The Processes of Anterior Pituitary Hormone Pulse Generation.

More than 60 years ago, Geoffrey Harris described his "neurohumoral theory," in which the regulation of pituitary hormone secretion was a "simple" hierarchal relationship, with the hypothalamus as the controller. In models based on this theory, the electrical activity of hypothalamic neurons determines the release of hypophysiotropic hormones into the portal circulation, and the pituitary simply responds with secretion of a pulse of hormone into the bloodstream. The development of methodologies allowing the monitoring of the activities of members of the hypothalamic-vascular-pituitary unit is increasingly allowing dissection of the mechanisms generating hypothalamic and pituitary pulses. These have revealed that whereas hypothalamic input is required, its role as a driver of pulsatile pituitary hormone secretion varies between pituitary axes. The organization of pituitary cells has a key role in the modification of their response to hypophysiotropic factors that can lead to a memory of previous demand and enhanced function. Feedback can lead to oscillatory hormone output that is independent of pulses of hypophysiotropic factors and instead, results from the temporal relationship between pituitary output and target organ response. Thus, the mechanisms underlying the generation of pulses cannot be generalized, and the circularity of feedforward and feedback interactions must be considered to understand both normal physiological function and pathology. We describe some examples of the clinical implications of recognizing the importance of the pituitary and target organs in pulse generation and suggest avenues for future research in both the short and long term.

Heterogeneity of Calcium Responses to Secretagogues in Corticotrophs From Male Rats.

Heterogeneity in homotypic cellular responses is an important feature of many biological systems, and it has been shown to be prominent in most anterior pituitary hormonal cell types. In this study, we analyze heterogeneity in the responses to hypothalamic secretagogues in the corticotroph cell population of adult male rats. Using the genetically encoded calcium indicator GCaMP6s, we determined the intracellular calcium responses of these cells to corticotropin-releasing hormone and arginine-vasopressin. Our experiments revealed marked population heterogeneity in the response to these peptides, in terms of amplitude and dynamics of the responses, as well as the sensitivity to different concentrations and duration of stimuli. However, repeated stimuli to the same cell produced remarkably consistent responses, indicating that these are deterministic on a cell-by-cell level. We also describe similar heterogeneity in the sensitivity of cells to inhibition by corticosterone. In summary, our results highlight a large degree of heterogeneity in the cellular mechanisms that govern corticotroph responses to their physiological stimuli; this could provide a mechanism to extend the dynamic range of the responses at the population level to allow adaptation to different physiological challenges.

Dynamics of anterior pituitary immunoreactive gonadotrophs in moulted hens supplemented with protein, symbiotic and probiotics.

The present work delineates redistribution patterns of the hormone-producing cells of the anterior pituitary, after the phase of moulting. Two hundred single comb White Leghorn hens at the end of their first production cycle (Age = 70 week) were purchased from the commercial poultry farm and were induced to moult by high-dietary zinc (3 g/kg feed/day) after 1 week of acclimatization, at the experimental research station, Department of Physiology and Pharmacology, University of Agriculture, Faisalabad. The moulted birds were equally (n = 50) and randomly allocated to their respective groups as G1 (control; CP (Crude protein) 16%, no supplement), G2 (CP18%, no other supplement), G3 (CP16%, symbiotic at does rate of 85 mg/l in drinking water daily) and G4 (CP16%, probiotic at dose rate of 85 mg/l in drinking water daily). Ten birds were slaughtered in each group at 5% and at peak of post-moult production stage to collect their pituitary glands. An earlier post-moult production recovery, sustained and lengthier production span was seen in the G2 as compared to all other groups. The lowest production and an earlier production decline were seen in G1. The cell diameter and area of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) gonadotroph increased (p ≤ 0.01) in G2 and G3 as compared to G1. The FSH gonadotroph nucleus diameter and area did increase (p ≤ 0.01) in G2 and G3, while LH gonadotroph nucleus diameter and area decreased (p ≤ 0.01) in G2 and G3 as compared to G1. The increased FSH and LH gonadotroph diameter in protein and symbiotic supplemented birds is accountable for the increased egg production in these groups.

Impact of Yoga Nidra on menstrual abnormalities in females of reproductive age.

OBJECTIVES: The aim of this study was to observe the effect of Yoga Nidra practice on hormone levels in patients who had menstrual irregularities. DESIGN: The study was a randomized controlled trial. SETTINGS/LOCATION: The study was conducted in the Department of Obstetrics and Gynecology at Chhatrapati Sahuji Maharaj Medical University, Uttar Pradesh, Lucknow, India. SUBJECTS were divided randomly into 2 groups-an intervention and a control group, with 75 subjects in each group. Of these subjects, 126 completed the study protocol. SUBJECTS: This study involved 150 subjects with menstrual irregularities; 126 of whom completed the protocol. INTERVENTIONS: The intervention was the practice of Yoga Nidra. The yogic intervention duration was 35-40 minutes/day, five times/week for 6 months. An estimation of hormonal profile was done for both groups at baseline and after 6 months. RESULTS: Thyroid-stimulating hormone (p<0.002), follicle-stimulating hormone (p<0.02), luteinizing hormone (p<0.001), and prolactin (p<0.02) were decreased significantly in the intervention group, compared with the control group. CONCLUSIONS: The present study demonstrated the efficacy of Yoga Nidra on hormone profiles in patients with menstrual irregularities. Yoga Nidra practice was helpful in patients with hormone imbalances, such as dysmenorrhea, oligomenorrhea, menorrhagia, metrorrhagia, and hypomenorrhea.

Hypothalamic control of anterior pituitary function: a history.

The concept of neurohumoral control of anterior pituitary function championed by Geoffrey Harris was based upon clinical and biological observation backed by rigorous experimental testing. The areas of the brain involved in the control of gonadotrophic hormone synthesis and release were identified by electrical stimulation, lesioning and fibre tract cutting. The medial preoptic area (MPOA) proved to be a major integrating centre, with axon terminals from this region terminating at the median eminence releasing factors into the portal vessels to give a direct route from brain to pituitary. It took over a decade before the gonadotrophic hormone-releasing hormone (GnRH) was isolated, sequenced and synthesised. With antibodies raised against this peptide, the MPOA was identified as a site rich in GnRH neurones and the hormone was detected at high levels in portal blood extracts. A natural knockout of the GnRH gene was discovered in a hypogonadal (hpg) mouse. Hormone injections, gene replacement methods and neural grafting in these mutants all confirmed the central role of GnRH in reproduction. The modern techniques of molecular biology have allowed us to extend our knowledge base. In the last few years the role of kisspeptin and its receptor (GPR54) in the control of the GnRH neurone has added a further level of hypothalamic involvement in the modulation of reproduction.

Normal physiology of hypothalamic pituitary regulation.

The anterior pituitary is a complex heterogeneous gland that exerts a central role in the integration of several regulatory systems. Its six key hormones affect peripheral glands or target tissues and are essential for reproduction, growth and development, metabolism, adaptation to external environmental changes, and stress. Each of the pituitary hormones is regulated by the central nervous system through neuroendocrine pathways involving the hypothalamus, by feedback effects from peripheral target gland hormones, and by intrapituitary mechanisms. The hormones are secreted in a pulsatile manner, which is distinct for each hormone and reflects the influence of its individual neuroendocrine control mechanisms.

Electrotonic coupling in the anterior pituitary of a teleost fish.

The anterior pituitary of teleost fish contains a variety of endocrine cells, which, under control from the hypothalamus, release trophic hormones and thereby play a major role in reproduction, social behavior, and growth. In fish, hypothalamic fibers directly innervate the pituitary. The hypothalamic hormones released from these fibers bind to membrane receptors on pituitary cells, triggering action potentials, a rise in cytosolic calcium, and exocytosis. It is unclear whether these activities are confined to the stimulated cell or propagate to adjacent cells. We addressed this issue using whole cell and perforated patch-clamp techniques in a novel, hypothalamo-pituitary slice preparation from the tilapia fish (Oreochromis niloticus). Pituitary cells at rest generated occasional spontaneous spikes and sharp depolarizations of lower amplitude. The latter probably represented spikes in neighboring, electrotonically coupled cells. The presence of electrotonic communication, probably mediated by gap junctions, was also supported by the finding that Lucifer Yellow diffuses between cells. To quantify this connectivity, we performed simultaneous recording from pairs of adjacent cells. Thirty-three percent of the cells exhibited strong reciprocal coupling. Coupling coefficients ranged between 0.18 and 0.31, and coupling resistances ranged between 16 and 39 GOhm. The electrical junctions were effective low pass filters, attenuating action potentials much more than low frequency waveforms. We conclude that electrical activities of anterior pituitary cells in teleost fish are synchronized by coupling through gap junctions. Regulation of this coupling may play a critical role in determining complex patterns of pituitary hormone secretion.

Multifunctional cells in human pituitary adenomas: implications for paradoxical secretion and tumorigenesis.

Pituitary adenomas are very common in humans. They are of monoclonal origin, very heterogeneous, and produce frequently paradoxical secretion. The normal anterior pituitary (AP) contains some unorthodox multifunctional cells able to store more than one AP hormone (polyhormonal) and/or to express multiple hypothalamic-releasing hormone receptors (multiresponsive). Multifunctional AP cells seem to be involved in plasticity processes such as transdifferentiation or paradoxical secretion. Here, we have characterized the single-cell phenotypes of 15 human pituitary tumors, including prolactinomas, nonfunctioning adenomas, and adenomas from multiple endocrine neoplasia type I (MEN-I) and pituitary Cushing's disease patients. Individual tumor cells were typed according to expression of AP hormones and hypothalamic-releasing hormone receptors by combination of calcium imaging and multiple sequential immunocytochemistry in the same cells. We found a large heterogeneity among the different tumors. In eight of the 15 tumors studied, more than 80% of the cells presented a multifunctional phenotype. This may explain the occurrence of paradoxical secretion. In addition, our results suggest that human pituitary adenomas might derive from multifunctional cells. This is consistent with the existence of a link between pituitary plasticity and tumorigenesis.

Hypothalamo-pituitary abnormalities in adult patients with langerhans cell histiocytosis: clinical, endocrinological, and radiological features and response to treatment.

Langerhans cell histiocytosis (LCH) is a rare disorder in which granulomatous deposits occur at multiple sites within the body, but which often involves the hypothalamo-pituitary axis (HPA). Although diabetes insipidus (DI) is a well recognized complication, the frequency of anterior pituitary and other nonendocrine hypothalamic (NEH) involvement has not been well defined, particularly in adult patients with the disease. We have evaluated the frequency and progression of LCH-related anterior pituitary and other NEH dysfunction and their responses to treatment in 12 adult patients with histologically proven LCH and DI. They were followed up for a median of 11.5 yr (range, 3-28 yr) after the diagnosis of DI was made. Study evaluations comprised clinical (including formal psychometric assessment where appropriate), basal and dynamic pituitary function tests, and radiology with computed tomography and/or magnetic resonance imaging scanning. Eleven patients received systemic treatment, and 5 patients received external beam radiotherapy confined to the HPA. The median age at diagnosis of DI was 34 yr (range, 2-47 yr); DI was the presenting symptom in four patients, whereas the remaining eight each developed DI 1-20 yr (median, 2 yr) after the diagnosis of LCH. Eight patients developed one or more anterior pituitary hormonal deficiencies at a median of 4.5 yr (range, 2-22 yr) after the diagnosis of DI: GH deficiency developed in eight patients (median, 2 yr; range, 2-22 yr), FSH-LH deficiency in 7 patients (median, 7 yr; range, 2-22 yr), and TSH and ACTH deficiency in five patients (median, 10 yr; range, 3-16 and 3-19 yr), respectively; five patients developed panhypopituitarism. In addition, seven patients with anterior pituitary dysfunction also developed symptoms of other NEH dysfunctions at a median of 10 yr (range, 1-23 yr): five morbid obesity (body mass index, >35), five short term memory deficits, four sleeping disorders, two disorders of thermoregulation, and one adipsia. All patients developed disease outside of the hypothalamus during the course of the study, and no fluctuation of disease activity in the HPA region was noted. Radiological examination of the HPA was abnormal in each of the eight patients with anterior pituitary involvement and in the seven patients with NEH dysfunction (one or more abnormalities): seven had thickening of the infundibulum, and one had hypothalamic and thalamic signal changes. All patients who had a magnetic resonance imaging scan had absence of the bright spot of the posterior pituitary on the T1-weighted sequences, and in four patients with DI and normal anterior pituitary function this was the only abnormality. The five patients who received radiotherapy to the HPA achieved a partial or complete radiological response, and there was no evidence of tumor progression in this region. No form of therapy, including chemotherapy, improved any established hormonal deficiencies or symptoms of NEH. In summary, in our adult patients with hypothalamic LCH and DI, anterior pituitary hormonal deficiencies developed in 8 of 12 patients; these occurred over the course of 20 yr. They were frequently accompanied by structural changes of the HPA, although these were often subtle in nature. In addition, symptoms of NEH dysfunction developed in up to 90% of such patients and complicated management. Radiotherapy may be useful in achieving local control of tumor, but established anterior, posterior pituitary, and other NEH dysfunctions do not improve in response to current treatment protocols. Patients with LCH and DI, particularly those with multisystem disease and a structural lesion on radiology, should undergo regular and prolonged endocrine assessment to establish anterior pituitary deficiency and provide appropriate hormonal replacement.

Role of nitric oxide in the neuroendocrine responses to cytokines.

During infection, bacterial and viral products, such as bacterial lipopolysaccharide (LPS), cause the release of cytokines from immune cells. These cytokines can reach the brain by several routes. Furthermore, cytokines, such as interleukin-1 (IL-1), are induced in neurons within the brain by systemic injection of LPS. These cytokines determine the pattern of hypothalamic-pituitary secretion which characterizes infection. IL-2, by stimulation of cholinergic neurons, activates neural nitric oxide synthase (nNOS). The nitric oxide (NO) released diffuses into corticotropin-releasing hormone (CRH)-secreting neurons and releases CRH. IL-2 also acts in the pituitary to stimulate adrenocorticotropic hormone (ACTH) secretion. On the other hand, IL-1 alpha blocks the NO-induced release of luteinizing hormone-releasing hormone (LHRH) from LHRH neurons, thereby blocking pulsatile LH but not follicle-stimulating hormone (FSH) release and also inhibiting sex behavior that is induced by LHRH. IL-1 alpha and granulocyte macrophage colony-stimulating factor (GMCSF) block the response of the LHRH terminals to NO. The mechanism of action of GMCSF to inhibit LHRH release is as follows. It acts on its receptors on gamma-aminobutyric acid (GABA)ergic neurons to stimulate GABA release. GABA acts on GABAa receptors on the LHRH neuronal terminal to block NOergic stimulation of LHRH release. This concept is supported by blockade of GMCSF-induced suppression of LHRH release from medial basal hypothalamic explants by the GABAa receptor blocker, bicuculline. IL-1 alpha inhibits growth hormone (GH) release by inhibiting GH-releasing hormone (GHRH) release, which is mediated by NO, and stimulating somatostatin release, also mediated by NO. IL-1 alpha-induced stimulation of prolactin release is also mediated by intrahypothalamic action of NO, which inhibits release of the prolactin-inhibiting hormone dopamine. The actions of NO are brought about by its combined activation of guanylate cyclase-liberating cyclic guanosine monophosphate (cGMP) and activation of cyclooxygenase and lipoxygenase with liberation of prostaglandin E2 and leukotrienes, respectively. Thus, NO plays a key role in inducing the changes in release of hypothalamic peptides induced in infection by cytokines. Cytokines, such as IL-1 beta, also act in the anterior pituitary gland, at least in part via induction of inducible NOS. The NO produced inhibits release of anterior pituitary hormones.

Circadian rhythms in adenohypophysial hormone levels and hypothalamic monoamine turnover in mycobacterial-adjuvant-injected rats.

The effect of Freund's adjuvant injection on 24-hour variation in circulating ACTH, prolactin, growth hormone (GH) and thyroid-stimulating hormone (TSH) levels, and of hypothalamic norepinephrine (NE) content and dopamine (DA) and serotonin (5HT) turnover was examined in adult rats. In control rats, serum ACTH and prolactin exhibited peak values at the light-dark transition while the maximum in TSH was found in the late afternoon. GH levels did not vary on a 24-hour basis. In Freund's-adjuvant-injected rats, 24-hour variations in TSH levels became blunted while 24-hour variations in prolactin and ACTH persisted. Freund's adjuvant treatment augmented serum ACTH and prolactin levels, and decreased GH and TSH levels. Hypothalamic NE content, and turnover of DA and 5HT varied on a 24-hour basis in rats receiving adjuvant's vehicle. The NE content of the anterior, medial and posterior hypothalamus peaked at 04.00 h, while that of the median eminence attained its maximum at 16.00-20.00 h. Maxima in hypothalamic DA and 5HT turnover occurred at 04.00 h regardless of the region examined. In Freund's-adjuvant-injected rats, reduced amplitude of daily variations of NE content in the median eminence and anterior and medial hypothalamus, as well as a phase advance in the 24-hour rhythm of the posterior hypothalamic NE content were seen. Mycobacterial adjuvant injection also reduced the amplitude of circadian rhythm in hypothalamic 5HT turnover, shifted the maximum in median eminence DA turnover towards light-dark transition, and decreased the amplitude of DA turnover rhythm in the anterior, medial and posterior hypothalamus. Administration of the immunosuppressant drug cyclosporine restored the augmented ACTH and prolactin levels and the depressed GH and TSH levels found in Freund's-adjuvant-injected rats. Cyclosporine was also effective to restore 24-hour rhythmicity of serum ACTH and TSH, but not of prolactin levels. Immunosuppression restored rhythmicity of NE content and of DA and 5HT turnover in anterior, medial and posterior hypothalamic regions. Cyclosporine did not modify the effect of Freund's adjuvant on median eminence but in was able to counteract the changes in the DA and 5HT turnover in the median eminence found after immunization. The results are in accord with a significant effect of immune-mediated inflammatory response at an early phase after Freund's adjuvant injection on ACTH, GH, prolactin and TSH release mechanisms, which was partially sensitive to immunosuppression induced by cyclosporine.

Idiopathic hypothalamic diabetes insipidus, pituitary stalk thickening, and the occult intracranial germinoma in children and adolescents.

We report nine consecutive children and adolescents [five females and four males; aged 2 yr 8 months (m) to 18 yr 1 m] studied over the last 5 yr with idiopathic central diabetes insipidus. In addition to vasopressin deficiency, anterior pituitary hormone deficiencies were detected, either on evaluation at presentation or during follow-up studies over the following 3 yr. Four patients had an increased concentration of plasma PRL. One patient had multiple pituitary hormone deficiencies at diagnosis, and two others developed the same by 21 m of follow-up. Brain magnestic resonance imaging scans, performed at presentation, were originally interpreted as normal in four of nine patients, except for absence of the bright posterior pituitary signal; after retrospective review, two of nine were considered normal. All of the brain magnetic resonance imaging (MRI) scans showed positive findings by 14 m of follow-up. The first abnormal finding in all patients was isolated pituitary stalk thickening. Evaluation of cerebrospinal fluid (CSF) for hCG was positive in three of eight evaluated patients; the three positive CSF values were found at presentation and 3 and 9 m after presentation. All eight patients assessed were negative for CSF alpha-fetoprotein and cytology, and no patient had serum tumor markers. Transsphenoidal biopsy of the lesion in seven of nine patients showed a germinoma in six patients and inflammatory cells in one. The six patients with documented germinoma comprise 31% of the intracranial germinomas diagnosed in this age group at the University of California-San Francisco during the last 5 yr. The patient with mononuclear inflammatory cells on biopsy along with one other patient have had spontaneous resolution of their stalk thickening. So-called "idiopathic" central diabetes insipidus warrants close follow-up to determine the etiology, especially if anterior pituitary hormone deficiencies are detected. Normal brain MRI scans or scans that show isolated pituitary stalk thickening merit follow-up with serial contrast enhanced brain MRI for the early detection of an evolving occult hypothalamic-stalk lesion. CSF evaluation is recommended at presentation because elevated CSF hCG may precede MRI abnormalities.

Desensitisation of somatostatin, TRH and GHRH responses to glucose in the diabetic (Goto-Kakizaki) rat hypothalamus.

We have studied the effects of glucose on the release of somatostatin (SS), TRH and GHRH from incubated hypothalami of normal and genetically diabetic, Goto-Kakizaki (GK) rats. The active isomer D-glucose caused a dose-related inhibition of SS, TRH and GHRH from normal rat hypothalami over a 20-min incubation period in vitro. In contrast, in GK rats the effects of glucose on TRH and SS were significantly reduced and the effects on GHRH were abolished. These data indicate that the sensitivity of SS-, TRH- and GHRH-producing hypothalamic neurones is reduced in diabetic rats. The effect is most pronounced for GHRH release as there was no change in the release of this peptide with increasing glucose concentrations. In conclusion, it appears that the diabetic state in GK rats causes differential desensitisation (GHRH > TRH and SS) of neuronal responses to subsequent changes in glucose concentrations in vitro. This may be due to alterations in the neurotransmitter control and/or a reduction in number, affinity or function of glucose transporters on these peptidergic neurones or other intermediary neuronal pathways.

Morphine withdrawal alters anterior pituitary hormone secretion, brain endopeptidase activity and brain monoamine metabolism in the rat.

Rats were made tolerant to morphine by a 5-day regimen with increasing doses. The time course of changes in serum anterior pituitary hormone levels, brain endo- and exopeptidase activity, levels of brain biogenic amines and body weight were studied during abrupt morphine withdrawal. Cold stimulated secretion of thyrotropin and the secretion of growth hormone were both decreased whereas that of prolactin was increased. In the hypothalamus both prolyl endopeptidase and dipeptidyl peptidase IV activities were concomitantly increased. The hypothalamic 5 hydroxyindole acetic acid levels were also increased. Changes in hormone secretion, peptidase activity and monoamine turnover had returned to baseline levels by 92 hr. Our results indicate that morphine withdrawal and the associated stress produce alterations in anterior pituitary thyrotropin and growth hormone secretion. Concomitant increases in hypothalamic prolyl endopeptidase and dipeptidyl peptidase activities may contribute to these changes.

Comparison of thermoregulatory characteristics of patients with intra- and suprasellar pituitary adenomas.

Thermoregulatory capabilities under physiologic cold and heat exposure of 37 patients with suprasellar pituitary adenomas (As) and 10 patients with intrasellar adenomas (Ai) were analyzed and compared to each other and to 13 controls (Ctr.) In Ai no shift of the thermoregulatory threshold temperatures was observed. In As the regulation was shifted to a 0.5 degrees C higher mean body temperature in 82% of the patients, indicating a "set-point" elevation. The accuracy of the regulation against thermal loads was maintained, the velocity was reduced. Postoperative examination of As revealed a normalisation of the "set-point". Modifications of the hypothalamic amine systems by the compressive effect of the suprasellar adenomas are discussed to be the most probable cause for the observed thermoregulatory alterations.

An interleukin-1-alpha-like neuronal system in the preoptic-hypothalamic region and its induction by bacterial lipopolysaccharide in concentrations which alter pituitary hormone release.

We studied the effect of intravenous injection of lipopolysaccharide (LPS) (30-250 micrograms) on the release of several anterior pituitary hormones as indicated by changes in their concentrations in plasma. Within 30 min after intravenous injection of LPS there was a dose-related stimulation of ACTH release; prolactin (PRL) release was induced only by the highest LPS dose injected (250 micrograms). Even the lowest dose of LPS (30 micrograms) decreased plasma growth hormone (GH) by 60 min. Higher doses lowered plasma GH by 30 min, but thyroid-stimulating hormone release was only significantly inhibited by the highest dose of LPS. The action of LPS seems to be primarily exerted on the central nervous system, since incubation of hemipituitaries with LPS for 3 h in doses ranging from 0.001 to 10 micrograms/ml had no effect on ACTH release. LPS is thought to induce its effects on hormones either by release of cytokines from immune cells which subsequently induce the hormonal changes or possibly by direct action within the hypothalamus. In this report we demonstrate the immunocytochemical localization of a population of interleukin-1 alpha (IL-1 alpha)-like cells in a region extending from the basal forebrain at the level of the diagonal band of Broca, caudally and dorsally to the dorsolateral preoptic region and the hypothalamus at the level of the paraventricular nucleus. Further caudally, IL-1 alpha-like immunoreactive cells were located in the midportion of the amygdala. Two hours after injection of the 125-micrograms dose of LPS, the number of these immunoreactive cells was dramatically increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypopituitarism after tuberculous meningitis in childhood.

OBJECTIVE: To study the prevalence and pathogenesis of hypopituitarism following tuberculous meningitis in childhood. DESIGN: A retrospective cross-sectional study. SETTING: A university teaching hospital and a tuberculosis referral center. PATIENTS: Forty-nine patients, aged 23.4 +/- 6.0 years (mean +/- SD), who had tuberculous meningitis in childhood (age at diagnosis, 5.9 +/- 5.0 years) were studied. MEASUREMENTS: A detailed assessment of hypothalamic-pituitary function, including conventional stimulation tests and responses to four hypothalamic releasing hormones, was done. Magnetic resonance imaging of the hypothalamic-pituitary region was performed in patients with abnormal endocrine function. RESULTS: Ten patients were found to have abnormal pituitary function: Seven had growth hormone deficiency, four of whom also had gonadotropin deficiency; the other three had gonadotropin deficiency, corticotropin deficiency, and mild hyperprolactinemia, respectively; none had diabetes insipidus. Among those with growth hormone deficiency, a significant correlation (r = 0.749, P < 0.05) was found between the height standard deviation score and the age at diagnosis of tuberculous meningitis. Growth hormone, corticotropin, and gonadotropin responses to growth hormone releasing hormone, corticotropin releasing hormone, and gonadotropin releasing hormone, respectively, suggested a hypothalamic defect in five patients. Magnetic resonance imaging scans of the hypothalamic-pituitary region were abnormal in five patients. CONCLUSIONS: Hypopituitarism was documented in 20% of a small subset of patients years after recovery from tuberculous meningitis in childhood. The cause appears to be tuberculous lesions affecting the hypothalamus, pituitary stalk and, directly or indirectly, the pituitary itself. Early recognition and treatment can be beneficial.