Subfertility as Overlapping of Nutritional, Endocrine, Immune, and Cardiometabolic Dysregulations—A Study Focused on Biochemical Endophenotypes of Subfertile Couples

Subfertility is a global health issue, and as many as 30% of cases are attributed to unexplained reasons. A hypercaloric, high-fat diet stimulates the expansion of pro-inflammatory gut microbiota with a consequent rise in circulating lipopolysaccharides. Adverse gut microbiota remodeling can exacerbate insulin resistance, while sex and thyroid hormones may influence the variability in gut microbiota. This cross-sectional study included 150 participants and was designed to determine a biochemical, nutritional-related pattern that may distinguish subfertile from fertile individuals and couples. A panel of 28 biomarkers was assessed. Four biochemical phenotypes of unexplained subfertility were found, including two metabolic and two immune, when assessed using binary logistic regression models. Two phenotypes were distinguished in women: cardio-metabolic with atherogenic dyslipidemia ((Low)HDL-cholesterol: OR = 10.9; p < 0.05) and autoimmune thyroid disorder ((High)anti-thyroid-peroxidase: OR = 5.5; p < 0.05) and two in men: hepato-metabolic with elevated liver injury enzymes ((High)HOMA-IR: OR = 6.1; p < 0.05) and immune type-2 response ((High)IgE: OR = 6.4; p < 0.05). The chances of a couple’s subfertility rose with the number of laboratory components of metabolic syndrome in the couple (OR = 1.7; p < 0.05) and if at least one partner had an elevated total IgE level (>100 kU/L) (OR = 6.5; p < 0.05). This study found that unexplained subfertility may be accompanied by mutually overlapping immune and metabolic dysregulations in individuals and couples. We propose one-time laboratory diagnostics taking into account the lipid profile, insulin resistance, anti-thyroid-peroxidase, and total IgE in both males and females with unexplained subfertility. This may allow for a one-time assessment of targeted medical and nutritional interventions and help optimize patients’ health. The gut–organ axes related to subfertility are discussed in the context of the obtained results.