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.

Photoperiod modulates access of 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) to the brain and its effect on gonadotropin and thyroid hormones in adult ewes.

The effects of photoperiod on the cerebrospinal fluid (CSF) concentration of six ortho-substituted polychlorinated biphenyls (PCBs: PCB28, PCB52, PCB101, PCB138, PCB153, and PCB180), the effects of an orally administered low dose of PCB153 (0.3mg/kg, three times a week for three weeks) on PCBs and thyroid hormones (THs) concentrations in the CSF and plasma, and the release of luteinizing hormone (LH) were determined in ovariectomized, estradiol-implanted ewes (2.5 years old) maintained indoors under artificial long day (LD, 16L: 8D) and short day (SD, 8L: 16D) conditions. Concentrations of two PCBs (PCB28 and PCB153) in the plasma and four PCBs in the CSF (PCB101, PCB138, PCB153, and PCB180) were significantly higher during LD than SD. Following PCB153 treatment, its concentration in the plasma was higher in SD (1.2 ± 0.3 ng/ml) than LD (0.2 ± 0.05 ng/ml), but similar in the CSF (10.2 ± 3.7 pg/ml vs. 13 ± 0.7 pg/ml) under both photoperiods. During SD, the concentration of PCB153 in the CSF was higher in treated animals than controls, while no differences were noted under LD. These findings indicate that in ewes, exposure of the brain to more highly chlorinated, ortho-substituted PCBs may be modulated by photoperiod. PCB153 treatment had no effect on plasma THs, but reduced total triiodothyronine concentration during LD and free thyroxine during SD in the CSF. Under both photoperiods, PCB153 reduced basal plasma LH and reinforced the inhibition of pulsatile LH release during LD. As PCB153 reduced LH and THs (which are involved in the seasonal control of reproduction in ewes), it may have a braking effect on seasonal transitions between active and inactive phases of reproduction.

Concentrations of estradiol in ewe cerebrospinal fluid are modulated by photoperiod through pineal-dependent mechanisms.

In the ewe, seasonal anestrus results from an increased responsiveness of the hypothalamus to the negative feedback of estradiol (E2) on the gonadotropic axis under long-day conditions. However, this seasonal effect could also depend upon variable uptake of steroids by the brain. The aim of the present experiment was to compare the concentration of E2 in the blood plasma and in the cerebrospinal fluid (CSF) from the third ventricle in groups of ovariectomized, estradiol treated ewes maintained under short day (SD) or long day (LD) conditions and to study the involvement of the pineal gland in this photoperiodic regulation. Pinealectomized and sham-operated ewes were equipped with an intracerebral cannula to sample the CSF. The plasma E2 concentrations showed no difference between LD and SD in sham-operated and pinealectomized animals. In contrast, in the CSF, E2 concentration was higher in the LD than the SD group, and pinealectomy suppressed this effect of photoperiod. Concomitantly, the stimulatory effect of SD on luteinizing hormone levels observed in sham-operated ewes was abolished by pinealectomy. The results demonstrate that LD increases the E2 concentration in the CSF by a mechanism involving the pineal gland.

Gonadotropin-releasing hormone in third ventricular cerebrospinal fluid of the heifer during the estrous cycle.

The release profile of GnRH in cerebrospinal fluid (CSF) and its correlation with LH in peripheral blood of ovary-intact heifers during the estrous cycle were investigated. A silicon catheter was placed into the third ventricle of six heifers using ultrasonography. During the mid-luteal phase, the heifers were injected with prostaglandin F(2alpha) to induce luteolysis. Surges of CSF GnRH (66.7 h after prostaglandin F(2alpha) administration) and peripheral LH (66.3 h) occurred simultaneously and were coincident with the onset of estrus (67.0 h). Duration of elevated GnRH concentration considerably overlapped with the estrous phase in each of the heifers. Mean pulse frequencies of both GnRH and LH were significantly higher during the proestrous and early luteal phases than during the mid-luteal phase, while mean concentration and pulse amplitude of both GnRH and LH were not different between these three phases. Of all the GnRH pulses identified, more than 80% were accompanied by an LH pulse during the proestrous and early luteal phases. However, the proportion of GnRH pulses that were coincident with an LH pulse during the mid-luteal phase decreased to 60%. The results clearly demonstrate that a dynamic (pulse) and longer-term (surge) changes of GnRH release into CSF are physiologically expressed during the estrous cycle in heifers, and the pattern of pulsatile GnRH secretion in heifers depends upon their estrous cycle.

Diagnostic and prognostic significance of lactate dehydrogenase in cerebrospinal fluid in patients of meningitis.

Activity of lactate dehydrogenase was measured in cerebrospinal fluid in 60 cases of meningitis (35 pyogenic, 18 tuberculous and 7 viral). Thirty age and sex matched healthy controls were taken to find out its diagnostic and prognostic significance in meningitis. The cerebrospinal fluid lactate dehydrogenase activity was significantly higher (p < 0.001) in cases of pyogenic meningitis and tuberculous meningitis as compared to the control group. The maximum elevation was seen on the 1st day in all types of meningitis but the activity declined significantly thereafter in patients of pyogenic meningitis who recovered without complications. However, in 2 cases of pyogenic meningitis and 5 cases of tuberculous meningitis who survived with complications, the lactate dehydrogenase activity on subsequent estimations increased serially. Further, the basal lactate dehydrogenase activity in 9 cases of pyogenic meningitis (who expired) was higher than those who survived without complications. The basal lactate dehydrogenase activity in pyogenic meningitis was significantly higher (p < 0.05) as compared to tuberculous meningitis and viral meningitis patients (p < 0.02) in this study.

In vivo alterations in the gonadotropin-releasing hormone pulse generator and the secretion and clearance of luteinizing hormone in the uremic castrate rat.

To investigate the mechanisms subserving the reported alterations in the pulsatile release of LH in uremia, we simultaneously studied endogenous accumulation of GnRH in the pituitary gland and the secretion and clearance of LH in vivo in experimentally uremic, orchidectomized rats. The temporal pattern of GnRH secretion was assessed by intrapituitary microdialysis, the dynamics of plasma LH by continuous exchange transfusion. Studies were performed in rats rendered uremic by subtotal nephrectomy (n = 8) and control rats which were either fed ad libitum (n = 8) or pair-fed with the uremic animals (n = 8). Blood samples were obtained at 5-min and microdialysate samples at 10-min intervals over a period of 270 min. The pulsatile secretory characteristics of GnRH and LH and the half-life of plasma LH were estimated by multiple-parameter deconvolution analysis. The temporal relationship between the hormone concentrations and between the secretory events of GnRH and LH was assessed by cross-correlation analysis and hypergeometric coincidence analysis. We observed that: (1) the estimated half-life of plasma LH was prolonged in uremic (59 +/- 10 min) rats compared to ad libitum-fed (17 +/- 3 min, p = 0.014) and pair-fed controls (19 +/- 3 min, p = 0.025); (2) the LH production rate was decreased in uremic animals (18 +/- 5 ng/ml.270 min) compared to ad libitum-fed (37 +/- 4 ng/ml.270 min, p = 0.002) and pair-fed controls (48 +/- 9 ng/ml.270 min, p = 0.0006); (3) the reduction of LH secretion rate in the uremic animals was accounted for by a decrease in detectable LH pulse frequency (2.1 +/- 0.2 peaks/h) compared to ad libitum-fed (3.1 +/- 0.1 peaks/h, p = 0.01) and pair-fed controls (2.8 +/- 0.2 peaks/h, p = 0.06) and a diminished mass of hormone released per burst (uremic 1.8 +/- 0.2 ng/ml, ad libitum-fed 2.6 +/- 0.3 ng/ml, p = 0.05, pair-fed 3.8 +/- 0.8 ng/ml, p = 0.025); (4) the secretion rate of GnRH was reduced to a similar degree in uremic rats (180 +/- 15 pg/tube.270 min, p = 0.04) and pair-fed controls (170 +/- 26 pg/tube.270 min, p = 0.04) compared to ad libitum-fed controls (270 +/- 36 pg/tube.270 min). In contrast to the reduced number of detectable LH secretory events, the frequency of GnRH secretory peaks in uremic rats was not different from ad libitum-fed and pair-fed controls.(ABSTRACT TRUNCATED AT 400 WORDS)

Cerebrospinal fluid and blood concentrations of luteinizing hormone, follicle stimulating hormone and prolactin following castration of adult male rats.

Comparative levels of LH, FSH, and PRL in the serum and cerebrospinal fluid (CSF) of adult male rats were studied at different periods following castration. Intact and sham-operated animals served as controls. Blood and CSF were collected at 1, 3, 7, 14, 21, 28, 35 and 46 days following castration. The CSF was collected via cisterna-magna puncture, while the blood was collected from abdominal aorta. Serum gonadotropins increased progressively beginning day 1 post-castration to reach maximum by day 35 or 46 post-castration. Sham operation and castration did not affect mean CSF, LH and FSH levels compared to intact controls. Analysis of the temporal pattern of serum and CSF gonadotropin levels following castration revealed significant positive correlation between CSF and serum LH (r = 0.58) and FSH (r = 0.64) levels respectively. The data suggest that CSF gonadotropins may be derived from systemic circulation. Serum PRL levels were not affected by castration, but CSF PRL levels were significantly reduced at days 28, 35 and 46 post-castration compared to intact controls. CSF PRL levels showed negative correlation with serum LH and FSH levels but failed to show a correlation with serum PRL levels. Hypothalamic norepinephrine turnover rate increased at days 28, 35 and 46 post-castration. Hypothalamic dopamine contents and turnover rates were reduced at days 21 and 28 post-castration. It is suggested that CSF PRL may have a role in the regulation of serum gonadotropins.

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.

LH and FSH levels in serum and cerebrospinal fluid (CSF) of human fetus.

The concentration of LH and FSH was measured in the fetal blood and cerebrospinal fluid (CSF) of 4 human fetuses between 21 and 24 weeks old. A comparison was made with 6 post menopausal females. In one fetus the serum and CSF levels of both hormones were determined after administration of 200 micrograms LRH and 400 micrograms TRH. The mean serum fetal levels of LH and FSH of 76.6 mIU/ml (range, 29.5-152.0) and 30.5 mIU/ml (range 3.1-60.3), respectively, were not significantly different from those of postmenopausal females, whereas the fetal CSF levels of these hormones were significantly higher (p less than 0.02) than those of post menopausal females. The serum to CSF ratios for the fetal LH and FSH were 4.6 +/- 1.1 and 2.4 +/- 0.61 respectively, significantly different (p less than 0.02 and p less than 0.001 respectively) from those of post menopausal females (29.1 +/- 6.6 for LH and 50.9 +/- 10.9 for FSH). In one fetus LRH did not provoke any change in circulating FSH and LH level 20 min. after administration, while a slight increase of these hormone in the CSF was observed. These data suggest that the permeability of blood-CSF barrier to gonadotropins in the fetus seems to be higher than in the adult who has no blood-CSF barrier (B--CSF--B) alterations.

LH and FSH in human cerebrospinal fluid.

LH and FSH of cerebrospinal fluid (CSF) and serum were radioimmunologically measured. Samples were obtained simultaneously from 116 subjects of the following groups: A. 22 patients with non-endocrine diseases, B. 18 patients with cranial diabetes insipidus (DI) of whom 4 with metastatic carcinomas, C. 5 patients with primary empty sella syndrome, D. one with hydatiform mole, and E. 70 patients with pituitary adenomas, i.e. growth hormone--or prolactin-secreting or "non-secreting" adenomas, of whom 38 patients with invasive and 32 with enclosed adenomas. LH and FSH are normal constituents of CSF and their CSF levels poorly correlates with the serum ones (LH r = 0.477 p less than 0.01). Enclosed adenomas with SSE showed low levels of LH in CSF. High CSF-gonadotropins concentrations (above 4.0 mIU/ml) with a low serum/CSF ratio (below 3) was frequently, but not constantly found in patients with invasive adenomas and are not indicative per se of this diagnosis. Some patients with brain metastasis from breast carcinoma and DI, or with non-tumoral diseases and DI showed similar high patterns of CSF gonadotropins though the serum levels were within normal range. This suggests that local vascular mechanisms, including the retrograde circulation of gonadotropins from the pituitary to the hypothalamus, influence the blood-brain barrier much more than the release of gonadotropins into the systemic blood circulation.

Serum and CSF concentrations of testosterone and LH related to negative feedback in male rhesus monkeys.

Testosterone and LH concentrations were studied in blood and cerebrospinal fluid (CSF) in 8 adult male rhesus monkeys. All males were initially intact and 7 were subsequently castrated and implanted with an ascending series of testosterone capsules. In 4 of the males, serum testosterone levels were significantly higher at 21.00 h than at 09.00 h when the monkeys were intact. Following castration of these 4 males, 4-10 testosterone capsules produced serum concentrations similar to those previously found at 09.00 h; levels equivalent to those at 21.00 h were attained with 12-14 capsules. The proportion of unbound testosterone in serum represented 2% of total serum concentrations, but increased to 4% at high serum concentrations (12-14 capsules). In contrast, the proportion of unbound testosterone in CSF represented 100% of CSF levels. The levels of testosterone in CSF remained at values equal to 2-3% of total serum concentrations throughout the study. The levels of unbound serum testosterone and testosterone levels in the CSF were similar throughout the study in 3 of the 4 monkeys. In the fourth animal, supraphysiological serum testosterone levels occurred with 12 and 14 implants, and, at this time, the level of testosterone in CSF was less than the concentrations of unbound testosterone in serum. Following an intravenous bolus injection of testosterone, the steroid rapidly entered CSF when either 6 or 14 capsules were in place. Although the clearance of testosterone was similar within either compartment during both treatments, the half-life of testosterone in CSF was significantly shorter than in serum at high serum concentrations (14 capsules). Serum and CSF LH levels rose rapidly after castration, reaching maximal levels 8-12 days later with CSF LH levels consistently representing 2-3% of serum concentrations. Post-castration LH concentrations did not change until nocturnal testosterone levels were reached (12-14 capsules), when LH levels were suppressed in both serum and CSF. Subsequent reduction of serum testosterone levels (to 6 capsules) maintained the low LH concentrations. Seemingly, high testosterone concentrations in either serum or CSF, equivalent to nocturnal levels in intact males, were required to initiate LH suppression, but not to maintain it.

Adenohypophyseal hormone levels in the cerebrospinal fluid of patients with pituitary disease.

Measurement of adenohypophyseal hormones in the cerebrospinal fluid (CSF) was recently proposed as an useful procedure to differentiate pituitary intra and extrasellar tumors. So far, data reported are conflicting. We measured the concentrations of GH, TSH, LH and PRL in CSF and plasma in 30 controls and in 37 patients with various pituitary diseases (18 intrasellar adenomas, 14 extrasellar adenomas and 5 empty sella syndromes). The concentrations of examined hormones in CSF were very low or undetectable in all control subjects. In most patients with pituitary tumors, adenohypophyseal hormones were found to be present in CSF, in great amounts. No significant differences were found between intra and extrasellar tumors. In agreement with recently reported data, no significant correlation was found between GH, TSH, FSH and LH levels in CSF and plasma, while a significant correlation (p less than 0.01) was obtained between CSF and plasma levels of PRL, either in all patients or in those with extrasellar tumors only. All patients bearing an empty sella had PRL detectable in CSF: in 2 cases PRL levels were very high. In conclusion our data do not confirm that measurement of adenohypophyseal hormones in CSF represents an useful screening to differentiate tumors with extrasellar extension. PRL data deserve interest in order to gain understanding of the hormone dynamics between CSF and vascular compartments.

Differential penetration of three anterior pituitary peptide hormones into the cerebrospinal fluid of rhesus monkeys.

This paper demonstrates marked differences between blood levels and those in the CSF for three anterior pituitary peptide hormones, prolactin, luteinizing hormone (LH) and adrenocorticotrophin (ACTH) in the rhesus monkey. CSF levels of endogenous prolactin (measured by radioimmunoassay) are about 20% of those in the blood, and this proportion remains constant under conditions of persistent ('steady-state') hyperprolactinaemia (induced by injecting sulpiride). Acutely elevating prulactin, by either an intravenous injection of exogenous ovine prolactin, or sulpiride, resulted in similar rates of entry by prolactin into the CSF, suggesting that retrograde portal flow is not an important mechanism. LH, measured by bioassay, is also present in the CSF, but the CSF/blood ratio is 5-10 times less than for prolactin. Castration, causing blood LH levels to rise, resulted in equivalent changes in CSF, so that the ratio remains constant, though still much lower than for prolactin. There are significant correlations between individual animals in the blood and CSF content of prolactin and LH. In marked contrast, whilst ACTH is found (by cytochemical assay) in the CSF of both intact and adrenalectomized monkeys, no significant change in CSF levels occurs despite 10-fold changes in the plasma of adrenalectomized animals following withdrawal of cortisol. Nor is there any correlation between blood and CSF ACTH levels over a wide range of concentrations. These results show that each of the three peptides studied has a distinct pattern of entry into the CSF from the vascular compartment.

Adenohypophyseal hormones in the CSF.

The presence of adenohypophyseal hormones in human cerebrospinal fluid (CSF) had been firmly established by radioimmunoassay procedures. The hormones can originate from the adenohypophysis itself and from brain, as well as from peripheral sites of production. These peptide hormones enter the CSF through the choroid plexus or by direct secretion. The hormones entering by direct secretion into the CSF have a higher CSF-blood ratio than the hormones entering through the choroid plexus. Elevated CSF levels of adenohypophyseal hormones are most likely to occur in the presence of hormone-producing pituitary tumors with suprasellar extension. Although the CSF concentrations of adenohypophyseal hormones may merely reflect their blood concentrations, it is more likely that these hormones also have paracrine as well as endocrine effects.

Anterior pituitary hormone levels in the cerebrospinal fluid of patients with pituitary and parasellar tumors.

Cerebrospinal fluid (CSF) concentrations of growth hormone, prolactin (PRL), adrenocorticotropin, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, and the glycoprotein hormone alpha subunit were determined in 30 patients with pituitary and parasellar tumors. Although many of the patients had elevated hormone levels, no differentiation between patients with intrasellar tumors and those with pituitary tumors with suprasellar extension or primary suprasellar tumors could be made based upon the absolute CSF hormone concentration. A highly significant correlation between serum and CSF PRL concentrations was found (r = 0.87; P less than 0.001), suggesting that CSF PRL is derived from the serum. No correlation was found between the serum and CSF concentrations of the other anterior pituitary hormones.

Testosterone, cortisol, prolactin and bioactive luteinizing hormone in day and night samples of cerebrospinal fluid and serum of male rhesus monkeys.

Testosterone (T), cortisol (C), prolactin (PRL) and bioactive luteinizing hormone (bLH) were found to be normal constituents of the cerebrospinal fluid (CSF) of all the 15 adult male rhesus monkeys studied. The CSF levels of the hormones showed a good correlation with their serum levels. The geometric mean values of circulating levels of T, PRL, bLH in all the animals studied were significantly lower in the samples of the two body fluids collected between 09.00 and 11.00 h as compared with those collected between 21.00 and 23.00 h. C levels were higher during the day as compared with the night samples. This marked difference between the day and night levels of the circulating hormones was not observed in a few individuals which suggests that the diurnal changes in circulating levels of these hormones may not occur as a rule in all rhesus monkeys. The serum:CSF ratios for C, PRL and bLH did not vary significantly between the day and night samples of the body fluids as they did for T. This suggests that T is poorly transferred from the blood to the CSF as compared with the other 3 hormones studied. The possible pathways by which the hormones are transferred into the CSF and the functional significance of their presence in the CSF are discussed.

Bioactive luteinizing hormone in the plasma and cerebrospinal fluid of female rhesus monkeys.

An in vitro bioassay method using Leydig cells from mouse testes has been validated for quantitating lutenizing hormone (LH) in the plasma and cerebrospinal fluid (CSF) of normally menstruating and ovariectomized rhesus monkeys. In all six normally menstruating monkeys studied, the mid-cycle peak of plasma LH coincided with the estradiol peak in blood samples taken at 24-hour intervals. Blood samples collected at 4-hour intervals during the periovulatory period showed multiple peaks of both bioactive LH and estradiol, and the major estradiol peak preceded the major bioactive LH peak by about 16 h. The plasma progesterone levels were about 1 ng/ml at the time of LH peak. Bioactive LH was detected also in the CSF samples of both intact and ovariectomized monkeys. The levels of LH in CSF were not elevated in the gonadectomized monkeys although their plasma LH levels were markedly increased.

Suprasellar extension of tumour associated with increased cerebrospinal fluid activity of LH and FSH.

A 65 year old man with pituitary adenoma, partial hypopituitarism and normal serum FSH and LH concentration is described. LH (but not FSH) partially increased following the administration of LH-RH. Subsequent FSH and LH assays of the cerebrospinal fluid, however, showed a high and correctly predicted suprasellar extension of the tumour.

Effect of chlorpromazine treatment on prolactin levels in cerebrospinal fluid and plasma of psychotic patients.

In psychotic patients, levels of prolactin in cerebrospinal fluid (CSF) and plasma were determined by radioimmunoassay before and after 2 and 4 weeks of treatment with chlorpromazine (CPZ). CPZ was given in one of three randomly selected fixed doses: 200, 400 or 600 mg per day. Before treatment, low levels of immunoreactive prolactin-like material (PRL) were found in the CSF of most patients. The concentration in CSF was about 20% of the plasma level. In CSF but not in plasma, the pre-treatment level of PRL was significantly higher in women than in men. During CPZ treatment, the PRL levels in CSF as well as in plasma were significantly elevated in both sexes after 2 as well as 4 weeks. The elevation was significantly greater in women, and was similar at the two time intervals studied. There was a significantly positive relationship between the dose of CPZ and the PRL elevation in both body fluids in both men and women. Before treatment no significant correlation between the PRL levels in CSF and plasma in either sex could be observed. During treatment, there was a significant correlation between the change in PRL levels in CSF and plasma in both men and women. CPZ treatment did not increase the levels of total protein, follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH) or oestradiol-(17-beta) in either the CSF or the plasma.