Disturbed sex hormone milieu in males and females with major depressive disorder and low-grade inflammation

J Affect Disord. 2024 Jul 1:356:167-176. doi: 10.1016/j.jad.2024.03.018. Epub 2024 Mar 15.


Sex hormones have biological effects on inflammation, and these might contribute to the sex-specific features of depression. C-reactive protein (CRP) is the most widely used inflammatory biomarker and consistent evidence shows a significant proportion (20-30 %) of patients with major depressive disorder (MDD) have CRP levels above 3 mg/L, a threshold indicating at least low-grade inflammation. Here, we investigate the interplay between sex hormones and CRP in the cross-sectional, observational Biomarkers in Depression Study. We measured serum high-sensitivity (hs-)CRP, in 64 healthy controls and 178 MDD patients, subdivided into those with hs-CRP below 3 mg/L (low-CRP; 53 males, 72 females) and with hs-CRP above 3 mg/L (high-CRP; 19 males, 34 females). We also measured interleukin-6, testosterone, 17-β-estradiol (E2), progesterone, sex-hormone binding globulin (SHBG), follicle-stimulating and luteinising hormones, and calculated testosterone-to-E2 ratio (T/E2), free androgen and estradiol indexes (FAI, FEI), and testosterone secretion index. In males, high-CRP patients had lower testosterone than controls (p = 0.001), and lower testosterone (p = 0.013), T/E2 (p < 0.001), and higher FEI (p = 0.015) than low-CRP patients. In females, high-CRP patients showed lower SHGB levels than controls (p = 0.033) and low-CRP patients (p = 0.034). The differences in testosterone, T/E2 ratio, and FEI levels in males survived the Benjamini-Hochberg FDR correction. In linear regression analyses, testosterone (β = -1.069 p = 0.033) predicted CRP concentrations (R2 = 0.252 p = 0.002) in male patients, and SHBG predicted CRP levels (β = -0.628 p = 0.009, R2 = 0.172 p = 0.003) in female patients. These findings may guide future research investigating interactions between gonadal and immune systems in depression, and the potential of hormonal therapies in MDD with inflammation.

Keywords: C-reactive protein; Inflammation; Major depressive disorder; Sex differences; Sex hormones.

Publication types

  • Research Support, Non-U.S. Gov't
  • Observational Study

MeSH terms

  • Adult
  • Biomarkers / blood
  • C-Reactive Protein* / analysis
  • Cross-Sectional Studies
  • Depressive Disorder, Major* / blood
  • Estradiol* / blood
  • Female
  • Follicle Stimulating Hormone / blood
  • Gonadal Steroid Hormones / blood
  • Humans
  • Inflammation* / blood
  • Interleukin-6* / blood
  • Luteinizing Hormone / blood
  • Male
  • Middle Aged
  • Progesterone* / blood
  • Sex Factors
  • Sex Hormone-Binding Globulin* / analysis
  • Testosterone* / blood


  • C-Reactive Protein
  • Testosterone
  • Sex Hormone-Binding Globulin
  • Estradiol
  • Progesterone
  • Interleukin-6
  • Biomarkers
  • Gonadal Steroid Hormones
  • Follicle Stimulating Hormone
  • Luteinizing Hormone