Evidence that thyrotropin-releasing hormone is not a major prolactin-releasing factor during suckling in the rat.

The purpose of this study was to investigate whether TRH could be an important PRL-releasing factor during suckling in the rat. Plasma PRL, TSH, beta-endorphin-like immunoreactivity, and GH responses in serial blood samples from unanesthetized suckled rats were determined. The resulting hormonal profile was compared with that obtained when TRH (500 ng/kg BW, iv) was injected at the onset of suckling. Suckling evoked a rise in plasma levels of PRL, beta-endorphin-like immunoreactivity, and GH, but not in TSH. In contrast, exogenous TRH caused a 9-fold increase in plasma TSH levels during suckling without further increasing the PRL response. Since plasma PRL responses are reportedly enhanced by previous suckling, we also determined plasma PRL and TSH levels when TRH (25 ng/rat, iv) was given 30 min after a brief suckling episode. TRH caused a 2.5-fold increase in plasma TSH, but did not significantly increase plasma PRL levels. Since suckling increases plasma PRL without increasing plasma TSH, and TRH increases TSH but not PRL levels, we conclude that TRH is not a major PRL-releasing factor during suckling.

Opiate modulation of the anterior pituitary hormone response during suckling in the rat.

We have investigated the influence of endogenous opiates on hormone responses during suckling in the rat. In complementary experiments, opiate receptors were blocked by naloxone (NAL) or endogenous opiate release from the pituitary was inhibited by dexamethasone (DEX). Serial blood samples from unanesthetized suckled rats were then assayed for plasma PRL, beta-endorphin-like immunoreactivity (beta-END-LI), TSH, and GH levels. Identical studies were also done in saline-treated (control) suckled rats and in unsuckled rats exposed to control objects. Whereas suckling caused a rise in plasma PRL, beta-END-LI, and GH, introduction of plastic control objects did not elevate hormone levels. NAL blocked the GH rise and depressed TSH levels, but did not significantly inhibit the PRL or beta-END-LI response. DEX prevented the beta-END-LI rise and blocked the GH rise, but did not inhibit TSH. DEX enhanced PRL release during suckling. These results demonstrate that 1) the responses of beta-END-LI, PRL, and GH are not an artifact of the sampling procedure; 2) PRL release during suckling is independent of beta-END-LI release by the pituitary; and 3) suckling stimulates the release of ACTH, beta-END, and beta-lipotropin from the anterior pituitary. Our results are consistent with both a role of pituitary beta-END in the control of GH and a role of corticosterone in the control of PRL during suckling.

Prolactin pulsatile characteristics in postmenopausal women.

Pulsatile PRL secretion undergoes diurnal variation, with maximal PRL release in the evening during sleep in both women and men. However, the impact of the menopause on PRL pulsatile dynamics are largely unknown. To characterize diurnal PRL pulsatile secretion in postmenopausal women, we performed frequent venous sampling over 24 h every 10 min for serum PRL in 7 postmenopausal women (age, 56 +/- 4 yr) and in 2 control groups, 8 men (age, 25 +/- 8 yr) and 22 cycling women (age, 28 +/- 5 yr), at 3 phases of the menstrual cycle. Standard TRH tests (200 microg, i.v.) were administered at 0900 h after completion of the 24-h sampling, and PRL levels were then obtained at 0, 10, 20, 30, and 60 min in all subjects. PRL pulse characteristics were similar between the postmenopausal women and men. Mean serum PRL levels and PRL pulse frequency were significantly higher in the cycling women than in either postmenopausal women or men over 24 h and during either the day or night periods. Mean serum PRL levels and pulse frequency were significantly higher during the night compared to those during the day in all groups. Pulse amplitude was higher during the night vs. the day in all groups and was highest in the cycling women. PRL responses to TRH administration were greatest in cycling women. These data demonstrate that PRL pulse dynamics are significantly different between postmenopausal women and cycling women, and endogenous estrogen levels may have an important role in this difference. Pulsatile PRL secretion is similar between postmenopausal women and men, suggesting that estrogen levels modulate PRL dynamics across genders.

Endocrine function following high dose proton therapy for tumors of the upper clivus.

The endocrine status of patients receiving proton radiation for tumors of the upper clivus was reviewed to evaluate the effect of high dose treatment on the pituitary gland. The fourteen patients had chordomas or low grade chondrosarcomas and were all treated by the same techniques. The median tumor dose was 69.7 Cobalt Gray Equivalent (CGE) with a range from 66.6 to 74.4 CGE. (CGE is used because modulated protons have an RBE of 1.1 compared to 60Co). The daily fraction size was 1.8-2.1 CGE. The median follow-up time is 48 months, ranging from 30 to 68 months. All treatments were planned using a computerized multi-dimensional system with the position of the pituitary outlined on the planning CT scan. Review of the dose distribution indicated that the dose to the pituitary ranged from 60.5 to 72.3 CGE, with a median of 67.6 CGE. One female patient had decreased thyroid and gonadotropin function at the time of diagnosis and has been on hormone replacement since that time. The other three females were all pre-menopausal at the time of radiotherapy. At this time four patients (3 males and 1 female) have developed endocrine abnormalities 14 to 45 months after irradiation. All four had evidence of hypothyroidism and two have also developed corticotropin deficiency. The three males had decreased testosterone levels; the female patient developed amenorrhea and hyperprolactinemia. All four are asymptomatic with ongoing hormone replacement.

Neurologic manifestations of hypothalamic disease.

The hypothalamus, in addition to regulating the anterior and posterior pituitary, controls water balance through thirst, regulates food ingestion and body temperature, influences consciousness, sleep, emotion and other behaviors. Much has been learned of these effects in human disease through the clinical manifestations that occur with hypothalamic lesions. This study reviews the clinical pathologic correlations that have been made in recent years showing that regions of the hypothalamus exert functions in humans that are similar to those identified in experimental animals. Clinical pathologic correlations have not always provided precise analysis of hypothalamic function. The hypothalamus is small and often lesions that come to clinical attention achieve considerable size before their recognition, making local anatomic dissections of the effects of the lesions difficult. Nevertheless, the use of modern non-invasive techniques including CT scans and magnetic resonance imaging (MRI) have provided new information not previously available. This paper reviews several cases of hypothalamic disorder recognized recently. (1) A 33-year-old black man with hypothalamic sarcoidosis. Manifestations of hypothalamic dysfunction included panhypopituitarism, aggressive hyperphagia, polydipsia (partially due to hyperglycemia secondary to diabetes mellitus), drowsiness, depression, and irritability. (2) A 37-year-old woman with a large intrahypothalamic tumor (biopsy showed pituitary adenoma), with drowsiness, poikilothermia, lack of satiety, confusion, and memory loss. She becomes depressed when she is transiently more alert (as after hypertonic contrast-dye infusion). (3) A 60-year-old man with hypothalamic compression by a pituitary tumor, associated with syndrome of inappropriate ADH (SIADH), severe anorexia, memory loss, but preserved thirst. After surgical decompression of the tumor his appetite acutely recovered, but he developed severe hypo(poikilo)thermia. (4) A 45-year-old woman with a suprasellar craniopharyngioma presented with severe drowsiness, hyperphagia, depression, and memory loss post-operatively, which responded to antidepressants (except for the memory loss). She had extremely labile blood pressures and serum Na for about 1 week post-operatively.

Tuberoinfundibular neurons: dopaminergic and norepinephrinergic sensitivity.

The techniques of microelectrophoresis and antidromic identification have been utilized in the female rat anesthetized with urethane to localize the tuberoinfundibular neurons and to determine their pharmacological sensitivity to dopamine (DA), norepinephrine (NE) and glutamate (GLUT). Extracellular recordings were made of 149 single units in the arcuate (ARC) nucleus; 79 of which were antidromically identified (43 were spontaneously active and 36 were silent) and the remaining 70 cells were determined to be spontaneously active but could not be antidromically identified (unidentified ARC neurons). The mean latency of the antidromically activated potentials was 9,5 msec, which gave a conduction velocity of 0.05 mm/msec. The spontaneous firing rate of antidromically identified ARC neurons varied from less than 1/sec to 8/sec while unidentified cells discharged at rates from less than 3/sec to 10/sec. These data indicate that ARC neurons exist which are capable of conducting impulses and send their axons into the external layer of the ME. Successful drug applications were made on 104 ARC neurons; of the 43 antidromically identified units, 37 were spontaneously active and 6 were silent. There were 61 spontaneously active, unidentified neurons. Two distinct pools of antidromically identified ARC neurons were found based on their sensitivity to NE and DA. Neurons displaying excitation to NE(N = 23) were either inhibited (N = 10) or non-responsive (N = 13) to DA applied electrophoretically; no NE-sensitive ARC neurons were excited by DA. The second pool of neurons (N = 14) was excited by DA. These neurons when tested with NE were either reproducibly inhibited (N = 3) or nonresponsive (N = 11); no DA-sensitive neurons were excited by NE. In the unidentified ARC neurons, iontophoretically applied NE and DA gave reproducible effects on individual neurons, so that some neurons were excited by both NE and DA, some were inhibited by both, and still others were excited by one and inhibited by the other chemical. Glutamate (GLUT) had a powerful excitant action on nearly all the neurons tested, increasing the electrical activity of the spontaneously active neurons as well as initiating activity in quiescent ARC neurons. These data are suggestive of a tuberoinfundibular neuronal system whose activity is modulated by either DA or NE. This evidence is certainly compatible with a functional role for both DA and NE in regulating pituitary function by altering the activity of presumed neurosecretory neurons which release hypophysiotropic hormones.

The effect of amphetamine on the in vivo release of dopamine, somatostatin and neuropeptide Y from rat caudate nucleus.

Somatostatin, neuropeptide Y and dopamine release from the conscious rat caudate nucleus were investigated using the push-pull perfusion method. Significant reductions in somatostatin and neuropeptide Y release coincided with increased dopamine release, suggesting that dopamine has an inhibitory effect on the release of both peptides. Changes in the levels of both peptides were positively correlated, consistent with their co-release from neuropeptide Y- and somatostatin-containing striatal neurons.

The regional hypothalamic distribution of type II 5'-monodeiodinase in euthyroid and hypothyroid rats.

The brain topographical distribution of type II 5'-monodeiodinase (5'D-II), which converts thyroxine (T4) to triiodothyronine (T3), was studied in euthyroid and hypothyroid rats. Low levels of 5'D-II activity were detected in the median eminence, but not in any other brain regions of euthyroid rats. The arcuate nucleus and median eminence were also the sites of highest 5'D-II activity in brains of hypothyroid rats. Under these conditions, the paraventricular nucleus contained almost no detectable 5'D-II, while intermediate enzyme activity was present in other medial basal hypothalamic sites.

Sex differences in vasoactive intestinal peptide (VIP) concentrations in the anterior pituitary and hypothalamus of rats.

Recent evidence suggests that vasoactive intestinal peptide (VIP), a putative prolactin (PRL)-releasing factor, is both synthesized and released by anterior pituitary cells, to act as a paracrine or autocrine factor. We have investigated the hypothesis that hypothalamic or pituitary VIP levels differ in male and female rats, since neuroendocrine control of PRL is sexually differentiated. Opposite sex differences were found in the hypothalamus and anterior pituitary. Random-cycle female rats had one-third higher VIP levels in the hypothalamus than males. In contrast, anterior pituitary VIP levels were 3 times as high in male rats as in females. Median eminence VIP levels were similarly low in both sexes. These results support a possible role of VIP in the sexually dimorphic regulatory mechanisms of PRL secretion. Moreover, demonstration that hypothalamic and pituitary VIP levels vary in opposite directions suggests that VIP is differentially regulated at the two sites.

Midbrain central gray: LHRH infusion enhances lordotic behavior in estrogen-primed ovariectomized rats.

Ovariectomized rats were implanted with 23 gauge stainless steel cannulae in the ventrolateral midbrain central gray. Twelve sexually active rats were estrone-primed and infused with saline and 50 ng luteinizing hormone-releasing hormone (LHRH) in counterbalanced order. Infusion of luteinizing hormone-releasing hormone significantly enhanced the lordotic response to coital stimulation compared to saline infusion. These results support the role of hypothalamo-mesencephalic LHRH-containing pathways in modulating lordotic behavior in estrogen-primed ovariectomized rats.

Midbrain LHRH infusions enhance lordotic behavior in ovariectomized estrogen-primed rats independently of a hypothalamic responsiveness to LHRH.

Lordotic behavior of ovariectomized estrone-primed rats was measured after infusions of luteinizing hormone-releasing hormone (LHRH), thyrotropin (TRH) or saline into the ventrolateral midbrain central gray (VL-MCG), or after LHRH or saline infusions into a lateral control site, the dorsolateral reticular formation (DL-RF). Infusion of LHRH, but not TRH, into the VL-MCG increased lordotic behavior. LHRH had no effect in the DL-RF. In a second experiment, rats were fitted with cannulae in the VL-MCG and in the arcuate-ventromedial nucleus area (ARC-VM). Serotonin was infused into the ARC-VM, and LHRH was infused into either the ARC-VM or the VL-MCG. Serotonin blocked the behavioral effect of LHRH infusion into the ARC-VM, but did not prevent enhancement of lordosis by LHRH infusions into the VL-MCG. These results suggest that LHRH infusions into the midbrain do not require hypothalamic responsiveness to LHRH for their effect, and are therefore unlikely to act by diffusion of LHRH rostrally. The effect of LHRH in the midbrain is site-specific, since lateral infusions (1.75 mm away) were ineffective.

Effects of lesions of putative LHRH-containing pathways and midbrain nuclei on lordotic behavior and luteinizing hormone release in ovariectomized rats.

Lordotic behavior and LH release were measured in ovariectomized rats after radiofrequency lesions of the midbrain central gray (MCG), interpeduncular nucleus (IPN), mammillary bodies (MMM), stria medullaris (SM), or fasciculus retroflexus (FR), areas which are reported to contain immunoactive luteinizing hormone-releasing hormone (LHRH), a hypothalamic decapeptide which has been implicated in the neuroendocrine control of lordosis. SM and FR lesions increased lordotic behavior after estrone-priming. IPN lesions reversed an increase in lordotic behavior seen in IPN sham-lesioned animals treated with estrone. MCG lesions decreased lordotic behavior after estrone-priming, while MMM lesions had no effect. None of the lesions significantly altered lordotic responsiveness when animals were repeatedly mated or were treated with estrone + progesterone. There was a slight decrease in serum LH levels in SM animals. Results are interpreted in terms of the role of LHRH in control of lordosis, and of midbrain mechanisms for influencing lordotic behavior.

Functional transplantation of the rat pituitary gland.

OBJECTIVE: These studies evaluated the ability of transplanted pituitary cells to restore pituitary function in hypophysectomized rats. METHODS: The pituitary glands of neonatal Lewis rats were rapidly removed, enzymatically dispersed, and stereotactically introduced into the third ventricle of hypophysectomized adult male Lewis rats. Four weeks after implantation, plasma levels of anterior pituitary hormones in implanted animals were compared with those of sham-transplanted control animals. RESULTS: Plasma levels of prolactin, growth hormone, thyroid-stimulating hormone, and beta-endorphin were below the range of detection in 14 sham-operated animals. In implanted animals, restitution of serum prolactin occurred in 100% of the animals tested, with levels of 2.6 +/- 1.0 ng/ml (mean +/- standard error of the mean; normal, 2-4 ng/ml). Growth hormone was assayable in 71% of the animals, with a mean value of 29 +/- 13 ng/ml over all animals (normal, 1-100 ng/ml); thyroid-stimulating hormone was restored in 68%, with mean resting levels of 79 +/- 13 ng/ml (normal, 100-400 ng/ml); luteinizing hormone levels were found in 53%, with mean levels over all animals of 0.2 +/- 0.1 ng/ml (normal, 0.5-1.0 ng/ml); and beta-endorphin was restored in 45% to high resting levels of 163 +/- 31 pg/ml (normal, 20-30 pg/ml). A challenge with hypothalamic releasing factor and a cold stress test were performed on the animals that had received transplants. Positive hormone responses to both of these tests suggested sensitivity of the pituitary grafts to both endogenous and exogenous sources of stimulation. Histological sections of paraformaldehyde-fixed brains from implanted animals clearly demonstrated survival of clusters of grafted pituitary cells. Positive immunohistochemical staining for adrenocorticotropic hormone and thyroid-stimulating hormone was demonstrated in sections of the grafted tissue. CONCLUSION: These data suggest survival of neonatal pituitary transplants in the third ventricle of adult hypophysectomized rats with concomitant restoration of anterior pituitary hormone function.

Effect of cysteamine on suckling-induced prolactin secretion in the rat.

We have examined the effects of the thiol agent cysteamine on physiological prolactin secretion in the female rat. Administration of cysteamine completely abolishes suckling-induced prolactin secretion in a dose-dependent manner. Cysteamine treatment does not alter nursing behavior of the mothers. Further, we have found that the prolactin-depleting ability of cysteamine is not altered by a prior suckling stimulus. These results indicate that cysteamine administration inhibits physiologically-induced prolactin secretion with similar potency and efficacy as previously reported for cysteamine effects on basal and pharmacologically-induced prolactin secretion. Furthermore, the effect of cysteamine is not compromised by a previous suckling stimulus, suggesting that "depletion-transformation" of pituitary prolactin stores does not protect against the effect of cysteamine.

Pregnancy modulates precursor cell proliferation in a murine model of focal demyelination.

In mice, pregnancy has been shown to have a beneficial effect on the endogenous repair of focal lysolecithin-induced CNS demyelinative lesions, enhancing the genesis of new oligodendrocytes and the degree of remyelination. To identify local cells undergoing mitosis in response to such lesions, we examined the time course of phospho-histone H3 (PH3) and myelin basic protein (MBP) expression by immunohistochemistry. After lysolecithin injection into the corpus callosum of virgin female mice, the number of dividing cells peaked about 48 h after injection and declined gradually to baseline by day 7; in pregnant mice, this initial peak was unchanged, but a new delayed peak on day 4 was induced. Colocalization data using PH3 and NG2 proteoglycan, or bromodeoxyuridine (BrdU) and oligodendrocyte transcription factor 1 (Olig1), suggested that about 75% of the proliferating cells on day 2, and about 40% of the cells on day 4, were likely of oligodendrocyte lineage; these differential percentages were of the same magnitude in both virgin and pregnant animals. Notably, the heightened proliferative response to focal lysolecithin injection during pregnancy was specific to gestational stage (early, but not late) and to lesion location (in the corpus callosum of the periventricular forebrain, but not in the caudal cerebellar peduncle of the hindbrain).

The role of prolactin in autoimmune demyelination: suppression of experimental allergic encephalomyelitis by bromocriptine.

Several lines of evidence suggest that the anterior pituitary hormone prolactin has a stimulatory role on immune function and that pharmacological suppression of prolactin secretion with the dopamine-agonist bromocriptine suppresses both humoral and cellular immunity. Here, we describe the effects of prolactin-suppression on the course of experimental allergic encephalomyelitis in female Lewis rats. Initiation of continuous bromocriptine treatment before immunization reduced both the severity and incidence of clinical signs of acute experimental allergic encephalomyelitis. Experimental allergic encephalomyelitis-immunized rats experienced a threefold rise in basal prolactin levels on day 4 after immunization and maintained elevated prolactin levels on day 10, before the onset of neurological signs of experimental allergic encephalomyelitis. Bromocriptine treatment reduced prolactin levels to those of sham-immunized rats. In vivo bromocriptine pretreatment inhibited splenic lymphocyte proliferative responses in vitro to the immunizing antigen and to concanavalin A. Moreover, bromocriptine therapy was protective when initiated 1 week after the initial immunization and was also effective in suppression of late disease. These results indicate that (1) prolactin levels are elevated after immunization and before the onset of experimental allergic encephalomyelitis, (2) bromocriptine inhibits both prolactin secretion and the severity of acute experimental allergic encephalomyelitis, and (3) inhibition is also present when treatment is begun after sensitization, suggesting an effect of prolactin on the effector limb of the immune response during experimental allergic encephalomyelitis.

Case report of unusual leukoencephalopathy preceding primary CNS lymphoma.

A previously healthy 35 year old woman presented with bilateral uveitis associated with multiple, evolving, non-enhancing white matter lesions consistent with a progressive leukoencephalopathy such as multiple sclerosis. Thirty months after her initial presentation, she was diagnosed with primary CNS lymphoma and died 14 months later. The unusual clinical course preceding the diagnosis suggests that a demyelinating disease may have preceded, and possibly heralded, the development of primary CNS lymphoma. Cases of "sentinel lesions" heralding the diagnosis of primary CNS lymphoma have been reported, and this case further corroborates such instances and raises further issues regarding possible neoplastic transformation occurring in inflammatory diseases such as multiple sclerosis.

Vasoactive intestinal peptide in the human pituitary gland and adenomas. An immunocytochemical study.

Recent evidence indicates that vasoactive intestinal peptide (VIP) may be involved in normal pituitary function. Immunocytochemistry was used to localize VIP in human biopsied pituitary adenomas and postmortem anterior pituitary glands. Paraffin sections were immunostained for VIP with the avidin-biotin-peroxidase technique. Strong VIP-like immunoreactivity (VIP-LI) was observed in 16 of 17 prolactinomas, 12 of 14 growth hormone-secreting tumors associated with acromegaly, four of 12 ACTH-secreting tumors, and 14 of 18 nonfunctioning pituitary adenomas. In most cases, VIP was colocalized with the classical pituitary hormones. Six of the 18 nonfunctioning tumors had no demonstrable hormone immunoreactivity; five of these stained strongly for VIP, whereas one was negative. Of 18 normal anterior pituitaries, 12 showed strong diffuse staining for VIP throughout the gland. One pituitary with VIP-LI came from an individual who had undergone pituitary stalk transection. Double-immunoenzyme labeling and immunoelectron microscopy demonstrated VIP-LI in many lactotrophs, scattered thyrotrophs, corticotrophs, and in an occasional gonadotroph. These results suggest the following: 1) VIP is present in more than one cell type in normal and adenomatous human pituitaries; and 2) VIP may be involved in the function and development of pituitary tumors.

Changes in motor cortex activation after recovery from spinal cord inflammation.

Diseases of the spinal cord are associated with reactive changes in cerebral cortex organization. Many studies in this area have examined spinal cord conditions not associated with recovery, making it difficult to consider the value of these cortical events in the restoration of neurological function. We studied patients with myelitis, a syndrome of transient spinal cord inflammation, in order to probe cortical changes that might contribute to recovery after disease of the spinal cord. Seven patients, each of whom showed improvement in hand motor function after a diagnosis of myelitis involving cervical spinal cord, were clinically evaluated then studied with functional MRI. During right and left index finger tapping, activation volumes were assessed in three cortical motor regions within each hemisphere. Results were compared with findings in nine control subjects. Compared to the control group, myelitis patients had larger activation volumes within contralateral sensorimotor as well as contralateral premotor cortex. The degree of daily hand use showed a significant correlation with the volume of activation in contralateral sensorimotor cortex. Recovery from myelitis is associated with an enlarged activation volume in contralateral motor cortices. This change in motor cortex function is related to behavioral experience, and thus may contribute to motor improvement. The expanded activation in motor cortex, seen with several forms of spinal cord insult may have maximal utility when corticospinal tract axons are preserved.