Retrospective analysis of 19 patients with 6-Pyruvoyl Tetrahydropterin Synthase Deficiency: Prolactin levels inversely correlate with growth.

BACKGROUND: Pyruvoyl Tetrahydropterin Synthase (PTPS) Deficiency is the most common form of BH4 deficiency resulting in hyperphenylalaninemia. It can have variable clinical severity and there is limited information on the clinical presentation, natural history and effectiveness of newborn screening for this condition. METHODS: Retrospective data (growth and clinical parameters, biochemical and genetic testing results, treatment) were collected from 19 patients with PTPS deficiency in different centers, to evaluate biochemical and clinical outcomes. Descriptive statistics was used for qualitative variables, while linear regression analysis was used to correlate quantitative variables. RESULTS: Patients with PTPS deficiency had an increased incidence of prematurity (4/18) with an average gestational age only mildly reduced (37.8 ± 2.4 weeks) and low birth weight (-1.14 ± 0.97 SD below that predicted for gestational age). With time, weight and height approached normal. VALUES: All patients were identified by newborn screening for an elevated phenylalanine level. However, phenylalanine levels were normal in two whose testing was performed at or before 24 h of age. Sapropterin dihydrochloride treatment normalized phenylalanine levels. Molecular testing identified novel variants in the PTS gene, some of which present in more than one affected family. The neurotransmitter derivatives 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in the CSF were decreased in most cases except in 2 families with the peripheral form of PTPS deficiency. With time, HVA and 5HIAA became abnormally low in two of these patients requiring therapy. Prolactin (whose secretion is inhibited by dopamine) levels were elevated in several patients with PTPS deficiency and inversely correlated with the z-scores for height (p < 0.01) and weight (p < 0.05). Most patients with PTPS deficiency had delayed development early in life, improving around school age with IQs mostly in the normal range, with a small decline in older individuals. From a neurological standpoint, most patients had normal brain MRI and minor EEG anomalies, although some had persistent neurological symptoms. DISCUSSION: Patients with PTPS deficiency have not only an increased incidence of prematurity, but also decreased birth weight when corrected for gestational age. Hyperphenylalaninemia can be absent in the first day of life. Therapy with sapropterin dihydrochloride normalizes phenylalanine levels and neurotransmitter precursors can improve CSF neurotransmitter metabolites levels. Insufficient dopaminergic stimulation (as seen from elevated prolactin) might result in decreased height in patients with PTPS deficiency. Despite early delays in development, many patients can achieve independence in adult life, with usually normal neuroimaging and EEG.

Evaluation of screening for drug use using postmortem prolactin levels in serum and cerebrospinal fluid.

Prolactin (PRL) levels can usually be controlled by PRL-inhibiting psychiatric drugs that include anti-dopamine agents. However, the use of dopamine (DA) antagonists may lead to hyperprolactinemia under certain clinical conditions. The aim of this study was to investigate postmortem PRL levels as potential markers of drug abuse, especially that of DA antagonists, in autopsy cases. We examined 121 autopsy cases, excluding cases involving acute hypoxia/ischemia, such as asphyxia, because PRL concentrations are reportedly increased under acute hypoxic conditions. Detected drugs were classified as either DA antagonists, stimulants, psychotropic drugs other than DA antagonists, or other non-psychotropic drugs, and many cases had no detected drugs. Samples comprised blood collected from the right heart chamber and cerebrospinal fluid (CSF). PRL protein level was measured by chemiluminescent immunoassay, and PRL gene expression in the anterior pituitary of autopsy cases was analyzed by reverse transcription-polymerase chain reaction. The PRL-positive cell ratio in the anterior pituitary gland was also measured by immunohistochemical analysis. The results indicated that PRL levels in the serum and CSF were higher in DA antagonist cases than in other cases. PRL levels in the serum and CSF also correlated with the PRL gene expression in cases with abuse of DA antagonists. However, no significant difference in the PRL-positive cell ratio in the anterior pituitary gland was evident between any of the classes of drug-detected and drug-undetected cases. These results suggest that postmortem measurements of PRL transcription levels may be useful for diagnosing cases of DA antagonist use.

Prolactin selectively transported to cerebrospinal fluid from blood under hypoxic/ischemic conditions.

AIM: The aim of this study was to determine and to verify the correlation between the amount of prolactin (PRL) levels in the blood and in the cerebrospinal fluid (CSF) by various causes of death as an indicator for acute hypoxia in autopsy cases. It is to confirm the cause of the change in prolactin level in CSF by in vitro system. MATERIALS AND METHODS: In autopsy materials, the PRL levels in blood from the right heart ventricle and in the CSF were measured by chemiluminescent enzyme immunoassay, and changes in the percentage of PRL-positive cells in the pituitary gland were examined using an immunohistochemical method. Furthermore, an inverted culture method was used as an in vitro model of the blood-CSF barrier using epithelial cells of the human choroid plexus (HIBCPP cell line) and SDR-P-1D5 or MSH-P3 (PRL-secreting cell line derived from miniature swine hypophysis) under normoxic or hypoxic (5% oxygen) conditions, and as an index of cell activity, we used Vascular Endothelial Growth Factor (VEGF). RESULTS AND DISCUSSION: Serum PRL levels were not significantly different between hypoxia/ischemia cases and other causes of death. However, PRL levels in CSF were three times higher in cases of hypoxia/ischemia than in those of the other causes of death. In the cultured cell under the hypoxia condition, PRL and VEGF showed a high concentration at 10 min. We established a brain-CSF barrier model to clarify the mechanism of PRL transport to CSF from blood, the PRL concentrations from blood to CSF increased under hypoxic conditions from 5 min. These results suggested that PRL moves in CSF through choroidal epithelium from blood within a short time. PRL is hypothesized to protect the hypoxic/ischemic brain, and this may be because of the increased transportation of the choroid plexus epithelial cells.

Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency.

Aromatic L-amino acid decarboxylase deficiency (AADCD) is a rare, autosomal recessive neurometabolic disorder that leads to a severe combined deficiency of serotonin, dopamine, norepinephrine and epinephrine. Onset is early in life, and key clinical symptoms are hypotonia, movement disorders (oculogyric crisis, dystonia, and hypokinesia), developmental delay, and autonomic symptoms.In this consensus guideline, representatives of the International Working Group on Neurotransmitter Related Disorders (iNTD) and patient representatives evaluated all available evidence for diagnosis and treatment of AADCD and made recommendations using SIGN and GRADE methodology. In the face of limited definitive evidence, we constructed practical recommendations on clinical diagnosis, laboratory diagnosis, imaging and electroencephalograpy, medical treatments and non-medical treatments. Furthermore, we identified topics for further research. We believe this guideline will improve the care for AADCD patients around the world whilst promoting general awareness of this rare disease.

Genome-wide association study of prolactin levels in blood plasma and cerebrospinal fluid.

BACKGROUND: Prolactin is a polypeptide hormone secreted by the anterior pituitary gland that plays an essential role in lactation, tissue growth, and suppressing apoptosis to increase cell survival. Prolactin serves as a key player in many life-critical processes, including immune system and reproduction. Prolactin is also found in multiple fluids throughout the body, including plasma and cerebrospinal fluid (CSF). METHODS: In this study, we measured prolactin levels in both plasma and CSF, and performed a genome-wide association study. We then performed meta-analyses using METAL with a significance threshold of p < 5 × 10(-8) and removed SNPs where the direction of the effect was different between the two datasets. RESULTS: We identified 12 SNPs associated with increased prolactin levels in both biological fluids. CONCLUSIONS: Our efforts will help researchers understand how prolactin is regulated in both CSF and plasma, which could be beneficial in research for the immune system and reproduction.

Serum and cerebrospinal fluid prolactin levels in male and female patients with clinically-isolated syndrome or relapsing-remitting multiple sclerosis.

There is considerable evidence that prolactin (PRL) exerts immunomodulatory actions, thus being involved in the processes of autoimmune diseases. Animal studies suggest that elevated serum PRL levels may be related to neuroprotection or participate in remyelination after brain injury. To address this question, we estimated PRL levels in both serum and cerebrospinal fluid (CSF) in drug-free male and female patients with clinically-isolated syndrome (CIS) suggestive of MS (i.e. after the first episode) as well as in patients with relapsing-remitting (RR) MS after two or more relapses, and related them to clinical, paraclinical and laboratory data. Seventy two patients with RR MS and 80 patients with CIS in the age range 17-61 years were studied. PRL levels of patients were compared with 74 control subjects, separately for males and females. Significantly higher PRL levels in serum and CSF were found in female RRMS patients but not in males. Patients with CIS had normal PRL levels. No associations were found with disease activity, duration of illness, presence of active lesions or the presence of oligoclonal bands in CSF. The elevated PRL levels observed in female but not in male RRMS patients, or in patients with CIS, could be suggestive of a sexually dimorphic response to central nervous system injury as a result of an increased proneness of females to synthesise and release PRL, which is possibly linked to the relatively more favourable prognosis of MS in women.

Serial neurochemical measurement of cerebrospinal fluid during the human sexual response cycle.

Recent studies examining the neuroendocrine response pattern underlying the human sexual response cycle revealed transient activation of the sympathoadrenal system and a substantial, long-lasting increase in plasma prolactin concentrations following orgasm in men and women. Prolactin has been discussed as being part of a feedback mechanism that signals centers in the central nervous system, such as the dopaminergic system controlling sexual arousal. To further elucidate the central role of neuropeptides, biogenic monoamines and neurotransmitters in human sexual behavior, a serial cerebrospinal fluid (CSF)-sampling technique was implemented using a previously established experimental paradigm for sexual activity in a laboratory setting. In parallel with peripheral endocrine measures, lumbar CSF was drawn via an indwelling spinal catheter during the sexual response cycle in 10 healthy males and 10 age-matched controls, and analysed for prolactin, oxytocin, biogenic monoamines and/or their metabolites as well as inhibitory and excitatory neurotransmitter concentrations. Parallel to raised peripheral sympathetic activity, norepinephrine also increased in CSF during audiovisual, masturbation-induced sexual arousal and orgasm, and remained elevated for the remainder of the session (F(4,72) = 8.79, P = 0.000). In contrast, none of the other measures, in particular prolactin and dopamine or its metabolites, reflected significant alteration. In conclusion, the human sexual response cycle is characterized by an increase in sympathetic activity in plasma and CSF, and by pronounced secretion of plasma prolactin after orgasm. However, alterations in dopaminergic or peptidergic activity are not found in lumbar CSF, possibly due to local and restricted release in diencephalic and mesencephalic brain regions.

Changes in cerebrospinal fluid neurochemistry during pregnancy.

BACKGROUND: Little is known about changes in brain function that may occur during pregnancy. Studies in rodents and sheep suggest that several brain neurotransmitter and neurohormonal systems known to modulate anxiety may be altered during pregnancy. METHODS: Cerebrospinal fluid (CSF) and plasma samples were obtained from 21 women (during weeks 38-39 of pregnancy) who were undergoing elective cesarean section and from 22 healthy nonpregnant women. RESULTS: The CSF levels of g-aminobutyric acid (GABA) and 3-methoxy-4-hydroxyphenylglycolwere reduced in pregnant women. There were no changes in CSF glutamate, 5-hydroxyindoleactic acid, and homovanillic acid. There was a large increase in CSF prolactin in pregnant women and also a trend toward an elevation in CSF oxytocin. Levels of prolactin, but not oxytocin, in CSF and plasma were correlated in pregnant women. CONCLUSIONS: These results suggest that pregnancy alters regulation of brain GABA, norepinephrine, and prolactin, which may play a role in changes in vulnerability to anxiety and depression during pregnancy and postpartum. Prolactin circulating in the bloodstream seems to be the major source of CSF prolactin during pregnancy.

Prolactin levels in cerebrospinal fluid of patients with infantile spasms.

Infantile spasms are an age-related epileptic syndrome of infancy and are characterized by the combination of clusters of epileptic spasms and specific electroencephalographic findings. The etiology and the pathogenesis of the disease is still unclear. Prolactin has been thought to be specifically related to epileptic seizures. To investigate the possible mechanism of prolactin secretion in infantile spasms cerebrospinal fluid prolactin levels were examined. Fifteen patients with infantile spasms (10 females and five males), 3-16 months of age, were evaluated and compared with age- and sex-matched control subject. Cerebrospinal fluid samples for prolactin were obtained before and after treatment. The mean prolactin levels in the cerebrospinal fluid of the patients before therapy (3.25 +/- 1.48 ng/mL) was higher than the control group (2.38 +/- 0.89 ng/mL), and the difference between the two groups was statistically significant (P < 0.001). The mean prolactin level in the cerebrospinal fluid of the patients after therapy (4.69 +/- 1.47 ng/mL) was demonstrated to be higher than the mean prolactin level before therapy (3.25 +/- 1.48 ng/mL) and the difference between the two groups was statistically significant (P = 0.037). Elevation of cerebrospinal fluid prolactin levels before and after treatment in patients with infantile spasms provided evidence that the cerebrospinal fluid prolactin level is related with neuronal injury.

Lack of correlation between cerebrospinal fluid thyrotropin-releasing hormone (TRH) and TRH-stimulated thyroid-stimulating hormone in patients with depression.

BACKGROUND: It has been proposed that elevated central thyrotropin-releasing hormone (TRH) is associated with the blunted thyroid-stimulating hormone (TSH) response to TRH in patients with depression. Few studies have directly evaluated this relationship between central nervous system and peripheral endocrine systems in the same patient population. METHODS: 15 depressed patients (4 male, 11 female, 12 bipolar, and 3 unipolar) during a double-blind, medication-free period of at least 2 weeks duration, underwent a baseline lumbar puncture followed by a TRH stimulation test. Cerebrospinal fluid (CSF) TRH and serial serum TSH, free thyroxine, triiodothyronine, prolactin, and cortisol were measured. A blunted response to TRH was defined as a delta TSH less than 7 microU/mL. RESULTS: There was no significant difference in mean CSF TRH between "blunters" (2.82 +/- 1.36 pg/mL) and "non-blunters" (3.97 +/- 0.62 pg/mL, p = .40). There was no evidence of an inverse relationship between CSF TRH and baseline or delta TSH. There was no correlation between CSF TRH and the severity of depression or any other endocrine measure. CONCLUSIONS: These data are not consistent with the prediction of hypothalamic TRH hypersecretion and subsequent pituitary down-regulation in depression; however, CSF TRH may be from a nonparaventricular nucleus-hypothalamic source (i.e., limbic area, suprachiasmatic nucleus, brain stem-dorsal raphe) and thus, not necessarily related to peripheral neuroendocrine indices.

Effect of immunization against melatonin on prolactin concentrations and the timing of reproductive transitions in ewes.

The objective of this experiment was to develop a procedure for immunizing ewes against melatonin that would alter the effects of changing photoperiod on seasonal reproduction and prolactin secretion. Ewes were immunized against human serum albumin (HSA) as controls (n = 9) or a melatonin-human serum albumin conjugate (0.25 mg; n = 10) on December 14th (Day 0) and boosted 9 times. They were maintained on natural photoperiod and then transferred indoors and exposed to long days for 35 d, followed by short days for 146 d, long days for 93 d, and short days for a further 123 d. Antibody titers to melatonin (at a serum dilution of 1:1,250) were significantly higher in immunized ewes (27.3 +/- 6.6%) than controls (0.7 +/- 0.1%; P < 0.001). At the end of the experiment, antibody titers in immunized ewes (at dilution of 1:50) were higher in blood (43.7 +/- 8.2%) than in cerebrospinal fluid (10.8 +/- 3.9%; P < 0.05), and highly correlated (r2 = 0.746). Onset of the breeding season was advanced slightly after the second transfer from long to short days in immunized ewes (April 12 +/- 3 d) compared with controls (April 25 +/- 3 d; P < 0.05). Mean serum prolactin concentrations were lower (P < 0.05) in melatonin-immunized ewes compared with controls on natural photoperiod, after transfer from long to short days, during long days, and after the second transfer from long to short days. In conclusion, despite melatonin-immunization increasing antibody titers in blood and cerebrospinal fluid, and decreasing prolactin concentrations over much of the experiment, minimal effects on the timing of reproductive transitions in the ewes were evident. This discrepancy between the response of the prolactin and reproductive axes to melatonin immunization supports the hypothesis of a dual site of action of melatonin, with melatonin acting in the pituitary gland to mediate the effects of photoperiod on prolactin secretion and in the mediobasal hypothalamus to affect reproductive responses.

The uncoupled couple? Prolactin and CD4 lymphocytes in HIV infection.

The possible role of prolactin (PRL) in human immunodeficiency virus (HIV) infection is unknown, despite the modulatory role of this hormone in humoral and cell-mediated immune responses. Recent studies have evidenced: (a) intralymphocyte synthesis of dopamine (DA) which down-regulates their own proliferation and differentiation; (b) decreased DA but increased PRL concentrations in cerebrospinal fluid of HIV-infected men; and (c) diminished hypothalamic DA tone in HIV-infected men. The present hypothesis proposes that, in HIV-infected men, a diminished generalized DA tone exists to stimulate human lymphocyte proliferation and differentiation at a maximum possible rate by: (1) decreasing the inhibitory influence of intralymphocyte DA; and (2) maintaining pituitary and extrapituitary (i.e. lymphocyte) PRL synthesis and release as high as possible. If this hypothesis is correct, it may have a potentially important therapeutic implication: the possibility to rebuild the battered immune system in HIV-infected patients from inside the body in a physiologic manner by the parenteral administration of recombinant human PRL.

Central metabolic messengers and the effects of nutrition on gonadotrophin secretion in sheep.

Nutrition influences the reproductive axis via alteration of gonadotrophin secretion. However, a link between nutrition and the secretion of GnRH, which drives the axis, has yet to be established. The aim of the present study was to measure the change in the concentrations of metabolic substances in the cerebrospinal fluid of adult male sheep offered a diet designed to maintain constant gonadotrophin secretion (Group M; n = 6), or a diet known to increase gonadotrophin secretion (Group M + L; n = 6). On days 1, 3 and 10 of the dietary treatments, cerebrospinal fluid and jugular blood were sampled and analysed for metabolic fuels (glucose, amino acids and free fatty acids) and metabolic hormones (insulin, insulin-like growth factor I, GH, prolactin, cortisol and the thyroid hormones). On day 11 of the dietary treatment, LH pulse frequency and mean FSH concentrations in Group M + L had increased relative to Group M and to day 0. Plasma concentrations of prolactin and insulin on days 3 and 10, and glucose and insulin-like growth factor I on day 10, were higher in Group M + L than in Group M, but only cerebrospinal fluid concentrations of insulin, glucose and certain amino acids were affected by the dietary treatments on days 3 and 10. Cerebrospinal fluid, but not plasma, concentrations of aspartate, tyrosine, cystine, phenylalanine and arginine on day 3, and glutamine, gamma-aminobutyric acid, threonine, alanine on days 3 and 10, were higher in Group M + L relative to Group M. On day 10, plasma and cerebrospinal fluid concentrations of arginine, phenylalaine, proline, tyrosine, methionine and phosphoserine, but only the plasma concentrations of linoleic acid, aspartate and serine, were higher in Group M + L than in Group M. Concentrations of triiodothyronine, thyroxine, and cortisol in plasma and cerebrospinal fluid were not affected. These results show that the nutritional stimulation of gonadotrophin secretion is accompanied primarily by fluctuations in plasma and cerebrospinal fluid concentrations of insulin and certain amino acids, which suggests that, when nutritional status is improved, insulin, amino acids and possibly glucose interact to modulate GnRH secretion.

Prolactin and interleukin-6 in neuropsychiatric lupus erythematosus.

We investigated the levels of prolactin (PRL) and interleukin-6 (IL-6) in the cerebrospinal fluid (CSF) and serum of systemic lupus erythematosus patients with central nervous system involvement (CNS-SLE), and examined whether PRL and IL-6 have a relationship. Serum and CSF PRL and IL-6 were measured in the following groups of patients and controls: group I: seven patients with CNS-SLE; group II: three SLE patients without CNS involvement (non CNS-SLE); group III: 10 patients with neurocysticercosis; and group IV: six healthy women. The patients were clinically assessed. CSF PRL and IL-6 were elevated in group I (CNS-SLE) in comparison with all other groups (p<0.001). In addition, four of seven patients had higher levels of IL-6 and PRL in CSF than in serum. A positive correlation between PRL and IL-6 in CSF of SLE was observed (r=0.88, p<0.001). The mean serum PRL concentrations were not significantly different in all groups, but high levels of IL-6 were found in the serum of group I in comparison with groups II and IV (p<0.001). The serum levels of group III were not different from those of group I. These results demonstrate the presence of intrathecal synthesis and elevations of CSF PRL and IL-6 in active CNS-SLE involvement and indicate that measurements of CSF PRL and IL-6 may be useful in the evaluation of neuropsychiatric lupus erythematosus.

Prolactin levels in the cerebrospinal fluid of patients with HIV infection and AIDS.

The objective of this study was to assess the levels of prolactin (PRL) in cerebrospinal fluid (CSF) of HIV-infected patients with regard to nonHIV-infected patients, and to assess the levels of prolactin in the CSF of HIV-infected patients with and without neurological HIV-involvement. Seventeen HIV-infected patients with different degrees of immunological and neurological involvement were studied. A second group of six HIV-seronegative patients with varying clinical conditions requiring lumbar punctures were included as controls. CSF was collected from patients and controls. Patients were studied neurologically and neuropsychologically, and computed tomography of the brain were performed. They were staged according to CDC clinical classification for HIV infection, and on the basis of tomographic findings into one of five stages. An additional classification for neurological involvement in AIDS was used. CD4+ cell counts, CSF studies, serum-prolactin levels and CSF-prolactin levels were performed as principal laboratory tests. CSF PRL concentrations were significantly higher in the HIV-infected group (n = 17) than the nonHIV infected control group (n = 6) (mean +/- s.d.; 5.77 +/- 2.22 vs. 3.53 +/- 0.69 x 10(-6) g l-1, respectively; p = 0.009, Mann-Whitney U-test). Moreover, even CSF-PRL concentration was higher in HIV-infected patients without cognitive impairment (stage 0 of the clinical classification), (n = 12) in comparison with nonHIV infected controls (n = 6) (mean +/- s.d.; 5.51 +/- 2.31 vs. 3.53 +/- 0.69 x 10(-1) g l-1, respectively; p = 0.028, Mann-Whitney U-test). There was a good correlation between serum and CSF-PRL levels in HIV-infected patients when measured by the Spearman Rank Test (rs = 0.773; p = 0.005). PRL raised serum levels were found in 4 out of 13 patients (30.73%). We conclude that higher levels of CSF-PRL are more frequently found in HIV-infected patients in comparison to uninfected controls. High levels of circulating PRL were also found in HIV-infected patients corroborating results from other work. A good correlation coefficient was found between circulating and CSF-PRL levels in HIV-infected patients, suggesting that disruption of the blood-brain barrier might account for a possible pathogenic mechanism.

Using age-appropriate prolactin levels to diagnose children with seizures in the emergency department.

OBJECTIVE: To assess the utility of serum and cerebrospinal fluid (CSF) prolactin levels for identifying children who have experienced seizures. METHODS: A prospective cohort study was performed in a pediatric ED at an urban children's hospital. A convenience sample of children underwent blood and CSF analyses in the ED over a 2-year period. RESULTS: Thirty-five children (aged 3 months-15 years) with generalized tonic-clonic seizures and 48 ill control patients were studied. Both groups included febrile and afebrile patients. The patient characteristics in the seizure and control groups were similar with respect to age, fever, current medications, and blood, urine, and CSF cultures. When serum prolactin levels were assigned age-adjusted dichotomous values of "elevated" or "normal," the rates of elevation between the seizure and control patients were different (p < 0.001). The positive and negative predictive values of these age-adjusted levels were 68% (95% CI 47-85%) and 76% (95% CI 61-87%), respectively. The mean CSF prolactin levels of the seizure and control groups were not significantly different. In addition, there was no single threshold CSF prolactin level that could delineate seizure patients from control patients. CONCLUSIONS: Age-adjusted serum prolactin levels are useful only as an adjunct in the prospective evaluation of the individual pediatric patient for epileptic seizure activity. CSF prolactin levels are not useful in the diagnosis of generalized seizures in children in the acute care setting.

Contrasting neuroendocrine responses in depression and chronic fatigue syndrome.

Hypothalamic-pituitary-adrenal (HPA) axis and central 5-HT function were compared in chronic fatigue syndrome (CFS), depression and healthy states. 10 patients with CFS and 15 patients with major depression were matched for age, weight, sex and menstrual cycle with 25 healthy controls. Baseline-circulating cortisol levels were highest in the depressed, lowest in the CFS and intermediate between the two in the control group (P = 0.01). Prolactin responses to the selective 5-HT-releasing agent d-fenfluramine were lowest in the depressed, highest in the CFS and intermediate between both in the healthy group (P = 0.01). Matched pair analysis confirmed higher prolactin responses in CFS patients than controls (P = 0.05) and lower responses in depressed patients than controls (P = 0.003). There were strong inverse correlations between prolactin and cortisol responses and baseline cortisol values. These data confirm that depression is associated with hypercotisolaemia and reduced central 5-HT neurotransmission and suggest that CFS may be associated with hypocortisolaemia and increased 5-HT function. The opposing responses in CFS and depression may be related to reversed patterns of behavioural dysfunction seen in these conditions. These findings attest to biological distinctions between these disorders.

Immunocytochemical demonstration of prolactin interaction with choroid plexus in aging and acute hyperprolactinemia.

Prolactin (PRL) exerts a direct effect on the central nervous system, reaching the PRL-responsive brain regions via cerebro-spinal fluid (CSF). The hormone enters the CSF by a specific receptor-mediated transport mechanism that is localized on the epithelium of the choroid plexus (CP) of brain ventricles. PRL interactions with the CP in aging were examined in young (3-month) and old (27-month) female Wistar rats using immunocytochemistry (immunogold technique). The enhancement of PRL uptake by the CP in animals at both ages was achieved by the modelling of acute hyperprolactinemia. A great age-related difference was found in the intensity of immunocytochemical reaction under activated conditions, the uptake of PRL by CP being significantly higher in young animals than in old. The character of the colloidal gold particle distribution in different components of CP epithelial cells appeared to be the same in both age groups. The weakening of PRL-transporting capacity in the CP of old animals may constitute one aspect of the alteration of neuroendocrine regulation in the CP-CSF system that occurs during aging.

Prolactin enhancement of its own uptake at the choroid plexus.

The choroid plexus contains PRL receptors that function in part to transport PRL from the blood into the cerebrospinal fluid (CSF). The blood PRL concentration of female rats was altered by 1) three daily injections of haloperidol (chronic hyperprolactinemia) with or without bromocriptine administration 4 h before death, 2) bromocriptine alone for 4 h (acute hypoprolactinemia), and 3) a single vascular injection of ovine PRL (acute hyperprolactinemia). Changes in the uptake of PRL by the choroid plexus was assessed by quantitative in vivo autoradiography after the injection of radiolabeled PRL. Correlation of changes in PRL uptake at the choroid plexus with changes in PRL transport from blood to CSF was evaluated by subjecting CSF samples to sodium dodecyl sulfate-polyacrylamide gel electrophoresis after vascular injection of radiolabeled PRL. Autoradiography revealed that both chronic and acute hyperprolactinemia resulted in a significant increase in the uptake of radiolabeled PRL by the choroid plexus compared to that in untreated control animals. In contrast, bromocriptine had no effect on PRL uptake at the choroid plexus relative to that in control (untreated) animals. Chronic hyperprolactinemia, but not acute hyperprolactinemia, resulted in a significant increase in the transport of radiolabeled PRL from the blood to the CSF compared to that in untreated controls. The results are consistent with the up-regulation of PRL receptors in the choroid plexus by circulating PRL and the consequent augmentation of transport of PRL from blood to CSF.