History of clinical studies on hypothalamic hormone analogs in Mexico

Early clinical trials in Mexico with analogs of luteinizing hormone-releasing hormone (LH-RH) also known as gonadotropin releasing hormone (Gn-RH), were reviewed. Extensive clinical studies were carried out at IMSS with agonists of LH-RH, both in men and woman. All subjects responded to LH-RH agonists with a release of LH and FSH, but repeated administration of these analogs, initially aimed at stimulation of fertility (thought to stimulate fertility), was later shown to result in inhibition due to desensitization of pituitary gland and downregulation of LH-RH receptors. Various clinical investigations with LH-RH antagonists were also carried out. This included the first demonstration that LH-RHantagonists can suppress LH and FSH and sex steroid secretion in men and women. Various studies in Mexico with early LH-RH antagonists aimed at the development of new contraceptive methods were reviewed. Modern LH-RH antagonist Cetrorelix was shown to be effective in men and women and useful in treatment of uterine leiomyomas and benign prostatic hyperplasia. Major oncological studies were also carried out with agonist D-Trp6-LH-RH and antagonist Cetrorelix in men with prostate cancer, which demonstrated therapeutic efficacy of both types of analogs. Some endocrine studies with early analogs of somatostatin were also cited and a clinical trial with somatostatin analog vapreotide in patients with relapsed prostate cancer was reviewed. All these studies played a major role in introducing analogs of hypothalamic-releasing hormones into clinical medicine.     

Unchanged response to stimulation of pituitary hormone release after serial UV irradiation in men

A group of 24 healthy young men were evaluated before and after serial suberythematous ultraviolet (UV) radiation: group I, control (no irradiation); groups II and III, 12 radiations in 4 weeks with two different spectra (both containing UV-B). Before the first and 2 days after the last exposure all the volunteers were given an intravenous injection of thyrotropin releasing hormone (TRH, protirelin 0.2 mg) and luteinizing hormone releasing hormone (LH-RH, gonadorelin 0.1 mg). The serum concentrations of TSH, follicle stimulating hormone, LH and prolactin were measured at 0, 20, 30, 45 and 60 min by radioimmunoassay. Neither basal nor stimulated levels of the pituitary hormones showed significant changes after UV radiation. The results showed that exposure to suberythematous doses of UV did not influence the regulation of pituitary hormones in these healthy individuals.     

The effects of dieting and weight loss upon the stimulation of thyrotropin (TSH) by thyrotropin-releasing hormone (TRH) and suppression of cortisol secretion by dexamethasone in men and women

The effects upon basal hormone levels and neuroendocrine responses of a weight reducing diet allowing 1200 kcal daily were determined in male and female volunteers. Thyrotropin (TSH) responses to thyrotropin-releasing hormone (TRH) were unchanged in men but attenuated in women; this effect was associated with a fall in basal TSH in women, not in men. Rates of non-suppression of cortisol in response to oral dexamethasone (1 mg) were unchanged during dieting although basal morning cortisol levels rose in males and females. The implications for the use of the TRH test and the dexamethasone suppression test (DST) in depressive illness are discussed.     

Combined pituitary function-test with four hypothalamic releasing hormones

Summary Anterior pituitary function was investigated in ten healthy subjects by administering a combination of 200 µg thyrotropin releasing hormone (TRH), 100 µg gonadotropin releasing hormone (GnRH), 100 µg growth hormone releasing factor (GRF^1–44), and 100 µg human corticotropin releasing factor (CRF). The same test protocol was performed in all subjects after pretreatment with 0.25 mg terguride. Five subjects were tested only with TRH and GnRH, five only with CRF, and six only with GRF. There was a prompt increase in all hormones after the administration of the four releasing hormones (RH). Pretreatment with terguride lowered the prolactin (PRL) increase (p<0.01) as well as the thyrotropin (TSH) peak (p<0.05) compared with the test without dopamine agonist pretreatment. The PRL levels after combined RH administration were significantly higher than after TRH and GnRH alone. Although four of the five subjects had higher TSH levels after combined RH administration than after TRH and GnRH alone, the difference was not significant. Other hormones were not significantly influenced by the combined RH administration or dopamine agonist pretreatment. Despite the fact that the interaction of the different releasing hormones and dopamine agonists influences the pituitary hormone response, combined RH administration seems to be a useful test for evaluating pituitary function also in patients receiving dopamine agonist therapy.Abbreviations ACTH Adrenocorticotropic hormone - CRF Human corticotropin releasing factor - DA Dopamine - FSH Follicle-stimulating hormone - GH Human growth hormone - GnRH Gonadotropin releasing hormone - GRF; GRF^1–44 Growth hormone releasing factor - LH Luteinizing hormone - PRL Prolactin - RH Releasing hormone (s) - RIA Radioimmunoassay - SE Standard error - TRH Thyrotropin releasing hormone - TSH Thyrotropin Supported by Deutsche Forschungsgemeinschaft (We 439/5-1 and Mu 585/2-2).     

Evaluation of hypothalamic-pituitary-adrenal axis in amenorrhoeic women with insulin-dependent diabetes

Diabetes is associated with a higher incidence of secondary hypogonadotrophic amenorrhoea. In amenorrhoeic women with insulin-dependent diabetes a derangement in hypothalamic-pituitary-ovary axis has been proposed. No data exist on hypothalamic-pituitary-adrenal function in these women. Gonadotrophin releasing hormone (GnRH), corticotrophin releasing hormone (CRH), metoclopramide and thyroid releasing hormone (TRH) tests were performed in 15 diabetic women, eight amenorrhoeic (AD) and seven eumenorrhoeic (ED). Frequent blood samples were taken during 24 h to evaluate cortisol plasma concentrations. There were no differences between the groups in body mass index, duration of diabetes, insulin dose and metabolic control. The AD women had lower plasma concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, oestradiol, androstenedione and 17-hydroxyprogesterone (17-OHP) than the ED women. The responses of pituitary gonadotrophins to GnRH, and of thyroid stimulating hormone (TSH) to TRH, were similar in both groups. The AD women had a lower prolactin response to TRH and metoclopramide, and lower ACTH and cortisol responses to CRH, than the ED women. Mean cortisol concentrations > 24 h were higher in the amenorrhoeic group. Significant differences in cortisol concentrations from 2400 to 1000 h were found between the two groups. Insulin-dependent diabetes may involve mild chronic hypercortisolism which may affect metabolic control. Stress-induced activation of the hypothalamic-pituitary-adrenal axis would increase hypothalamic secretion of CRH. This would lead directly and perhaps also indirectly by increasing dopaminergic tonus to inhibition of GnRH secretion and hence hypogonadotrophic amenorrhoea. Amenorrhoea associated with metabolically controlled insulin-dependent diabetes is a form of functional hypothalamic amenorrhoea that requires pharmacological and psychological management.     

Thyrotropin releasing hormone (TRH): its changes in discrete hypothalamic areas after treatment with triiodothyronine, thyroidectomy and acute cold exposure

In order to elucidate the specific thyrotropic area in the hypothalamus, thyrotropin releasing hormone (TRH) content and concentration were measured in discrete hypothalamic nuclei and areas after triiodothyronine (T3) administration (T3 10 micrograms/rat/day for 6 days), thyroidectomy (TX) and acute cold exposure in male rats. In th TX and T3 groups, serum TSH levels were significantly increased in TX group and markedly decreased in T3 and TX with T3 groups as compared to the sham operated control group (Sham). TX produced a slight but nonsignificant decrease in TRH content in most of the hypothalamic nuclei examined as compared with the Sham group. However, a significant increase in TRH contents was seen in the anterior hypothalamic nucleus (AHN), median eminence (ME) and posterior pituitary (PP) in TX with T3 group as compared to the rats with only TX. In the acute cold stress experiments, serum TSH levels were elevated from 15 to 30 min of 4 degrees C exposure. Together with these peripheral changes, TRH content and concentration in the suprachiasmatic nucleus (SC) were increased significantly at 15 min and had returned to the normal level by 30 min after 4 degrees C cold exposure. However, in the paraventricular nucleus (PV) and dorsal premammillary nucleus (PMD), marked decrease in TRH concentrations were observed with this stress. Therefore, 1) decreased TSH release in TX rats treated with T3 was induced by the block of TRH release from the AHN and ME as compared with the TX group, and 2) elevated serum TSH levels in 4 degrees C cold stress might be induced by the release of TRH from the PMD and PV. These experiments demonstrate that the specific hypothalamic area for TSH release was located in some of the anterior and posterior hypothalamic nuclei and in the ME.     

Effects of growth hormone treatment on thyroid function in pediatric patients with Prader–Willi syndrome

It is unclear whether hypothyroidism is present in patients with Prader–Willi syndrome (PWS). This study aimed to clarify the state of the hypothalamic–pituitary–thyroid axis and the effects of growth hormone (GH) treatment on thyroid function in pediatric patients with PWS. We retrospectively evaluated thyroid function in 51 patients with PWS before GH treatment using a thyroid‐releasing hormone (TRH) stimulation test (29 males and 22 females; median age, 22 months). We also evaluated the effect of GH therapy on thyroid function by comparing serum free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH) levels at baseline, 1 year, and 2 years after GH therapy. TSH, fT4, and fT3 levels were 2.28 μU/ml (interquartile range [IQR]; 1.19–3.61), 1.18 ng/dl (IQR; 1.02–1.24), and 4.02 pg/dl (IQR; 3.54–4.40) at baseline, respectively. In 49 of 51 patients, the TSH response to TRH administration showed a physiologically normal pattern; in two patients (4.0%), the pattern suggested hypothalamic hypothyroidism (delayed and prolonged TSH peak after TRH administration). TSH, fT4, and fT3 levels did not change significantly during 1 or 2 years after GH treatment. The TSH response to TRH showed a normal pattern in most patients, and thyroid function did not change significantly during the 2 years after initiating GH treatment.     

Comparison of thyroid stimulating hormone and triiodothyronine response to thyrotrophin releasing hormone in the assessment of thyroid status.

The response to an intravenous dose of 200 microng of thyrotrophin releasing hormone (TRH) has been studied by estimating, by radioimmunoassay, baseline levels followed by further estimations of thyroid stimulating hormone (TSH) 20 minutes after the injection and triiodothyronine (T3) three hours after the injection in 112 patients referred for routine thyroid assessment. Comparison of diagnostic accuracy of the response to TRH gave similar results with both procedures but slightly better overall accuracy for the response measured by TSH assay. However, estimation of baseline T3 is a valuable test for hyperthyroidism, in contrast to baseline TSH, and combined with the estimation of T3 three hours after TRH injection provides an accurate additional test in borderline cases.     

Secretion of growth hormone and thyroid-stimulating hormone in patients with dementia

We studied the growth hormone (GH) response to GH-releasing hormone (GHRH) and the thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) in four groups of patients with dementia and examined whether GH and TSH secretion is altered in patients with Alzheimer's disease. The four groups included those with Alzheimer's disease (n=28), parkinsonism with dementia (n=10), progressive supranuclear palsy with dementia (n=10), and dementia of vascular origin (n=28). The results showed no differences among the four groups in GH response to GHRH (12.2 ± 2, 10.7 ± 2, 8.9 ±1.1, and 9.9 ± 1.9 g/ml, respectively); there was no correlation between GH response to GHRH and sex, stage of the disease, or cerebral atrophy. The proportion of patients with exaggerated, normal, or lower GH response was similar in the four groups. There were also no differences among the groups in terms of TSH response to TRH (9.2 ±0.9, 11.1 ± 1, 11.1 ± 1, and 10.3 ± 1 mU/ml, respectively), nor was there a correlation between TSH response to TRH and sex, stage of the disease, cerebral atrophy, or GH response to GHRH. The proportion of those with exaggerated, normal, or lower TSH response was similar in the four groups. Cerebrospinal somatostatin levels were similar in Alzheimer's disease and vascular dementia patients. These findings indicate that neither GH response to GHRH nor TSH response to TRH provides a useful diagnostic adjunt in Alzheimer's disease patients.Abbreviations AD Alzheimer's disease - PD parkinsonism with dementia - PSP progressive supranuclear palsy - VD dementia of vascular origin - GH growth hormone - GHRH growth hormone releasing hormone - TRH thyrotropin releasing hormone - TSH thyroid stimulating hormone Correspondence to: J.M. Gomez     

Effect of a long-acting somatostatin analogue (SMS 201-995) on a growth hormone and thyroid stimulating hormone-producing pituitary tumor

A 46-year-old woman with acromegaly and hyperthyroidism due to a pituitary adenoma. She had high serum thyroid-stimulating hormone (TSH) levels and very high serum growth hormone (GH) levels. Transsphenoidal removal of the tumor, post-operative irradiation, frontal craniotomy for removal of residual tumor and large-dose bromocriptine therapy were carried out consecutively. After therapy, serum GH levels gradually decreased, but not to the normal range, and serum TSH levels remained at inappropriately normal levels. Using immunoperoxidase techniques, GH-, TSH- and follicle-stimulating hormone (FSH)-containing cells were demonstrated in the adenoma. A long-acting somatostatin analogue (SMS 201-995, 600 micrograms/day) suppressed the serum GH level to the normal range with a concomitant suppression of TSH. Furthermore, the paradoxical serum GH responses to TRH and LH-RH were slightly improved. No important subjective side-effects were noted. Therefore, SMS 201-995 appeared to be a very effective drug in this patient with a GH- and TSH-producing pituitary tumor.     

Effect of diphenylhydantoin on hypothalamic-pituitary-thyroid function in the rat

Chronic diphenylhydantoin (DPH) administration (5 mg x 100 g body wt-1 x day-1) to the normal rat is associated with a decrease in the serum thyroxine (T4) and triiodothyronine (T3) concentrations without an appropriate rise in the serum thyrotropin (TSH) concentration, suggesting a possible direct effect of DPH on TSH secretion. To further study this possibility, DPH was administered chronically to thyroidectomized, hypothyroid rats. In the hypothyroid rats treated chronically with DPH, serum TSH did not increase, pituitary TSH content was significantly decreased, and the serum TSH response to thyrotropin-releasing hormone (TRH) was decreased compared to that of diluent-treated, hypothyroid rats. Hypothalamic TRH content was similar in DPH and diluent-treated rats. These findings suggest that DPH suppresses pituitary TSH secretion, probably as a thyroid hormone agonist. The effect of a single large dose of DPH (20 mg/100 g body wt) administered to thyroidectomized rats also decreased serum tSH but, in contrast to the findings in chronically treated rats, hypothalamic TRH and pituitary TSH content and the serum TSH responses to TRH were increased. These differences may be due to the acute inhibitory effect of a large dose of DPH on hypothalamic TRH release. Furthermore, because the effect of thyroid hormone on regulating pituitary TSH synthesis and release is dose and time dependent, the effect of DPH as a thyroid hormone agonist on pituitary TSH dynamics may also be variable.     

Serum FSH and LH levels in men after administration of a long-acting LH-RH preparation

The effects of the natural gonadotropin releasing hormone (LH-RH) and of a long-acting analogue, desgly10-D-leu6-LH-RH ethylamide, on the serum FSH, LH, testosterone and oestradiol-17 beta levels were studied in healthy men. The basal value for FSH was 3.58 +/- 0.47 mU/ml (SE), for LH 6.33 +/- 1.19 mU/ml. Following an intravenous dose of LH-RH the values increased by 3.40 +/- 0.88 and 25.99 +/- 5.67 mU/ml, respectively. After intravenous administration of the long-acting analogue, the peak FSH exceeded the basal value by 12.89 +/- 6.95 mU/ml, while LH increased by 41.27 +/- 4.72 mU/ml. The effect of the analogue on FSH and LH lasted 693 min and 862 min, respectively. Neither preparation changed the serum testosterone or oestradiol-17 beta levels essentially. The results suggest that the long-acting variant of LH-RH is more suitable than the natural hormone for examination of the FSH and LH reserves in men.     

Thyroid antoantibodies and the response to thyrotropin releasing hormone in patients with subclinical hypothyroidism.

AIM--To evaluate the clinical usefulness of the thyrotropin releasing hormone (TRH) test and estimation of thyroid autoantibody concentrations in patients with borderline raised thyroid stimulating hormone (TSH). METHODS--The records of 34 consecutive patients with persistent borderline increased TSH (4.4-9.9 mU/l) referred to the Medical Investigation Unit were reviewed. The response of patients with thyroid autoantibodies to the TRH test was compared with that of patients with a negative antibody screen. RESULTS--Eleven (44%) of 25 patients with positive anti-thyroid microsomal and/or thyroglobulin antibody tests and three (33%) of nine patients with a negative antibody screen had hypothyroid responses to TRH. Neither age nor sex affected the response to TRH. Basal TSH alone was poorly correlated with these indices. Twelve (35%) patients who had elevated basal TSH had a normal response to the TRH test. CONCLUSION--Patients with positive or negative thyroid autoantibodies and an exaggerated response to the TRH test should be regarded as hypothyroid and treated with thyroxine. Patients with positive thyroid autoantibodies and normal TSH response may subsequently develop hypothyroidism and should be given long term follow up.     

In vitro effects of endogenous opiate peptides on thyrotropin function: inhibition of thyrotropin-releasing hormone release and absence of effect on thyrotropin release

Thyrotropin-releasing hormone (TRH) or thyroid-stimulating hormone (TSH) was measured by radioimmunoassay in the incubation medium of rat hypothalami or anterior pituitary halves, respectively. We studied the effect of opioid peptide addition (10(-8) to 10(-6) M) on TRH or TSH release. alpha- or beta-Endorphin decreased TRH release in a dose-dependent manner while only 10(-6) M Leu- or Met-enkephalin decreased TRH release. These inhibitory effects were prevented by addition of naloxone (10(-5) M). In the dose range used none of the opioid peptides modified TSH release. These results indicate that opioid peptides may play a role in the regulation of thyrotropin secretion via a hypothalamic action on TRH release.     

Thyrotropin-releasing hormone receptors in gut tissues resemble pituitary receptors

The relative order of activity of thyrotropin-releasing hormone (TRH) and various analogs in contracting the isolated guinea pig antrum and duodenum correlated with their potencies in activating thyroid-stimulating hormone (TSH) release. The action of TRH in both tissues was selectively antagonized by the putative pituitary TRH receptor antagonist, chlordiazepoxide (10 microM). The data indicate that the contractions produced by TRH in these gut tissues are mediated by TRH receptors with similar characteristics as the pituitary TRH receptors responsible for TSH release.     

The TRH stimulation test and reverse T3 in depression

Blunted TSH response to TRH and elevation of reverse T3 (rT3) have been reported in depression, though the relationship between these two abnormalities has not been clear. The authors measured basal levels of T4, T3, rT3 and the TSH response to TRH in a group of 28 depressed men and women, unipolar and bipolar subtypes. No significant difference was found between these two subtypes of depression with respect to mean basal hormonal levels or magnitude of the TSH response to TRH. Two males had slight, but significant elevations of rT3 though only one of them had a blunted TSH response to TRH levels and the TSH response to TRH. Finally no significant correlation was found between rT3 levels and the TSH response to TRH.     

A revised interpretation of the TRH test results in female depressed patients. Part I: TSH responses. Effects of severity of illness, thyroid hormones, monoamines, age, sex hormonal, corticosteroid and nutritional state

Thyrotropin secreting hormone (TSH) levels were recorded in baseline conditions and 20 and 60 min after thyrotropin releasing hormone (TRH) administration (200 micrograms i.v.) in 60 depressed females categorized according to DSM-III. Basal TSH (TSHB) and peak TSH responses (TSHP) were measured using ultrasensitive RIA assays. The use of delta max TSH (TSHP minus TSHB) had no advantage over the use of TSHP since both factors were almost linearly (r = 0.98) correlated. TSHP was largely (72% of the variance) predicted by TSHB. It was suggested that TSHP consisted of two components. The first part was a relative deduction from TSHB. The second part was the newly proposed concept of the residual TSH (TRHR). This part was computed by partialling out the relative effects of TSHB on TSHP by means of regression analysis. In clinical practice two relevant factors should be used to evaluate the hypothalamic-pituitary-thyroid (HPT) axis: (1) TSHB reflecting the setpoint of the HPT axis and (2) TSHR reflecting the latent capacity of the HPT axis to respond to overwhelming amounts of exogenous TRH. TSHB was significantly reduced in severely depressed patients (296.X3, 296.X4) as compared with minor depressives (300.40, 309.00). These differences could be attributed to significantly increased free thyroxine levels and to noradrenergic hyperactivity in the severely depressed females. TSHR correlated significantly and negatively with follicle stimulating hormone levels, age, body mass index and the post-dexamethasone cortisol values. TSHR was significantly reduced in the post-menopausal state.     

Luteinizing hormone responses to luteinizing hormone releasing hormone (LHRH) in acute mania and the effects of lithium on LHRH and thyrotrophin releasing hormone tests in volunteers

The endocrine responses to Luteinizing Hormone Releasing Hormone (LHRH) of eight drug-free males with mania were determined. Basal levels of Luteinizing Hormone (LH) and the plasma levels following injection of LHRH were elevated in patients compared with controls; Follicle Stimulating Hormone (FSH) and testosterone were not different. Elevated levels of LH have been described previously in recovered manic patients and have been suggested to be state-independent features of mania. In order to clarify the status of this finding, the effects of lithium administration upon hormone responses to LHRH in six male volunteers were also investigated, together with the effects upon Thyrotrophin Releasing Hormone (TRH) stimulation of Thyroid Stimulating Hormone (TSH) and prolactin release. Lithium increased the basal levels of LH and levels after injection of LHRH without effect upon FSH and testosterone. Lithium also increased basal and TRH stimulated release of TSH and basal prolactin levels. Lithium was without effect upon prolactin responses to TRH. The results are discussed in relation to current information on the mechanism of lithium's action. The implications for neuroendocrine work on recovered patients taking lithium are also explored.     

Neuroendocrinology of the pituitary gland

The hypophysial-portal chemotransmitter hypothesis of control of the anterior pituitary was first set forth in the 1940s on the basis of physiological studies of the effects of lesions of the hypothalamus, and of section of the pituitary stalk on pituitary function. Morphological demonstration of specific neuropeptide pathways in the hypothalamus, which project to the median eminence, and the chemical identification of releasing hormones in the hypothalamus have fully established this theory. Specific neuropeptides have been isolated which stimulate the secretion of ACTH (CRF, corticotrophin releasing hormone), TSH (TRH, thyrotropin releasing hormone), GH (GHRH, growth hormone releasing hormone), and the gonadotropins (LHRH, luteinizing hormone releasing hormone; GnRH, gonadotropin releasing hormone). Prolactin secretion is regulated by both an inhibitory hormone (dopamine), and by one or more releasing factors. A factor inhibitory to GH and TSH secretion has also been identified. All factors except for the prolactin inhibitory hormone (which is a biogenic amine) are peptides, all synthesized as part of large prohormones. These substances have all been introduced into medical and veterinary practice where they are useful for regulation of pituitary abnormalities, and study of normal physiology.     

Effects of TRH and TRH analogues on the central regulation of breathing in the rat

Respiratory activity was studied in rats during light halothane anesthesia. Thyrotropin releasing hormone (TRH) and two TRH analogues: the desamidated form (TRH-OH) and gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate (DN 1417) were administered intracerebroventricularly. TRH 0.5-5 micrograms induced a marked tachypnoea with a rapid onset and a duration of at least 20 min. DN 1417, a potent analogue of TRH with a very low TSH (thyroid stimulating hormone) releasing activity was more effective in stimulating respiratory frequency, while TRH-OH, regarded to have neither TSH releasing nor extra hypothalamic effects, at equimolar doses was unable to induce any changes in the respiratory pattern. When TRH was given into the fourth ventricle the dose response curve was slightly shifted to the left. In experiments employing the occluded breath technique, P0.1 was increased in the same magnitude as the mean inspiratory flow (VT/T1). The results also indicated an increase in the gain of the inflation reflex loop whereas the central bulbopontine setting for T1 and TTOT were not significantly changed. Local injection of TRH into the nucleus tractus solitarii induced a stimulation of respiratory frequency which was slower in onset compared to the response seen after injection into the lateral or fourth ventricles. Concomitantly to the respiratory changes, i.c.v. TRH injection induced a hypocarbia and an alkalosis. No changes in blood pressure or heart rate were seen. The respiratory stimulant effect of TRH could be potentiated by pretreatment with naloxone, methylatropine or a low dose of GABA. Haloperidol or propranolol did not significantly change the respiratory effects of TRH, while reserpine pretreatment seemed to blunt some of the ventilatory effects of TRH. It seems likely that TRH has few direct effects on brain stem neurones involved in the central regulation of respiration, but the main effects seem to be elicited in areas rostral to the brain stem. The respiratory stimulating effect of TRH is unrelated to TSH. Furthermore, other neurotransmitter systems might also be involved in modulation of the respiratory stimulation evoked by TRH.