Specific changes of blood-brain-barrier permeability for estrogens and gonadotrophins at menopause

Introduction. Estrogens are known to have a neuroprotective role and to influence the permeability of the blood brain barrier (BBB). An ongoing debate exists on the changing effects of estrogens on target tissues with advancing age and at menopause and on the potential disruptive role of increasing gonadotropin levels. The aim of the present study was to assess the permeability of the BBB for estradiol, FSH and LH in three physiological states: early follicular phase, preovulatory phase and at menopause. Method. Hormonal levels were assessed simultaneously in the serum and cerebrospinal fluid (CSF) of 15 women at menopause (mean age 60 +/- 8 years), 16 of reproductive age in early follicular phase and 11 in preovulatory phase (mean age 31 +/- 7 years), all undergoing surgery for benign gynecologic disorders. FSH, LH and estradiol levels were assessed using chemo luminescence and are expressed as median and 10-90 percentile interval. Statistical analysis assessed the serum-CSF correlation and the CSF/serum ratio for each hormone between groups. Results. Estradiol serum levels were 26.2 pg/ml (6.4-43.5) at menopause (n=15), 58.5 pg/ml (25.7-75.9) in early follicular phase (EFP, n=16) and 221.2 pg/ml (113.7-405.5) in preovulatory phase (PREOV, n=11). CSF estradiol is 18.5 pg/ml (0.4-30.5) at menopause, 5.4 pg/ml (2.2-10.2) in EFP (p < 0.001) and 17.3 pg/ml (10.3-34.6) in PREOV patients. Estradiol serum and CSF levels correlate positively in the fertile cycle (r=0.72, p < 0.0001) and negatively at menopause (r=-0.88, p < 0.05). The CSF/serum ratio for estradiol is 0.8 (0.01-4.4) at menopause, 0.1 (0.04-0.13) in EFP and 0.1 (0.03-0.13) in PREOV patients. FSH serum levels were 75.8 mUI/ml (35.9-129.8) at menopause, 7.7 mUI/ml (3.5-11.4) in EFP and 7.3 mUI/ml (3.1-10.7) in PREOV patients. CSF FSH is 2.7 mUI/ml (0.4-5.9) at menopause, significantly higher than 0.7 mUI/ml (0.3-1) in EFP (p < 0.001) and 0.5 mUI/ml (0.2-1) in PREOV patients (p < 0.05). FSH serum and CSF levels correlate positively in the fertile cycle (r=0.8, p < 0.0001) and do not correlate at menopause (p=NS). The CSF/serum ratio for FSH is 0.03 (0.01-0.1) at menopause, significantly lower than 0.09 (0.06-0.16) in EFP (p < 0.001) and is 0.06 (0.03-0.13) in PREOV phase. LH serum levels were 57.4 mUI/ml (27.5-84.8) at menopause, 4.7 mUI/ml (1.7-7.1) in EFP and 5.5 mUI/ml (4.9-8.02) in PREOV phase. CSF LH is 1.6 mUI/ml (0.7-2.6) at menopause, significantly higher than 0.4 mUI/ml (0.1-1) in EFP (p < 0.001) and 0.5 mUI/ml (0.2-0.9) in preovulatory phase (p < 0.05). The CSF/serum ratio for LH is 0.03 (0.01-0.07) at menopause, it is significantly lower than 0.09 (0.03-0.27) in EFP (p < 0.001) and is 0.07 (0.03-0.14) in preovulatory phase. Conclusions. This study shows the negative correlation of serum and CSF estradiol levels at menopause reflecting the need of constant estrogen levels within the CSF despite low chronic serum levels. Simultaneously, the CSF/serum ratio for gonadotrophins is reduced sianificantly at menopause and the positive correlation of serum and CSF levels is lost, reflecting a protective mechanism against rising levels of FSH and LH.