additional categorization by nadir CBG. Primary outcome was intensive care unit (ICU) mortality. Secondary outcomes were 28- and 90-day mortality, norepinephrine requirements, renal replacement therapy, and clinician-instituted hydrocortisone. 135 patients were included. Mortality rates in ICU were higher in the CBG < 200 nmol/L vs the CBG ≥ 200 nmol/L group: 32.4% vs 13.9% [odds ratio (OR) 2.97 (95% CI 1.19, 7.41); P = 0.02] with 28-day mortality OR 2.25 (95% CI 0.99, 5.11) and 90-day mortality OR 2.21 (95% CI 0.99, 4.91). Multivariate analysis revealed 4 factors independently associated with ICU mortality: CBG < 200 nmol/L (adjusted OR 3.23, 95% CI 1.06, 9.88), Acute Physiology and Chronic Health Evaluation II > 25 (adjusted OR 3.58, 95% CI 1.20, 10.68), Sequential Organ Failure Assessment (SOFA) liver score (adjusted OR 1.98, 95% CI 1.04, 3.72), and renal replacement therapy (adjusted OR 6.59, 95% CI 2.17, 20.01). Nadir CBG levels were associated with higher SOFA cardiovascular scores and norepinephrine total dose (μg; P < 0.01) and duration (days; P < 0.01). Plasma cortisol concentrations and hydrocortisone administration did not relate to ICU mortality. Septic shock patients with CBG < 200 nmol/L had higher norepinephrine requirements and 3.2-fold higher ICU mortality. CBG concentration was the only directly reversible independent mortality risk factor.