Thyrotropin-releasing Hormone Therapy Research Articles

P-MD008. Differential effects of thyrotropin releasing hormone on motor performance and motor adaptation in patients with spinocerebellar degeneration

Introduction . The cerebellum is known to play an important role in motor adaptation, including prism adaptation. Thyrotropin releasing hormone (TRH) has been used as a treatment for cerebellar ataxia in Japan. However, effects of TRH on cerebellar adaptation function have not been studied. Herein, we studied effects of TRH treatment on the prism adaptation task. Methods . Eighteen patients with spinocerebellar degeneration (SCD), including MSA-C, SCA3, SCA6, SCA31, participated in this study. The participants received intravenous injection of 2 mg/day protirelin tartrate once a day for 14 days. In the prism adaptation task, the participants reached to the target on the screen wearing wedge prisms. We compared the Scale for Assessment and Rating of Ataxia (SARA), baseline errors and the after effect (AE) of the prism adaptation task between before and after TRH therapy. We also performed correlation analysis between improvement of baseline errors or AE in the adaptation task, and 1) improvement of the total SARA score, 2) improvement of upper limb ataxia score, and 3) improvement of axial ataxia score. Results . TRH therapy significantly improved SARA (p = 0.005). Multiple regression analysis revealed that improvement of SARA score was mainly due to improvement of “Stance” category score. TRH decreased baseline errors of the prism adaptation task (p = 0.021), while unaffected AEs (p = 0.25). Correlation analysis revealed no significant correlation between any factors. Conclusion . TRH differentially affected cerebellar ataxic symptoms including baseline reaching performance in the prism adaptation task, whereas TRH did not affect the learning process of prism adaptation. Different cerebellar functional aspects may underlie the learning process of motor adaptation and simple motor performance (classical ataxia).

Differential effects of thyrotropin releasing hormone (TRH) on motor execution and motor adaptation process in patients with spinocerebellar degeneration

BackgroundThe cerebellum is known to play a crucial role in sensori-motor adaptation, which includes the prism adaptation. TRH has been widely used as a treatment for cerebellar ataxia in Japan, however effects of TRH on cerebellar adaptation process have not been studied. Here, we studied effects of TRH treatment on the prism adaptation task. MethodsEighteen spinocerebellar degeneration (SCD) patients participated in this study. The participants received intravenous injection of 2 mg/day protirelin tartrate once a day for 14 days. In the prism adaptation task, the participants reached to the target on the screen wearing wedge prisms. We compared the Scale for Assessment and Rating of Ataxia (SARA), baseline errors and the aftereffect (AE) of the prism adaptation task between before and after TRH therapy. ResultsTRH therapy improved SARA significantly (p = .005). Multiple regression analysis revealed that improvement of SARA score was mainly due to improvement of “Stance” category score. TRH decreased baseline errors of the prism adaptation task (p = .021), while unaffected AEs (p = .252). ConclusionTRH differentially affected clinical cerebellar ataxia including baseline reaching performance in the prism adaptation task, whereas TRH did not affect the learning process of prism adaptation. Different cerebellar functional aspects may underlie the learning process of sensori-motor adaptation and simple motor execution (clinically evaluated cerebellar ataxia).

New quantitative method for evaluation of motor functions applicable to spinal muscular atrophy

ObjectiveThe aim of this study was to develop and introduce new method to quantify motor functions of the upper extremity. MethodsThe movement was recorded using a three-dimensional motion capture system, and the movement trajectory was analyzed using newly developed two indices, which measure precise repeatability and directional smoothness. Our target task was shoulder flexion repeated ten times. We applied our method to a healthy adult without and with a weight, simulating muscle impairment. We also applied our method to assess the efficacy of a drug therapy for amelioration of motor functions in a non-ambulatory patient with spinal muscular atrophy. Movement trajectories before and after thyrotropin-releasing hormone therapy were analyzed. ResultsIn the healthy adult, we found the values of both indices increased significantly when holding a weight so that the weight-induced deterioration in motor function was successfully detected. From the efficacy assessment of drug therapy in the patient, the directional smoothness index successfully detected improvements in motor function, which were also clinically observed by the patient’s doctors. ConclusionWe have developed a new quantitative evaluation method of motor functions of the upper extremity. Clinical usability of this method is also greatly enhanced by reducing the required number of body-attached markers to only one. This simple but universal approach to quantify motor functions will provide additional insights into the clinical phenotypes of various neuromuscular diseases and developmental disorders.

Successful Hyperbaric Oxygen Therapy with Thyrotropin-Releasing Hormone Therapy for Delayed Neuropsychiatric Sequelae after Acute Carbon Monoxide Poisoning: A Case Study

Delayed neuropsychiatric sequelae (DNS) after acute carbon monoxide (CO) poisoning is a complication of CO intoxication. Hyperbaric oxygen (HBO) therapy is one of the only established treatments for CO poisoning, but as there is no specific treatment for DNS, the prognosis of DNS patients is generally poor. A 40-year-old male patient, following attempted suicide by CO poisoning, was referred to our department after having received HBO therapy at another hospital, but treatment had been subsequently discontinued due to patient agitation. The patient was diagnosed with DNS after acute CO poisoning, and we reinitiated HBO therapy. However, due to manifestation of symptoms of severe dementia, treatment was discontinued. After initiating thyrotropin-releasing hormone (TRH) therapy, psychiatric symptoms, such as difficulty in following instructions, improved, enabling the resumption of HBO therapy. Daily activities returned to premorbid levels following treatment. Thus, TRH therapy could be effective for patients with DNS due to acute CO poisoning who experience difficulty with HBO therapy.

Efficacy of thyrotropin-releasing hormone therapy for standing disabilities in patients with spinocerebellar degeneration: Evaluation using short-term stabilometry

This study evaluated the effect of thyrotropin-releasing hormone (TRH) therapy on standing disabilities in 6 patients with spinocellular degeneration (SCD). Each patient was examined using a stabilometer before and after TRH treatment consisting of daily intravenous TRH injections for 2 weeks. The stabilography was performed while the patient's eyes were open and closed and while the patient stood with both feet together for 60 seconds. The total length, envelope area, length/area, length/time, area of root mean square (RMS) and area of rectangle were measured. A decrease in the area of the RMS after TRH treatment, compared with the baseline value, was statistically confirmed in all 6 patients. A stabilographical examination was also performed twice at an interval of 2 weeks in 6 normal subjects, but no significant differences in any of the parameters were detected between the first and second examinations. TRH therapy was assumed to be effective for the treatment of standing disabilities in patients with SCD, since the decrease in the value of the area after treatment appeared to result not from habituation, but from the effect of the therapy.

Evaluation of the Effects of Thyrotropin Releasing Hormone (TRH) Therapy on Regional Cerebral Blood Flow in the Cerebellar Variant of Multiple System Atrophy Using 3DSRT

Thyrotropin releasing hormone (TRH) improves cerebellar ataxia and cerebellar perfusion in patients with spinocerebellar degeneration. It is not known whether TRH therapy can improve the cerebellar regional cerebral blood flow (rCBF) or not in patients with cerebellar variant of multiple-system atrophy (MSA-C). Seven patients with MSA-C received TRH intravenously (2 mg/day) for 14 days. Clinical efficacy was assessed using the International Cooperative Ataxia Rating Scale (ICARS) and brain perfusion single photon emission-computed tomography was performed before and after therapy. The rCBF in each region of interest (ROI) was calculated using 3DSRT, a fully automated the ROI technique. The ICARS scores slightly improved in 6 of the 7 patients after TRH therapy, but this was not statistically significant. After TRH therapy, the cerebellar rCBF reduced in the 6 of 7 patients and the mean rCBF in cerebellum also significantly decreased (P=0.029, paired t-test), whereas the rCBF in the precentral segment tend to increase (P=0.048, paired t-test). TRH therapy may be less effective on cerebellar ataxia and cerebellar rCBF in MSA-C. The 3DSRT program may be useful for the evaluation of the efficacy of TRH therapy on cerebral blood flow.

Oral Administration of the Thyrotropin-Releasing Hormone (TRH) Analogue, Taltireline Hydrate, in Spinal Muscular Atrophy

Spinal muscular atrophy is an entity of neurodegenerative disorders at the anterior horn neuron of the spinal cord caused by telomeric survival motor neuron gene abnormality. There is no definitive treatment for spinal muscular atrophy, but recent reports have indicated the efficacy of intravenous injection, but not oral administration, of thyrotropin-releasing hormone (TRH). We treated an 18-year-old male patient with spinal muscular atrophy type III by oral administration of the thyrotropin-releasing hormone analogue, taltireline hydrate. His muscle strength increased significantly after the therapy, and he showed no clinical or laboratory identifiable adverse effects, including thyroid-stimulating hormone suppression that had been observed with intravenous thyrotropin-releasing hormone therapy. Oral administration of this thyrotropin-releasing hormone analogue should be noted as a promising therapy for spinal muscular atrophy.

Evaluation of the effect of thyrotropin releasing hormone (TRH) on regional cerebral blood flow in spinocerebellar degeneration using 3DSRT

Thyrotropin releasing hormone (TRH) therapy improves cerebellar ataxia in patients with spinocerebellar degeneration (SCD). We investigated the effect of TRH on regional cerebral blood flow (rCBF) using the fully automated region of interest (ROI) technique, 3DSRT. Ten patients with SCD received TRH intravenously (2 mg/day) for 14 days and underwent brain perfusion single photon emission computed tomography before and after therapy. Clinical efficacy was assessed using the International Cooperative Ataxia Rating Scale (ICARS). The rCBF in each ROI was measured using the noninvasive Patlak plot method and calculated using 3DSRT. TRH significantly improved the ICARS scores and increased rCBF in the callosomarginal segment and cerebellum. Cerebellar rCBF increased in 4 of 5 patients with improved ICARS scores and in 3 of 5 patients without improved ICARS scores after TRH therapy. The correlation between the change in cerebellar rCBF and the improved ICARS score, however, was not significant. These findings indicate that TRH therapy may increase cerebellar rCBF in some patients with cerebellar forms of SCD and that 3DSRT may be useful for evaluating the efficacy of TRH for increasing CBF. The beneficial effects of TRH may be due to increased cerebellar rCBF or the increased rCBF may be a secondary effect of TRH therapy.

Thyrotropin-releasing hormone (TRH) in the neuroaxis: Therapeutic effects reflect physiological functions and molecular actions

Nearly four decades of research have yielded thousands of publications on the physiology, pharmacology and therapeutic effects of TRH and TRH mimetic analogs. This work addresses both the neuroendocrine and the extrahypothalamic actions and functions of the tripeptide. The many reports of clinical effects of TRH in diverse medical conditions, unrelated to pituitary or thyroid function, can appear bewildering, as can its widespread involvement in a plethora of neuronal and physiological processes. Herein, we hypothesize that a logical and causal interrelationship exists between the fundamental molecular and cellular actions of TRH, its broader physiological functions and the therapeutic effects that attend the administration of exogenous TRH and TRH analogs. When viewed from this perspective, the basic neurobiological actions and functions of TRH provide a rational basis for understanding its diverse therapeutic effects. We posit: that the fundamental excitatory actions of TRH throughout the neuroaxis result from blocking various K+ channels linked to G-protein coupled TRH receptors in neurons and pituitary cells in distinct TRH-innervated anatomical pathways; that the functional consequences of blockade of these K+ channels are to enhance neuronal and secretory outputs in TRH regulatory circuits to modulate behavioral and energy homeostasis, and; that in clinical situations the resultant broad and useful therapeutic effects following administration of TRH reflect the state-dependent normalizing effects of activation of these regulatory circuits. In this light, the spectrum of reported clinical effects of TRH agonism remains unique and impressive but is less enigmatic. With the understanding that the neurobiological actions of TRH underlie and are rationally antecedent to its documented, extensive clinical 'normotrophic' effects, continued empirical efforts to assess the medical uses of TRH and related drugs seem rational and warranted. We predict that the range of disorders whose symptoms are alleviated by TRH therapy will continue to expand and that TRH agonism could conceivably become a near-universal therapeutic adjunct, particularly in the practice of neuropsychiatric medicine.

TRH therapy in a patient with juvenile Alexander disease

Alexander disease is a rare disorder of the central nervous system caused by a de novo mutation in the glial fibrillary acidic protein (GFAP) gene. Unlike the much more common infantile form, the juvenile form is slowly progressive with bulbar, pyramidal and cerebellar signs. Herein, we report a 9-year old Japanese girl suffering from frequent vomiting, slurred speech and truncal ataxia. Juvenile Alexander disease was diagnosed by genetic analysis, which detected a novel GFAP mutation, D360V. We also describe our clinical success in treating this patient with thyrotropin releasing hormone (TRH).

Alteration of regional cerebral blood flow to thyrotropin-releasing hormone therapy in acute encephalitis and encephalopathy during childhood

Background Thyrotropin-releasing hormone (TRH) is now used as a therapeutic agent for various neurological disorders. Animal study has shown that TRH was attributable to increased cerebral blood flow (CBF). Aims There have been occasional reports that TRH therapy was effective for improving symptoms of persistent disturbance of consciousness after acute encephalitis or encephalopathy during childhood. To determine whether TRH has an effect on increasing CBF to patients who have consciousness disturbance caused by acute encephalitis or encephalopathy, and to determine the optimal method of administration. Methods Sixteen patients aged 0.7–10.9 years (mean age, 3.2±3.1 years) who presented with persistent disturbance of consciousness resulting from acute encephalitis or encephalopathy and were treated with TRH. Regional CBF (rCBF) was measured by single photon emission computed tomography before and after TRH therapy. The alteration rates of rCBF were compared between the divided two groups concerning the dose levels, dosing periods, and treatment lags. Results The alteration rates of rCBF of the high dose group were higher than those of the low dose group. Differences in the dosing periods and treatment lags did not cause any significant difference of the alteration rates of rCBF. Conclusion The study showed that higher alteration rates of the CBF were observed in the higher dosing group, and TRH have the potency of increasing CBF. TRH therapy would have the potential for effective treatment of persistent consciousness disturbance caused by childhood acute encephalitis or encephalopathy.

Is there a role for antenatal TRH therapy for the prevention of neonatal lung disease?

Unfortunately, surfactant therapy is not routinely available to infants in some parts of the world because of its cost. It is the hypothesis of this article that in situations where surfactant is not available, there may be a role for antenatal thyrotropin-releasing hormone (TRH) plus glucocorticoid therapy. Data from randomized clinical trials, which compared therapy with antenatal glucocorticoid plus TRH to that with glucocorticoid alone were extracted and subjected to meta-analysis. The trials that incorporated surfactant therapy were analyzed separately from those in which surfactant was not used. In addition, because surfactant therapy was only available to some patients in the Australian ACTOBAT trial, each group analysis was performed with and without the ACTOBAT data. A characteristic of the earlier presurfactant trials is that few were designed for "intention to treat" analysis. In most of these studies, it was decided a priori to include babies who delivered within a specified time period after hormone therapy. The addition of TRH did not decrease respiratory distress syndrome in those trials in which surfactant therapy was used. In the presurfactant trials, respiratory distress syndrome was significantly decreased when "intention to treat" data were examined, as well as in those infants who delivered between 1 and 10 days after maternal therapy. There was also a significant decrease in oxygen dependency at 28 days after birth, and in oxygen dependency or death at this time, in those infants who delivered 1 to 10 days after treatment. Antenatal TRH had no significant effect of on neonatal complications such as air leak, intraventricular hemmorhage, patent ductus arteriosus, retinopathy of prematurity, or necrotizing enterocolitis. However, TRH did produce transient suppression of the pituitary thyroid axis. There were also a variety of transient complications in the mothers, including nausea, vomiting or flushing, light-headed feeling, and increased blood pressure. The authors conclude that the implementation of appropriate antenatal glucocorticoid treatment is the first priority. Once this has been established, the data presented here suggest that addition of antenatal TRH should be considered in those situations where surfactant is not available.

TRH increases cerebrospinal fluid concentration of kynurenine.

We have analyzed changes in cerebrospinal fluid (CSF) concentrations of monoamine-related substances to clarify the mechanism of the antiepileptic action of thyrotropin-releasing hormone (TRH). TRH-tartrate was administered to 14 patients with intractable epilepsy. Before and 2 weeks after TRH administration, CSF was collected and analyzed for tryptophan and tyrosine metabolites. Among monoamine-related substances, only CSF concentrations of kynurenine were increased after TRH therapy. Considering the fact that kynurenic acid acts as antagonist on the NMDA receptor complex, the results of this study may explain at least one of the mechanisms of the effectiveness of TRH therapy for intractable epilepsy.

Antenatal Thyrotropin-Releasing Hormone to Prevent Lung Disease in Preterm Infants

Background Pulmonary disease is common in preterm infants, despite antenatal glucocorticoid therapy. The addition of antenatal thyrotropin-releasing hormone therapy has been reported to decrease pulmonary morbidity in these infants. Methods We enrolled 996 women at 13 North American centers who were in preterm labor at <30 weeks' gestation in a double-blind, placebo-controlled, randomized trial of antenatal thyrotropin-releasing hormone, given intravenously in four doses of 400 μg each at eight-hour intervals. The primary outcome was chronic lung disease or death of the infant on or before the 28th day after delivery, and secondary outcomes were respiratory distress syndrome and chronic lung disease or death at 36 weeks' postmenstrual age. Complete data were available for 981 women and their 1134 live-born infants. The 769 infants born at <32 weeks' gestation were defined as the group at risk. Results There were no significant differences between the at-risk treatment and placebo groups in mean (±SD) birt...

Successful Treatment of Progressive Myoclonus Epilepsy With TRH

Thyrotropin-releasing hormone (TRH) is sometimes used for the treatment of neurologic disorders such as intractable epilepsy and spinocerebellar degeneration. A 14-year-old girl with progressive myoclonus epilepsy was treated with intravenous TRH for 12 months. Clinical symptoms, such as cortical myoclonus and cerebellar signs, were improved, and P25-N33 amplitudes of somatosensory-evoked potentials decreased after TRH therapy. P100 amplitudes on flash visual- evoked potentials and photosensitivity on electroencephalograms also decreased but only temporarily. Changes in neurophysiologic findings after TRH therapy indicate that TRH inhibits hyperexcitability in the sensorimotor cortex and the visual cortex. Therefore, intravenous TRH therapy is recommended as an alternative therapy in the treatment of progressive myoclonus epilepsy.

Efficacy of Thyrotropin‐Releasing Hormone in the Treatment of Intractable Epilepsy

Purpose: Despite rapid advances in the treatment of epilepsy with the introduction of new drugs, the seizures in a number of children with epilepsy remain uncontrollable. Thus a more potent, yet safer therapy is needed. Adrenocorticotropic hormone (ACTH) has been used to treat children with intractable epilepsy, such as West syndrome and Lennox‐Gastaut syndrome. However, ACTH administration is occasionally associated with serious side effects, including immunosuppression, hypertension, and brain shrinkage. Consequently, in this study, the efficacy of an endogenous hormone, thyrotropin‐releasing hormone (TRH), was reevaluated for the treatment of intractable epilepsy. Methods: From 1991 to 1996, we studied the efficacy of TRH‐tartrate (TRH‐T) in 34 children with intractable epilepsy (16 with West syndrome, 11 with Lennox‐Gastaut syndrome, three with localization‐related epilepsies, two with severe myoclonic epilepsy, one with early myoclonic encephalopathy, and one with Angelman syndrome). TRH‐T was administered intravenously or intramuscularly at a dose of 0.05 mg/kg/day once per day for 4 weeks. The subjects were classified into three groups based on the frequency of their seizures and the EEG effects: cessation of seizures and seizure discharges for &gt;1 year (very effective group), a &gt;50% reduction in the frequency of seizures or seizure discharges or both (effective group), and no changes in the frequency of seizures or seizure discharges (ineffective group). Results: There were eight cases in the very effective group, 10 in the effective group, and 16 in the ineffective group. The patients in the very effective group stopped having seizures, including infantile spasms, tonic seizures, atypical absence, atonic seizures, myoclonic seizures, and partial seizures within 11 days to 3 months after the initiation of the TRH therapy. It is noteworthy that no seizures occurred for &gt;3 years in four of the eight cases in the very effective group. The 16 patients with West syndrome comprised five cases in the very effective group, two in the effective group, and nine in the ineffective group. The 11 patients with Lennox‐Gastaut syndrome were subdivided into three cases in the very effective group, three in the effective group, and five in the ineffective group. All three patients with localization‐related epilepsies were in the effective group. Conclusions: TRH should be considered as a possible treatment for Lennox‐Gastaut syndrome and West syndrome, especially for a patient who has an. infection or severe organic lesions in the brain, or who is immunosuppressed. It is noteworthy that TRH is also effective in the treatment of intractable localization‐related epilepsies. The relatively long duration of the action of TRH after the termination of administration may indicate that the mechanism for its anticonvulsant action differs from those of other anticonvulsant drugs.

Maternal-to-fetal transfer of thyrotropin-releasing hormone in vivo

Our purpose was to determine the transplacental transfer of thyrotropin-releasing hormone at the time of fetal blood sampling. Four hundred micrograms of thyrotropin-releasing hormone was given intravenously to 13 pregnant women between 24 and 35 weeks' gestation and maternal-to-fetal transfer of thyrotropin-releasing hormone was determined at fetal blood sampling 1 to 93 minutes later. The fetal thyrotropic response to thyrotropin-releasing hormone was determined by measuring thyroid-stimulating hormone, thyroxine, and prolactin. For comparison, endogenous fetal and maternal levels of thyrotropin-releasing hormone, thyroid-stimulating hormone, thyroxine, and prolactin levels were determined in a further 20 patients undergoing fetal blood sampling between 19 and 35 weeks' gestation. The concentration of thyrotrophin-releasing hormone was measured by radioimmunoassay and thyroid-stimulating hormone, thyroxine, and prolactin by chemiluminescence assay. Thyrotropin-releasing hormone was undetectable in the maternal circulation, whereas endogenous levels were detectable in the fetus from 19 weeks' gestation (median 150; range 50 to 276 pmol/L) and did not correlate with gestational age. After thyrotropin-releasing hormone injection as an intravenous bolus, peak levels in the mother were attained at 3 minutes (50,000 pmol/L). Maximal transplacental transfer of thyrotropin-releasing hormone occurred within 5 minutes of maternal administration but accounted in fetal blood for only 0.01% of initial dose administered (median 250; 30 to 550 pmol/L). Thyrotropin-releasing hormone-stimulated fetal peak thyroid-stimulating hormone levels occurred within 13 minutes and were higher than maternal values (p < 0.001). There was no change in fetal prolactin level with thyrotropin-releasing hormone therapy. Although maternally administered thyrotropin-releasing hormone crosses the placenta sparingly, it still elicits a thyroid-stimulating hormone but not a prolactin response in the human fetus.

Prenatal Hormonal Therapy Improves Pulmonary Morphology in Rats with Congenital Diaphragmatic Hernia

The high mortality of congenital diaphragmatic hernia (CDH) is due to associated pulmonary hypoplasia, which resembles that seen in premature newborns with respiratory distress syndrome (RDS). By use of successful therapies extrapolated from RDS, quantitative stereologic morphometry techniques were applied to evaluate pulmonary development following prenatal hormonal therapy in rats with nitrofen-induced CDH. Antenatal hormonal therapy was administered on Days 18.5 and 19.5 prior to delivery on Day 21.5 (term = Day 22), using dexamethasone (Dex), thyrotropin-releasing hormone (TRH), Dex-TRH, or normal saline (NS) as vehicle control. Lungs from CDH rats (n= 5) and non-nitrofen-fed controls (n= 5) were studied, and 10 morphometric airspace parameters were determined by point counting 18–30 fields/lung/animal. Indices of maturation, including total internal surface area (SA), airspace volume fractions (VValv), duct fractions (VVducts), and radial alveolar count (RAC), were improved by Dex and Dex-TRH compared with NS-CDH controls (P= 0.0001), as were five other morphometric airspace parameters (P< 0.05). Strikingly, Dex and Dex-TRH treatment corrected average airspace volume (AAV) and the volume fraction of air-conducting elements (VVducts) toward normal values seen in non-nitrofen-fed control animals. TRH therapy alone had minimal beneficial effects. Prenatal steroid ± TRH thus improved multiple morphometric parameters of lung maturity in CDH rats, supporting the potential use ofin uterohormonal therapy to treat humans with antenatally diagnosed CDH.

Thyrotropin-releasing hormone in treatment of intractable epilepsy: Neurochemical analysis of CSF monoamine metabolites

The efficacy of thyrotropin-releasing hormone in children with intractable epilepsy was investigated and changes in cerebrospinal fluid monoamine metabolites were analyzed. The 18 patients had either West syndrome (12 patients) or Lennox-Gastaut syndrome (6 patients), which was intractable to antiepileptic drug therapy and to adrenocorticotrophic hormone. Thyrotropin-releasing hormone-tartrate was administered for 4 weeks. Before and after the thyrotropin-releasing hormone administration, cerebrospinal fluid was collected and analyzed for 5-hydroxyindoleacetic acid, kynurenine, homovanillic acid, and 3-methoxy-4-hydroxyphenyl glycol. The patients were classified into 3 groups, based on seizure frequency and electroencephalographic effects: cessation of seizures and seizure discharges (very effective; group A), reduction of seizures and/or seizure discharges (effective; group B), and no changes in frequency of seizures or discharges (not effective; group C). There were 6 patients in group A, 3 in group B, and 9 in group C. There were no significant differences in monoamine metabolites before and after the thyrotropin-releasing hormone therapy. A trial of thyrotropin-releasing hormone for the treatment of intractable epilepsy is warranted and further study is required on the mechanism of the antiepileptic action of thyrotropin-releasing hormone.

135 PRENATAL HORMONAL THERAPY IMPROVES PULMONARY MORPHOLOGY IN RA WITH NTTROFEN-INDUCED CONGENITAL DIAPHRAGMATIC HERNIA

The high mortality of Congenital Diaphragmatic Hernia (CDH) is due in large part to the pulmonary hypoplasia, which resembles that seen in premature neonates with respiratory distress syndrome (RDS). Using therapies extrapolated from RDS, we applied quantitative stereologic morphometric techniques to evaluate pulmonary development following prenatal hormonal therapy in the nitrofen CDH rat model. Antenatal hormonal therapy was administered on days 18.5 and 19.5 prior to delivery on day 21.5, using dexamethasone (Dex), thyrotropin releasing hormone (TRH), Dex-TRH, or normal saline (NS) as control. Lungs from CDH rats (n=5) in each treatment group were studied, ten morphometric airspace parameters determined by point-counting 18-30 fields/lung/animal, and analysis of variance with post hoc testing was performed.Equivalent striking maturational changes were observed in the lungs of Dex and Dex-TRH treated animals (Figure). Total internal surface area, the volume fraction of airspaces, and radial alveolar counts were all significantly improved by Dex and Dex-TRH compared to NS treated controls (p=0.0001), as were five other parameters. TRH therapy had minimal beneficial effects.Prenatal corticosteroid ± TRH treatment of CDH significantly improved multiple morphometric parameters of lung maturity in the rat model, further supporting the potential use of hormonal therapy for in utcro treatment of human CDH.