A biological characterization of patients with postmenopausal Parkinson's disease.

Menopause increases the risk for Parkinson's disease (PD), although the underlying biological mechanisms have not been established in patients. Here, we aimed to understand the basis of menopause-related vulnerability to PD. Main motor and non-motor scores, blood levels of estradiol, testosterone, follicle-stimulating hormone, and luteinizing hormone, CSF levels of total α-synuclein, amyloid-ß-42, amyloid-ß-40, total tau, and phosphorylated-181-tau were examined in 45 women with postmenopausal-onset PD and 40 age-matched controls. PD patients had higher testosterone and lower estradiol levels than controls, and the residual estradiol production was associated with milder motor disturbances and lower dopaminergic requirements. In PD but not in controls, follicle-stimulating hormone levels correlated with worse cognitive scores and CSF markers of amyloidopathy and neuronal loss. In conclusion, menopause-related hormonal changes might differentially contribute to clinical-pathological trajectories of PD, accounting for the peculiar vulnerability to the disease.

Weak correlations between serum and cerebrospinal fluid levels of estradiol, progesterone and testosterone in males.

BACKGROUND: Neuroactive steroids seem to be implicated in a variety of neurophysiological and behavioral processes, such as sleep, learning, memory, stress, feeding and aging. Numerous studies have also addressed this implication in various cerebral disorders and diseases. Yet, the correlation and association between steroids in the periphery, e.g. blood, and the central compartments, e.g. cerebrospinal fluid (CSF), have not yet been comprehensively assessed. As the brain is not directly accessible, and the collection of human CSF usually requires invasive procedures, easier accessible compartments, such as blood, have always attracted attention. However, studies in humans are scarce. In the present study we determined estradiol, progesterone and testosterone levels in CSF and serum of 22 males without cerebral disorders or diseases. RESULTS: Samples were taken under conditions corresponding closest to basal conditions with patients expecting only spinal anesthesia and minor surgery. All samples per patient were collected concomitantly. Total estradiol, progesterone and testosterone concentrations were measured by electro-chemiluminescence immunoassay. The strength of correlation was assessed by Spearman's rank correlation coefficient. Correlation analysis revealed merely weak to very weak correlations for estradiol, progesterone and testosterone respectively between the CSF and serum compartments. CONCLUSIONS: Total steroid levels of estradiol, progesterone and testosterone in CSF and serum of males without neurological disorders were determined. Weak to very weak correlations between CSF and serum were found thus suggesting that concentrations in the periphery do not parallel concentrations in the central compartments. Further research is needed to clarify to what extent and under which conditions serum levels of estradiol, progesterone and testosterone may possibly serve as a biomarker reflecting the respective concentrations in the CSF or in the brain.

Short-term sleep fragmentation enhances anxiety-related behavior: The role of hormonal alterations.

INTRODUCTION: The neuroendocrine background of acute sleep fragmentation in obstructive sleep apnea and sleep fragmentation involvement in psychiatric comorbidities, common in these patients, are still largely unknown. The aim of this study was to determine the effects of short-term experimental sleep fragmentation on anxiety -like behavior and hormonal status in rats. METHODS: Male rats were adapted to treadmill (ON and OFF mode with belt speed set on 0.02m/s and 0.00m/s) and randomized to: 1) treadmill control (TC, only OFF mode); 2) motion, activity control (AC, 10min ON and 30min OFF mode) and 3) sleep fragmentation (SF, 30s ON and 90s OFF mode) group. Six hours later, the animals were tested in the open field, elevated plus maze and light/dark test (n = 8/group). Testosterone, estradiol, progesterone and corticosterone were determined in separate animal cohort immediately upon sleep fragmentation (n = 6/group). RESULTS: SF rats showed decreased rearings number, decreased time spent in the central area and increased thigmotaxic index compared to TC and AC rats in the open field test. Similarly, increased anxiety upon sleep fragmentation was observed in the elevated plus maze and the light/dark test. Significantly lower testosterone, estradiol and progesterone levels were determined in SF in comparison to AC and TC groups, while there was no significant difference in the levels of corticosterone. CONCLUSION: Short term sleep fragmentation enhances anxiety-related behavior in rats, which could be partly mediated by the observed hormonal changes presented in the current study in form of testosterone, estradiol and progesterone depletion.

Increased cerebrospinal fluid levels of GABA, testosterone and estradiol in women with polycystic ovary syndrome.

STUDY QUESTION: Do cerebrospinal fluid (CSF) concentrations of gamma-aminobutyric acid (GABA), testosterone (T) and estradiol (E2) differ in women with polycystic ovary syndrome (PCOS) as compared to eumenorrheic, ovulatory women (EW)? SUMMARY ANSWER: Women with PCOS displayed higher CSF levels of GABA and E2, and possibly T, than EW. WHAT IS KNOWN ALREADY: The chronic anovulation characteristic of PCOS has been attributed to increased central GnRH drive and resulting gonadotropin aberrations. Androgens are thought to regulate GABA, which in turn regulates the neural cascade that modulates GnRH drive. STUDY DESIGN, SIZE, DURATION: This cross-sectional observational study included 15 EW and 12 non-obese women with PCOS who consented to a lumbar puncture in addition to 24 h of serum blood collection at 15-min intervals. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 27 women were studied at a the General Clinical Research Center (GCRC) at the University of Pittsburgh. Serum analytes included T, E2 and androstenedione. CSF analytes included GABA, glutamate, glucose, T and E2. MAIN RESULTS AND THE ROLE OF CHANCE: Women with PCOS had higher CSF GABA as compared to EW (9.04 versus 7.04 µmol/L, P < 0.05). CSF glucose and glutamate concentrations were similar between the two groups. CSF T was 52% higher (P = 0.1) and CSF E2 was 30% higher (P < 0.01) in women with PCOS compared to EW. Circulating T was 122% higher (P < 0.01) and circulating E2 was 75% higher (P < 0.01) in women with PCOS than in EW. LIMITATIONS REASONS FOR CAUTION: The study is limited by its small sample size and the technical limitations of measuring CSF analytes that are pulsatile and have short half-lives. WIDER IMPLICATIONS OF THE FINDINGS: Women with PCOS displayed significantly higher circulating levels of T and E2, significantly higher CSF levels of E2, and higher levels of CSF testosterone, although the latter was not statistically significant. A better understanding of the central milieu informs our understanding of the mechanisms mediating increased the GnRH drive in PCOS and lends a new perspective for understanding the presentation, pathogenesis and potential health consequences of PCOS, including gender identity issues. STUDY FUNDING/COMPETING INTEREST(S): No conflicts of interest. The study was funded by NIH grants to SLB (RO1-MH50748, U54-HD08610) and NIH RR-00056 to the General Clinical Research Center of the University of Pittsburgh. TRIAL REGISTRATION NUMBER: NCT01674426.

Neuroactive steroid levels and psychiatric and andrological features in post-finasteride patients.

Recent reports show that, in patients treated with finasteride for male pattern hair loss, persistent side effects including sexual side effects, depression, anxiety and cognitive complaints may occur. We here explored the psychiatric and andrological features of patients affected by post-finasteride syndrome (PFS) and verified whether the cerebrospinal fluid (CSF) and plasma levels of neuroactive steroids (i.e., important regulators of nervous function) are modified. We found that eight out of sixteen PFS male patients considered suffered from a DSM-IV major depressive disorder (MDD). In addition, all PFS patients showed erectile dysfunction (ED); in particular, ten patients showed a severe and six a mild-moderate ED. We also reported abnormal somatosensory evoked potentials of the pudendal nerve in PFS patients with severe ED, the first objective evidence of a neuropathy involving peripheral neurogenic control of erection. Testicular volume by ultrasonography was normal in PFS patients. Data obtained on neuroactive steroid levels also indicate interesting features. Indeed, decreased levels of pregnenolone, progesterone and its metabolite (i.e., dihydroprogesterone), dihydrotestosterone and 17beta-estradiol and increased levels of dehydroepiandrosterone, testosterone and 5alpha-androstane-3alpha,17beta-diol were observed in CSF of PFS patients. Neuroactive steroid levels were also altered in plasma of PFS patients, however these changes did not reflect exactly what occurs in CSF. Finally, finasteride did not only affect, as expected, the levels of 5alpha-reduced metabolites of progesterone and testosterone, but also the further metabolites and precursors suggesting that this drug has broad consequence on neuroactive steroid levels of PFS patients.

Impact of aromatase genetic variation on hormone levels and global outcome after severe TBI.

Although experimental traumatic brain injury (TBI) studies support estradiol as a neuroprotectant and potent stimulator of neuroplasticity, clinical studies suggest a negative association between endogenous estradiol profiles and mortality/poor outcomes. However, no studies have evaluated associations with cerebral spinal fluid (CSF) hormone profiles and aromatase gene (cytochrome P450 [CYP]19A1) variability on clinical TBI outcomes. We evaluated 110 adults with severe TBI. Average and daily estradiol, testosterone, and estradiol/testosterone ratios (E2:T) were measured using CSF and serum samples and compared to healthy controls. Eighteen tagging and four functional single-nucleotide polymorphisms (SNPs) for CYP19A1 were genotyped and compared to hormones, acute mortality, and Glasgow Outcome Scale (GOS) scores 6 months post-TBI. TBI subjects had lower CSF estradiol over time versus controls. CSF testosterone was initially high, but declined over time. E2/T ratios were initially low, compared to controls, but rose over time. Higher mean E2/T ratio in bivariate analysis was associated with lower mortality (p=0.019) and better GOS-6 scores (p=0.030). rs2470152 influenced CSF E2/T ratio and also serum and CSF testosterone (p≤0.05 all comparisons). Multiple-risk SNPs rs2470152, rs4646, and rs2470144 were associated with worse GOS-6 scores (p≤0.05, all comparisons), and those with>1 risk SNP variant had a higher risk for poor outcome, compared with those with ≤1 risk variant. TBI results in low CSF estradiol and dynamic CSF testosterone and E2/T ratio. In contrast to clinical serum hormone studies, higher CSF E2/T ratio was associated with better outcome. Further, genetic variation in CYP19A1 influences both hormone dynamics and outcome post-TBI.

Monoamines and neurosteroids in sexual function during induced hypogonadism in healthy men.

CONTEXT: Although the behavioral effects of high-dose androgen administration may involve alterations in serotonergic activity, few studies have investigated the impact of androgen withdrawal on the central nervous system in humans. OBJECTIVE: To examine the effects of pharmacologically induced hypogonadism on several cerebrospinal fluid (CSF) systems that could mediate the behavioral concomitants of hypogonadism. DESIGN: Double-blind assessment of the effects of the short-term induction of hypogonadism and subsequent replacement with testosterone and placebo in a crossover design. SETTING: National Institutes of Health, Bethesda, Md. PARTICIPANTS: Twelve healthy male volunteers. INTERVENTIONS: We administered the gonadotropin-releasing hormone agonist leuprolide acetate (7.5 mg intramuscularly every 4 weeks) to the healthy male volunteers, creating a hypogonadal state, and then either replaced testosterone (200 mg intramuscularly) or administered a placebo every 2 weeks for 1 month. MAIN OUTCOME MEASURES: Mood and behavioral symptoms were monitored with daily self-ratings, and lumbar punctures were performed during both hypogonadal (placebo) and testosterone-replaced conditions for CSF levels of steroids and monoamine metabolites. RESULTS: The CSF testosterone, dihydrotestosterone, and androsterone levels were significantly lower during hypogonadism (P=.002, .04, and .046, respectively), but no significant changes were observed in CSF measures of 5-hydroxyindoleacetic acid, homovanillic acid, dehydroepiandrosterone, or pregnenolone. Decreased sexual interest was observed during the hypogonadal state compared with both baseline and testosterone replacement (P=.009) and correlated significantly with CSF measures of androsterone during both hypogonadism and testosterone replacement (r = -0.76 and -0.81, respectively; P<.01). Moreover, the change in severity of decreased sexual interest correlated significantly with the change in CSF androsterone levels between testosterone replacement and hypogonadism (r = -0.68; P<.05). The CSF 5-hydroxyindoleacetic acid and homovanillic acid levels did not correlate significantly with any behavioral or CSF measure. CONCLUSION: These data suggest that the neurosteroid androsterone contributes to the regulation of sexual function in men.

Cerebrospinal fluid and plasma testosterone levels in post-traumatic stress disorder and tobacco dependence.

BACKGROUND: Little is known about the relationship between endogenous central nervous system (CNS) testosterone and any psychiatric syndrome. The goal of this study was to screen for potential abnormalities in CNS testosterone levels in patients with post-traumatic stress disorder (PTSD) and/or tobacco dependence. METHODS: We sampled cerebrospinal fluid (CSF) via a subarachnoid catheter over six hours and determined hourly basal CSF concentrations of testosterone in 11 combat veterans with PTSD and 12 normal volunteers. Smokers were abstinent for 11-17 h. Testosterone in CSF and matching plasma samples was assayed by radioimmunoassay. RESULTS: A factor analysis for effects of PTSD status, smoking status and sample time revealed significant effects of PTSD or smoking status, but not time, on CSF testosterone. CSF testosterone levels were lower in individuals with PTSD as compared with normal volunteers. When divided by smoking status, abstinent smokers had mean CSF testosterone levels higher than those of non-smokers. A similar analysis of plasma testosterone revealed no significant effects of any factor on plasma testosterone. CONCLUSIONS: These results indicate that CSF testosterone is significantly influenced by PTSD and smoking status. The exposure of the brain to altered levels of testosterone in smokers and patients with PTSD may have pathophysiologic significance in these conditions.

Dopamine in the cerebrospinal fluid of prepubertal and adult horses.

Catecholamine concentrations (pg/ml) in the cerebrospinal fluid (CSF) of prepubertal (n = 9) and adult (n = 18) horses were determined by radioenzymatic assay. Norepinephrine was low or non detectable in all CSF samples. In contrast, measurable CSF dopamine concentrations were effected by age, reproductive status and exogenous steroid treatments. The concentration of dopamine in the CSF of prepubertal females (733 +/- 92) was greater (p less than 0.05) than the concentration in the CSF of prepubertal males (117 +/- 67). Prepubertal male horses which were treated with testosterone for 5 days (50 mg/day) had elevated (p less than 0.05) dopamine concentrations (2,533 +/- 1,160) in the CSF compared to control males. In adult mares, dopamine was lower (p less than 0.05) in the ovulatory season (25 +/- 10) than during the anovulatory season (200 +/- 101). Daily intramuscular estradiol-17 beta (5 mg/day) injections had no effect (p less than 0.05) on dopamine concentrations in the CSF of seasonally anovulatory mares (250 +/- 35). Further, concentrations of dopamine in the CSF of long-term ovariectomized mares (80 +/- 21) were not influenced (p less than .05) by season. These results suggest that age, sex and gonadal steroids may effect dopamine, but not norepinephrine, concentrations in the brain ventricular system of the equine species. Further, seasonal effects on CSF dopamine concentrations are dependent upon the presence of the ovaries.

Studies on the transfer of steroid hormones across the blood-cerebrospinal fluid barrier in the rhesus monkey. II.

The movement of progesterone (P), cortisol (F) and 17-hydroxyprogesterone (17-OHP) across the blood-cerebrospinal fluid (CSF) barrier was determined using six adult male rhesus monkeys with indwelling canulae in the lateral ventricles of their brains. Tritiated steroids were given iv as a bolus followed by a constant 6 h infusion with continuous collection of CSF and periodic sampling of blood before and during the infusion. The amounts of authentic steroid in the plasma and CSF were determined by recrystallization to constant isotopic ratio and the amount of free plasma steroid was determined by equilibrium dialysis against Ringer's solution. Tritiated progesterone was undetectable in the pooled samples of CSF. The average concentration of tritiated 17-OHP in the CSF was 10.3% of the concurrent plasma level while the concentration of tritiated F was 22.5% of the concurrent plasma level. Plasma free steroid was found to be 2.2% for P, 6.3% for 17-OHP and 22.3% for F, showing a rough correlation between steroid entry into the CSF and free steroid concentration in plasma.

Studies on the transfer of steroid hormones across the blood-cerebrospinal fluid barrier in the Rhesus Monkey.

Indwelling canulae were placed in the lateral ventricles of the brains of six adult male rhesus monkeys, and the movement of estradiol-17beta (E2), testosterone (T), and 5alpha-dihydrotestosterone (DHT) across the blood-cerebrospinal fluid (CSF) barrier was measured. Serial samples of blood and CSF were collected every 30 minutes during a 6 hour infusion of the tritiated steroids, and the quantity of free steroid in the blood and CSF was determined by recrystallization to constant specific activity. During the course of the 6-hour infusion, the average CSF concentration of steroid, expressed as dpm/ml, was about 3.5% of the concurrent plasma level of E2, 1.6% of the concurrent plasma level of T, and 0.08% of the concurrent plasma level of DHT. It is proposed that these differences in steroid transfer can be attributed to differential binding of these steroids to testosterone-estrogen-binding globulin (TeBG) in plasma.

Cellular and humoral pathways in the neuroendocrine regulation of reproductive function.

PIP: Studies carried out in recent years, including those conducted by the author on the rhesus monkey, which have added more information on the possible cellular and humoral pathways by which the neural and endocrine functions concerned with reproductive phenomena are integrated are reviewed. The possible involvement of the circumventricular structures, especially the tanycyte ependyma and the pineal gland in the detection of the endogenous levels of gonadal hormones, and the cerebrospinal fluid (CSF) in the transmission of hormonal information to the various parts of the brain indicated further areas of research to be explored. Such exploration should be conducted in diverse, yet complimentary, disciplines so that the whole spectrum of events known to occur in the neuroendocrine regulation of reproduction can be studied.^ieng