The hypothalamic-pituitary axis: co-development of two organs

The C-525 laser dye at micromolar concentration range is shown to enhance up to two to three orders of magnitude the chemiluminescence (CL) accompanying tert-butyl hydroperoxide (t-BHP)-induced rat liver microsome oxidation and Fe(2+)-induced lipid peroxidation (LPO) in liposomes. C-525 is shown to be a more efficient sensitizer of CL accompanying LPO in membrane systems than the known low-energy excited triplet carbonyl sensitizer, chlorophyll-alpha, (Cl-a). Regarding the sensitization mechanism, C-525 and Cl-a were compared in (a) a peroxyl radical-producing system (2,2'-azobis(2-dimethylvaleronitrile) (AMVN); (b) excited carbonyl-producing systems (3-hydroxymethyl-3,4,4-trimethyl-1,2-dioxetane (HTMD) thermal decomposition and horseradish peroxidase (HRP)-catalyzed isobutanal oxidation); and (c) excited singlet oxygen-producing system [endoperoxide of 3,3-(1,4-naphthylidene)-dipropionate (NDPO2)]. C-525 sensitized CL only in the systems where peroxyl radical and/or triplet excited carbonyls are produced, the mechanism of CL sensitization apparently is energy transfer from the excited triplet carbonyls formed in the peroxyl radical self-reaction via Russell's mechanism or by dioxetane decomposition. Cl-a was found to considerably sensitize CL related to NDPO2 thermal decomposition, a source of singlet oxygen, in addition to acting as a sensitizer of triplet carbonyl CL. The chemical stability of the C-525 laser dye in excited state-generating systems was shown to be appropriate for its application as a sensitizer of CL related to LPO reactions in membranes, but not in the HRP-catalyzed peroxidation system.     

Effects of aging and gonadal failure on the hypothalamic-pituitary axis in women

OBJECTIVE: Our aim was to determine the effect of aging on the hypothalamic-pituitary-gonadal axis function. STUDY DESIGN: We studied 9 women aged 25 to 40 years with well-defined idiopathic premature ovarian failure and compared them with 8 women aged 51 to 70 years who had age-appropriate menopause. All women underwent 24 hours of frequent blood sampling every 10 minutes before and after replacement with transdermal estradiol targeted to achieve serum concentrations of approximately 100 pg/ml. RESULTS: In the absence of estrogen exposure, women with premature ovarian failure demonstrated a greater 24-hour mean luteinizing hormone concentration compared with that in the older women with age-appropriate menopause (32.3+/-4.3 mlU/ml vs 19.2+/-2.4 mlU/ml, p=0.0001). Despite the lesser luteinizing hormone serum levels in the older group, the luteinizing hormone pulse frequency per 24 hours was similar (22.1+/-3.0 pulses per 24 hours in prematurely menopausal women vs 21.9+/-2.5 pulses per 24 hours in the older postmenopausal women, p=0.94). When exposed to estrogen, mean luteinizing hormone concentrations decreased to 11.6+/-2.7 mlU/ml in prematurely menopausal women versus 4.4+/-1.0 mlU/ml in older postmenopausal women, p=0.017. Both groups had suppressed mean luteinizing hormone secretion compared with their paired, non-estradiol-exposed studies, p=0.0001. Frequency of luteinizing hormone pulsations was reduced to 16.5+/-3.5 pulses per 24 hours in prematurely menopausal women exposed to estradiol (p < 0.0058, compared with non-estradiol-exposed women). Further reduction was observed in older postmenopausal women (11.5+/-1.1 pulses per 24 hours, p=0.0001, compared with nonestradiol exposure, and p=0.0125, vs prematurely menopausal, estradiol-exposed women). Pulse amplitude was suppressed in both prematurely menopausal women (5.6+/-0.5 mlU/ml to 2.3+/-0.5 mlU/ml, p=0.0001) and older postmenopausal women (3.6+/-0.4 mlU/ml to 2.3+/-0.6 mlU/ml p=0.04) in the presence of estradiol. Although luteinizing hormone pulse amplitudes were greater in the women with premature menopause in the absence of estradiol (p=0.0028) compared with those in older postmenopausal women, pulse amplitudes became similar in the presence of estradiol. Parallel changes in mean follicle-stimulating hormone were observed. Women with premature ovarian failure had a mean follicle-stimulating hormone level of 71.1+/-9.4 mlU/ml that was suppressed to 18.0+/-4.1 mlU/ml after estradiol exposure (p=0.0001); values in older postmenopausal women were 45.9+/-6.0 and 10.3+/-2.0, respectively (p=0.0001). Although the women with premature ovarian failure secreted more follicle-stimulating hormone in the absence and presence of estradiol, only the former situation was statistically significant (p=0.0008 and p=0.23, respectively). CONCLUSIONS: These data suggest that there is an age-related decrease in gonadotropin secretion that may be hypothalamic or pituitary in origin. There is less luteinizing hormone secreted in women older than age 50. There is greater suppression of luteinizing hormone and follicle-stimulating hormone secretion by estradiol in aged women. Thus these data indicate that postmenopausal hormone changes involve central hypothalamic-pituitary alterations, as well as ovarian changes.     

The transepicondylar axis approximates the optimal flexion axis of the knee

The traditional understanding of knee kinematics holds that no single fixed axis of rotation exists in the knee. In contrast, a recent hypothesis suggests that knee kinematics are better described simply as two simultaneous rotations occurring about fixed axes. Knee flexion and extension occurs about an optimal flexion axis fixed in the femur, whereas tibial internal and external rotations occur about a longitudinal rotation axis fixed in the tibia. No other translations or rotations exist. This hypothesis has been tested. Tibiofemoral kinematics were measured for 15 cadaveric knees undergoing a realistic loadbearing activity (simulated squatting). An optimization technique was used to identify the locations of the optimal flexion and longitudinal rotation axes such that simultaneous rotations about them could best represent the measured kinematics. The optimal flexion axis was compared with the transepicondylar axis defined by bony landmarks. The longitudinal rotation axis was found to pass through the medial joint compartment. The optimal flexion axis passed through the centers of the posterior femoral condyles. No significant difference was found between the optimal flexion and transepicondylar axes. To an average accuracy of better than 3.4 mm in translation, and 2.9 degrees in orientation, knee kinematics were represented successfully by simple rotations about the optimal flexion and longitudinal rotation axes. The optimal flexion axis is fixed in the femur and can be considered the true flexion axis of the knee. The transepicondylar axis axis, which is identified easily by palpation, closely approximates the optimal flexion axis.     

Lactic acid does not directly activate hypothalamic-pituitary corticotroph function

The role that metabolic products play in regulating the hypothalamic-pituitary-adrenal (HPA) axis during strenuous exercise is speculative. This investigation examined the extent to which lactic acid, a major metabolite of anaerobic exercise, directly affects hypothalamic-pituitary function. Specifically, beta-endorphin secretion was measured from AtT-20 (D-16) mouse corticotroph tumor cells treated either acutely (15 min - 180 min) or chronically (1 day - 3 day) with physiologic levels of lactate (0. 5 x 10-3 M to 5 x 10-2 M) or lactate in combination with the corticotroph releasing factors: corticotroph releasing hormone (CRH), arginine vasopressin (AVP), norepinephrine and/or epinephrine. Findings with AtT-20 cell cultures were shown to be representative of responses in primary cultures of rat anterior pituitary. Lactic acid did not alter the spontaneous release of beta-endorphin by AtT-20 cells under either acute or chronic conditions. While CRH, norepinephrine, and epinephrine evoked significant increases in beta-endorphin release, lactate, in combination with these secretagogues did not alter their effects. Similarly, lactic acid failed to alter basal or stimulated release of beta-endorphin by primary cultures of rat anterior pituitary. The addition of lactate (3 x 103 M) to rat hypothalamic explants did, however, produce a modest but significant reduction in spontaneous CRH release, suggesting that lactate may facilitate the return to basal secretion following exercise. The present findings show that physiologic concentrations of lactate have no effect, either alone or in combination with other pituitary secretagogues, on corticotroph secretion. Whereas a physiologic action for lactate within the hypothalamus is possible, the present findings indicate that lactate is an inhibitor of CRH release. Thus, lactate does not appear to play a direct role in the profound activation of the HPA axis that occurs in response to strenuous exercise.     

Inhibition and activation of the thyroidal axis by the adrenal axis in vertebrates

PURPOSE: To determine the long-term effects of 75.6- and 81.0-Gy doses of three-dimensional conformal radiation therapy in a dose-escalation study in patients with stage T2c-T3 prostatic cancer. MATERIALS AND METHODS: Fifty patients received an initial 75.6-Gy dose, and the dose in 46 patients was subsequently escalated to 81.0-Gy. Median follow-up was 60 and 40 months, respectively. RESULTS: The rates of effects of acute toxicity during the course of treatment were similar for both dose levels. Among the 96 patients, the rate of grade 2 morbidities necessitating medication to relieve acute symptoms was 17% (16 patients) for rectal and 36% (35 patients) for urinary morbidities. All other patients had either no or grade 1 morbidities. Fourteen patients (15%) developed late grade 2 rectal morbidities. There were no differences in 5-year actuarial rates of late grade 2 rectal or urinary morbidities among patients who received 75.6 Gy versus those who received 81.0 Gy. One patient treated with 81.0 Gy developed a grade 3 urethral stricture, which was resolved with dilatation. CONCLUSION: Tumor dose escalation beyond conventional radiation doses for localized prostatic cancer is feasible when delivered with three-dimensional conformal radiation therapy, with no increase in morbidity in normal tissue.     

Circadian rhythms: eyes of the clock

The daily light-dark cycle synchronizes the internal circadian clock with the outside world. Blind organisms maintain this light-induced entrainment, suggesting the existence of a non-visual phototransduction pathway. The photoreceptor is unknown, but several intriguing candidates have recently come to light.     

Drug-induced alterations of the hypothalamus-hypophysis axis

Omitting hormonal variations caused by other drugs already objects of research, the behaviour pattern of GH, PRL, TSH, following acute administration of cimetidine, nomifensine, domperidone has been considered in normal subjects, in patients with pituitary non-secreting and PRL-secreting adenomas and in patients with amenorrhea-galactorrhea syndrome without evidence of adenoma. The results confirm the influence which drugs employed in the therapy of non-endocrine diseases provide a way to alter the functions of the hypothalamus, sometimes relatively specifically, and the secretion of pituitary hormones provides us with a possibility of analyzing the CNS output.     

Circadian patterns of ischemic events

These is evidence of circadian variations in the occurrence of ischemic events such as: silent myocardial ischemia, stable angina, instable angina, acute myocardial infarction, sustained ventricular tachycardia, cerebral infarction, transient ischemic attack (TIA) and sudden cardiac death. In the general population many cardiovascular disorders occur with the greatest frequency between 6 and 12 a.m. (i.e. after awakening). Blood pressure, too, follows a distinct circadian pattern. Factors affecting circadian variations in cardiovascular disorders include physiological determinants, such as heart rate, catecholamine release, and platelet aggregation-which themselves cyclically vary-, and exogenous factors such as mental stress, anxiety, and physical activity. In chronotherapy, circadian variations in disease states and in the pharmacodynamic properties of drugs are exploited to improve prevention and treatment. Characterization of diseases states with this approach allows more accurate determination of the times when patients are at highest risk and therefore in greatest need of preventive measures; it also provides a mechanism for designing optimal drug regimens. In this review we therefore describe recent findings about the effects of biorhythms on cardiovascular disorders and their implications for optimal drug therapy.     

Circadian time perception.

The variability of anticipating a meal was investigated. Sprague-Dawley rats earned food by inspecting a food source during a 3-hr interval. Food was not available at other times. In Experiment 1, the meal started 3 or 7 hr after light offset in a 12-hr light-dark cycle. Experiment 2 was conducted in constant darkness with 14-, 22-, 22.5-, 24-, 25.5-, 26-, or 34-hr intermeal intervals. Inspections increased before the meal. Rats timed intervals in the circadian range (22–26 hr) with lower variability than that for intervals outside this range (3–14 and 34 hr). Higher precision in timing selected intervals violates the scalar property. Proximity to a circadian oscillator improves timing precision. Variability may be used to identify oscillators with noncircadian periods. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nitric oxide in the stress axis

Calcitonin gene-related peptide in sensory primary afferent neurons has an excitatory effect on postsynaptic neurons and potentiates the effect of substance P in the rat spinal dorsal horn. It has been established that calcitonin gene-related peptide expression in dorsal root ganglion neurons is depressed, and the effect of calcitonin gene-related peptide on dorsal horn neurons is attenuated, following peripheral nerve injury. We report here that a subpopulation of injured dorsal root ganglion neurons show increased expression of calcitonin gene-related peptide. Using in situ hybridization and the retrograde tracer, FluoroGold, we detected an increased number of medium- to large-sized rat dorsal root ganglion neurons projecting to the gracile nucleus that expressed alpha-calcitonin gene-related peptide messenger RNA following spinal nerve transection. Immunohistochemistry revealed a significant increase in calcitonin gene-related peptide immunoreactivity in the gracile nucleus and in laminae III-IV of the spinal dorsal horn. These results indicate that a subpopulation of dorsal root ganglion neurons express alpha-calcitonin gene-related peptide messenger RNA in response to peripheral nerve injury, and transport this peptide to the gracile nucleus and to laminae III-IV of the spinal dorsal horn. The increase of the excitatory neuropeptide, calcitonin gene-related peptide, in sites of primary afferent termination may affect the excitability of postsynaptic neurons, and have a role in neuronal plasticity following peripheral nerve injury.     

Circadian modulation of the rat acoustic startle response.

The acoustic startle response (ASR) of male rats was measured during several sessions over a 24-hr period in both a light–dark cycle and a constant-dark condition. Each session consisted of 10 trials each at 80, 90, 100, 110, and 120 dB white noise. The results indicate robust daily and circadian modulation of ASR amplitude that consist of an approximately 2-fold nocturnal increase at eliciting-stimuli intensities above 80 dB. Similar results were observed in female rats in constant-dark conditions. To determine whether daily changes in auditory thresholds were responsible for the observed modulation, ASR reflex modification procedures were used. These procedures were designed to measure auditory thresholds at frequencies of 10 and 40 kHz at several times of day. The results suggest a lack of significant circadian differences in auditory thresholds at these frequencies. This study demonstrates a novel role of the rat circadian system in the modulation of ASR amplitude. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Listener responsiveness and the coordination of conversation.

To examine how feedback influences conversation, 76 speaker Ss (selected from a group of university moviegoers and students) watched a movie and then summarized it to 1 or 2 listeners. The listeners provided varying amounts of feedback to the speaker. When 2 listeners were present, one could influence the speaker through feedback and the other could only eavesdrop on the conversation. When speakers received more feedback, both listeners understood the movie better. Feedback individuated communication—the listener who provided the feedback understood the movie better than the eavesdropper who listened to the same conversation. In part, feedback produced these effects by coordinating what the speaker said with what the listener needed to know. Listener feedback signaled listeners' prior knowledge of the movie, and speakers talked most efficiently about those sections of the movie about which listeners had prior knowledge. (32 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Positional determination of the naso-temporal retinal axis coincides with asymmetric expression of proteins along the anterior-posterior axis of the eye primordium

We used two different methodologies to examine at what stage development retinal positional specificity is established and which molecules are responsible. The first goal was achieved by removing parts of the presumptive temporal primary optic vesicle at stage 11 (40 to 45 hr of incubation) and fate mapping of tissue with presumptive nasal properties that shifted into the wound during the events of wound-healing. Participation of the shifted tissue in the healing resulted in assembly of a temporal retina with mosaic-like projection properties, as examined by retrograde double staining of the retinal ganglion cells from the optic tectum. In addition to cells with normal temporal-rostral projections, clusters of ganglion cells with nasal-like projection identities appeared labelled within the temporal hemiretina. The number of clusters increased with the amount of resected tissue, and by almost complete ablation of the presumptive temporal anlage, a temporal hemiretina with predominantly nasal retinotectal specificity was created. These neuroanatomical results suggested that neuroepithelial cells had fixed nasal and temporal positional specificities at stage 11. To examine differences in the cells derived of either half of the eye cup, we performed biochemical one- and two-dimensional gel electrophoresis of the hemianlagen at stage 11. In addition, incorporation of 35S-methionin into newly synthesized peptides was investigated. Both techniques revealed the exclusive expression of one major and three less-abundant proteins within the presumptive nasal anlage. The most abundant of these proteins has a molecular weight of about 40 kDa and is clearly distinguishable both in gel electrophoresis and autoradiography. The asymmetric protein patterns had disappeared when the retina was analysed with the same methods at the more advanced embryonic days E4 and E6. The asymmetry in the expression of proteins in the retinal primordium may be the biochemical correlate of an early positional specification of the retinal neuroepithelium. The difference in the protein expression may explain that mixing the positionally specified cells of either origins results in projection mosaics.     

Circadian variation in incidence of cardioembolism

Cardioembolism is most likely to occur after waking in the morning. The identification of periods of high risk for cardioembolism may have important therapeutic implications, such as matching drug effects with vulnerability.     

Circadian variations of the urinary excretion of catecholamines and electrolytes

Concomitant measurements of circadian variations in the urinary excretion of dopamine (DA), homovanillic acid (HVA), norepinephrine (NE), epinephrine (E) as well as of creatinine, sodium and potassium under controlled dietary conditions during relative physical and emotional rest in 13 volunteers have shown that maximum excretion of all these substances occurred in the afternoon period between 14:30h and 18:00h, and minimum excretion in the morning between 4:00h and 5:00h. The changes were in some cases progressive from one collection period to the other, and synchronized for NE and E. DA and HVA excretions fluctuated from subject to subject. Excretory rhythms of sodium and potassium were found to be similar to those of the catecholamines. This can be explained by diurnal changes in renal blood flow and different renal excretory mechanisms of catecholamines. None of the catecholamines correlated with the urinary volume but urinary NE and E positively correlated with urinary creatinine, urinary NE and E with urinary DA and urinary sodium with urinary E. There are some common patterns in the diurnal rhythms of catecholamines and electrolytes but their interrelationship is different for individual catecholamines.     

Circadian chemotherapy in cancer patients

Continuous infusion of 5-FU at night was performed for four patients: three had liver metastasis (one with gastric cancer and two with rectal cancer) and one had local recurrence of rectal cancer. The chemotherapy schedule was 400 mg/m2/day 5-FU intraarterial or intravenous infusion from 6:00 p.m. to 6:00 a.m. for five days repeated every 3 weeks. There were one complete response, two partial responses and one with no change. It is expected that the chemotherapy of 5-FU at night will result in a high efficacy and lower toxicity.     

Food and the circadian activity of the hypothalamic-pituitary-adrenal axis

Temporal organization is an important feature of biological systems and its main function is to facilitate adaptation of the organism to the environment. The daily variation of biological variables arises from an internal time-keeping system. The major action of the environment is to synchronize the internal clock to a period of exactly 24 h. The light-dark cycle, food ingestion, barometric pressure, acoustic stimuli, scents and social cues have been mentioned as synchronizers or "zeitgebers". The circadian rhythmicity of plasma corticosteroids has been well characterized in man and in rats and evidence has been accumulated showing daily rhythmicity at every level of the hypothalamic-pituitary-adrenal (HPA) axis. Studies of restricted feeding in rats are of considerable importance because they reveal feeding as a major synchronizer of rhythms in HPA axis activity. The daily variation of the HPA axis stress response appears to be closely related to food intake as well as to basal activity. In humans, the association of feeding and HPA axis activity has been studied under physiological and pathological conditions such as anorexia nervosa, bulimia, malnutrition, obesity, diabetes mellitus and Cushing's syndrome. Complex neuroanatomical pathways and neurochemical circuitry are involved in feeding-associated HPA axis modulation. In the present review we focus on the interaction among HPA axis rhythmicity, food ingestion, and different nutritional and endocrine states.     

Neuronal circuit regulation of the hypothalamo-pituitary-adrenocortical stress axis

The hypothalamo-pituitary-adrenocortical (HPA) axis is the primary modulator of the adrenal glucocorticoid stress response. Activation of this axis occurs by way of a discrete set of neurons in the hypothalamic paraventricular nucleus (PVN). The PVN neuron appears to be affected by multiple sources, including (1) brainstem aminergic/peptidergic afferents; (2) blood-borne information; (3) indirect input from limbic system-associated regions, including the prefrontal cortex, hippocampus, and amygdala; and (4) local-circuit interactions with the preoptic-hypothalamic continuum. Analysis of the literature suggests that different classes of stressor employ different stress circuits. Severe physiologic ("systemic") stress appears to trigger brainstem/circumventricular organ systems that project directly to the paraventricular nucleus. In contrast, stressors requiring interpretation with respect to previous experience ("processive" stressors) reach the PVN by way of multisynaptic limbic pathways. Limbic regions mediating processive stress responses appear to have bisynaptic connections with the PVN, forming intervening connections with preoptic/hypothalamic GABAergic neurons. Stressors of the latter category may thus require interaction with homeostatic information prior to promoting an HPA response. The HPA stress response thus appears to be a product of both the physiologic importance of the stimulus and the specific pathways a given stimulus excites.