Dehydroepiandrosterone (DHEA) Serum Levels Indicate Cerebrospinal Fluid Levels of DHEA and Estradiol (E2) in Women at Term Pregnancy.

Neuroactive steroids such as dehydroepiandrosterone (DHEA), estradiol (E2), and progesterone (P4) are associated with structural and functional changes in the central nervous system (CNS). Measurement of steroid levels in the CNS compartments is restricted in accessibility. Consequently, there is only limited human data on the distributional equilibrium for steroid levels between peripheral and central compartments. While some neuroactive steroids including DHEA and E2 have been reported to convey excitatory and proconvulsant properties, the opposite was demonstrated for P4. We aimed to elucidate the correlation between peripheral and central DHEA, E2, and P4 levels in women at term pregnancy. CSF and serum samples of 27 healthy pregnant women (22-39 years) at term pregnancy were collected simultaneously under combined spinal and epidural anesthesia and used for DHEA ELISA and E2, and P4 ECLIA. All three neuroactive steroids were detected at markedly lower levels in CSF compared to their corresponding serum concentrations (decrease, mean ± SD, 97.66 ± 0.83%). We found a strong correlation for DHEA between its serum and the corresponding CSF levels (r = 0.65, p = 0.003). Serum and CSF levels of E2 (r = 0.31, p = 0.12) appeared not to correlate in the investigated cohort. DHEA serum concentration correlated significantly with E2 (r = 0.58, p = 0.0016) in CSF. In addition, a strong correlation was found between DHEA and E2, both measured in CSF (r = 0.65, p = 0.0002). Peripheral DHEA levels might serve as an indicator for central nervous levels of the neuroactive steroids DHEA and E2 in pregnant women.

Relationships between cerebrospinal fluid GABAergic neurosteroid levels and symptom severity in men with PTSD.

Allopregnanolone and pregnanolone (together termed allo + pregnan) are neurosteroid metabolites of progesterone that equipotently facilitate the action of gamma-amino-butyric acid (GABA) at GABAA receptors. The adrenal steroid dehydroepiandrosterone (DHEA) allosterically antagonizes GABAA receptors and facilitates N-methyl-D-aspartate (NMDA) receptor function. In prior research, premenopausal women with posttraumatic stress disorder (PTSD) displayed low cerebrospinal fluid (CSF) levels of allo + pregnan [undifferentiated by the gas chromatography-mass spectrometry (GC-MS) method used] that correlated strongly and negatively with PTSD reexperiencing and negative mood symptoms. A PTSD-related decrease in the ratio of allo + pregnan to 5α-dihydroprogesterone (5α-DHP: immediate precursor for allopregnanolone) suggested a block in synthesis of these neurosteroids at 3α-hydroxysteroid dehydrogenase (3α-HSD). In the current study, CSF was collected from unmedicated, tobacco-free men with PTSD (n = 13) and trauma-exposed healthy controls (n = 17) after an overnight fast. Individual CSF steroids were quantified separately by GC-MS. In the men with PTSD, allo + pregnan correlated negatively with Clinician-Administered PTSD Scale (CAPS-IV) total (ρ=-0.74, p = 0.006) and CAPS-IV derived Simms dysphoria cluster (ρ=-0.71, p = 0.01) scores. The allo+pregnan to DHEA ratio also was negatively correlated with total CAPS (ρ=-0.74, p = 0.006) and dysphoria cluster (ρ=-0.79, p = 0.002) scores. A PTSD-related decrease in the 5α-DHP to progesterone ratio indicated a block in allopregnanolone synthesis at 5α-reductase. This study suggests that CSF allo + pregnan levels correlate negatively with PTSD and negative mood symptoms in both men and women, but that the enzyme blocks in synthesis of these neurosteroids may be sex-specific. Consideration of sex, PTSD severity, and function of 5α-reductase and 3α-HSD thus may enable better targeting of neurosteroid-based PTSD treatments.

Reduced cortisol levels in cerebrospinal fluid and differential distribution of 11beta-hydroxysteroid dehydrogenases in multiple sclerosis: implications for lesion pathogenesis.

Relapses during multiple sclerosis (MS) are treated by administration of exogenous corticosteroids. However, little is known about the bioavailability of endogenous steroids in the central nervous system (CNS) of MS patients. We thus determined cortisol and dehydroepiandrosterone (DHEA) levels in serum and cerebrospinal fluid (CSF) samples from 34 MS patients, 28 patients with non-inflammatory neurological diseases (NIND) and 16 patients with other inflammatory neurological diseases (OIND). This revealed that MS patients - in sharp contrast to patients with OIND - show normal cortisol concentrations in serum and lowered cortisol levels in the CSF during acute relapses. This local cortisol deficit may relate to poor local activation of cortisone via 11beta-hydroxysteroid dehydrogenase type 1 (11bHSD1) or to inactivation via 11bHSD2. Accordingly, 11bHSD2 was found to be expressed within active plaques, whereas 11bHSD1 was predominantly detected in surrounding "foamy" macrophages. Our study thus provides new insights into the impaired endogenous CNS cortisol regulation in MS patients and its possible relation to MS lesion pathogenesis. Moreover, an observed upregulation of 11bHSD1 in myelin-loaded macrophages in vitro suggests an intriguing hypothesis for the self-limiting nature of MS lesion development. Finally, our findings provide an attractive explanation for the effectivity of high- vs. low-dose exogenous corticosteroids in the therapy of acute relapses.

Decreased cerebrospinal fluid allopregnanolone levels in women with posttraumatic stress disorder.

BACKGROUND: Alterations in the gamma-amino-butyric acid (GABA) neurotransmitter system have been identified in some populations with posttraumatic stress disorder (PTSD). METHODS: To further investigate factors of relevance to GABAergic neurotransmission in PTSD, we measured cerebrospinal fluid (CSF) levels of allopregnanolone and pregnanolone combined (ALLO: congeners that potently and positively modulate effects of GABA at the GABA(A) receptor), 5alpha-dihydroprogesterone (5alpha-DHP: the immediate precursor for allopregnanolone), dehydroepiandrosterone (DHEA: a negative modulator of GABA(A) receptor function), and progesterone with gas chromatography, mass spectrometry in premenopausal women with (n = 9) and without (n = 10) PTSD. Subjects were free of psychotropic medications, alcohol, and illicit drugs; all were in the follicular phase of the menstrual cycle except three healthy and four PTSD subjects receiving oral contraceptives. RESULTS: There were no group differences in progesterone, 5alpha-DHP, or DHEA levels. The PTSD group ALLO levels were < 39% of healthy group levels. The ALLO/DHEA ratio correlated negatively with PTSD re-experiencing symptoms (n = -.82, p < 008; trend) and with Profile of Mood State depression/dejection scores (n = -0.70, p < 0008). CONCLUSION: Low CSF ALLO levels in premenopausal women with PTSD might contribute to an imbalance in inhibitory versus excitatory neurotransmission, resulting in increased PTSD re-experiencing and depressive symptoms.

Changes with aging of steroidal levels in the cerebrospinal fluid of women.

OBJECTIVE: Age-related changes of steroid levels in the central nervous system (CNS) are not well understood. To investigate whether steroidal conditions in the CNS of women change with aging and menopause, steroid levels have been measured in serum and cerebrospinal fluid (CSF), and examined correlations with aging. METHODS: Serum and CSF concentrations of estradiol (E2), cortisol, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS) and albumin were measured in 80 female patients who underwent operations for benign gynecological diseases. They had no endocrinological or neurological disorders and were aged 17-71 years; 62 patients were in premenopause and 18 were in postmenopause. RESULTS: Serum levels of E2 decreased markedly after menopause, while levels of DHEA and DHEAS decreased gradually with age. There was no significant change with age of serum cortisol levels. The CSF concentrations of E2 (0.2-3 pg/ml) decreased with age [correlation coefficient (r)= 0.31, P < 0.01]. The CSF DHEA levels (0.1-0.8 ng/ml) did not change with age although not significantly, but CSF cortisol levels (0.1-0.6 microg/dl) increased with age (r = 0.35, P < 0.01). The CSF DHEAS concentrations were below the sensitivity of the radioimmunoassay (RIA) (1 ng/ml). The CSF/serum ratios of cortisol increased with age (r = 0.30, P < 0.01), as did those of DHEA (r = 0.55, P < 0.01). Although serum albumin levels did not change throughout life, CSF albumin levels and CSF/serum albumin ratios increased gradually with age (r = 0.28, P = 0.052; r = 0.23, P = 0.114, respectively), but there was no significance. There were marked decreases of serum E2 and DHEA levels and CSF E2 levels in postmenopausal women (P < 0.05), but CSF cortisol levels increased (P < 0.05) and DHEA levels in CSF were maintained after menopause. CONCLUSION: These results indicate that steroids in CSF become cortisol dominated and deficient in estrogens with aging, especially after menopause.

Neurosteroids in cerebrospinal fluid in neurologic disorders.

In order to investigate the role of "neurosteroids" in the central nervous system (CNS), cerebrospinal fluid (CSF) levels of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) were determined by radioimmunoassay in 57 patients with various neurologic disorders and 26 patients with non-neurologic disorders. The content of CSF DHEA and DHEAS in patients with Guillain-Barré syndrome (GBS), and the content of CSF DHEAS in patients with carcinomatous meningitis were significantly higher as compared to non-neurological control patients. These changes may be explained by the breakdown of blood-nerve barrier in these disorders. A significant positive correlation was observed between DHEAS and total protein in CSF. In males but not females, a negative correlation was observed between CSF DHEAS and aging. The level of CSF DHEAS, but not DHEA, was significantly higher in males than in females.