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Hypothalamus as an Endocrine Organ

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Abstract

The endocrine hypothalamus constitutes those cells which project to the median eminence and secrete neurohormones into the hypophysial portal blood to act on cells of the anterior pituitary gland. The entire endocrine system is controlled by these peptides. In turn, the hypothalamic neuroendocrine cells are regulated by feedback signals from the endocrine glands and other circulating factors. The neuroendocrine cells are found in specific regions of the hypothalamus and are regulated by afferents from higher brain centers. Integrated function is clearly complex and the networks between and amongst the neuroendocrine cells allows fine control to achieve homeostasis. The entry of hormones and other factors into the brain, either via the cerebrospinal fluid or through fenestrated capillaries (in the basal hypothalamus) is important because it influences the extent to which feedback regulation may be imposed. Recent evidence of the passage of factors from the pars tuberalis and the median eminence casts a new layer in our understanding of neuroendocrine regulation. The function of neuroendocrine cells and the means by which pulsatile secretion is achieved is best understood for the close relationship between gonadotropin releasing hormone and luteinizing hormone, which is reviewed in detail. The secretion of other neurohormones is less rigid, so the relationship between hypothalamic secretion and the relevant pituitary hormones is more complex. © 2015 American Physiological Society. Compr Physiol 5:217‐253, 2015.

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Figure 1. Figure 1. The neuroendocrine cells of the hypothalamus, that secrete neurohormones into the hypohysial portal system and stimulate or inhibit the function of the cells of the anterior pituitary gland are found in discrete nuclei. The peptides shown localized to various nuclei in this diagram are also produced in other regions of the hypothalamus/brain, but the distribution here relates specifically to neuroendocrine cells. POA = preoptic area; PVN = paraventricular nucleus; DMH = dorsomedial nucleus of the hypothalamus; ARC = arcuate nucleus of the hypothalamus GnRH = gonadotropin releasing hormone; AVP = arginine vasopression; CRH = corticotropin releasing hormone; SRIF = somatotropin release inhibitory hormone or somatostatin; TRH = thyrotropin releasing hormone; GnIH = gonadotropin inhibitory hormone; GHRH = growth hormone releasing hormone; DA = dopamine. NB. GnIH is not secreted into portal blood in rats or mice.
Figure 2. Figure 2. Schematic version of the hypophysial portal blood system to emphasize how multiple neuroendocrine factors travel together through the median eminence to the anterior pituitary gland. Blood enters the primary capillary bed of the hypophysial portal system from the superior hypophysial artery and then courses through the long portal vessels to the secondary capillary bed in the anterior pituitary gland. Neurohormones are released from effector neurons in the neurosecretory zone of the median eminence and travel to the anterior pituitary gland as an admixture. Each neurohormone acts on the relevant cells of the anterior pituitary gland that express the cognate receptors for the specific neurohormone. Secretion of neurohormones may be modulated by factors secreted from modulatory neurons within the neurosecretory zone.
Figure 3. Figure 3. Distribution of neuroendocrine peptides within the paraventricular nucleus of the rat. Animals were given systemic injections of Fast Blue dye, which is taken up by terminals of neuroendocrine cells and retrogradely transported to the soma of the cells. Immunostaining then identified neuroendocrine cells of various types within the paraventricular nucleus. In A, images are taken at three levels through the nucleus and the upper row shows Fast Blue (FB) labeling. The other panels show the regionality of distribution for vasopressin (VAS), corticotropin releasing hormone (CRH) and oxytocin (OXY), using fluorescence immunohistochemistry. The arrows in Series B indicate the same anatomical location for all three images. In B, paired sections were mapped for each peptide or transmitter, indicating which were neuroendocrine cells (blue dots) and which were non‐neuroendocrine cells (red dots). GRH = growth hormone releasing hormone SS = somatostatin; DA = dopamine; TRH = thyrotropin releasing hormone. Adapted, with permission, from ().
Figure 4. Figure 4. The GnRH neurosecretory terminal bed in the external zone of the median eminence as seen in the sheep. The fluorescent immunohistochemistry shown here indicates beaded fibers (in green) in close proximity to the vessels of the primary plexus of the hypophysial portal system, which are unstained (arrows). IIIV = third ventricle, EZ = external zone of the median eminence; PT = pars tuberalis.
Figure 5. Figure 5. The number of GnRH cells found in various regions of the hypothalamus of the ewe brain. dBB = diagonal band of Broca; POA = preoptic area; AHA = anterior hypothalamus; MBH = mediobasal hypothalamus. Adapted from ().
Figure 6. Figure 6. Location of GnIH cells in non‐human primates, sheep and rats. Panel A is taken from () and Panel B from (). In both cases, the GnIH cells are identified in the dorsomedial nucleus by in situ hybridization. Panel C is an image of the hypothalamus of a rat bearing a green fluorescent protein (GFP)‐GnIH transgene described by (). In Panel C, the area outlined in red is the dorsomedial nucleus and the area outlined in yellow is a smaller population of GnRH‐GFP labeled cells in the dorsotuberomammillary nucleus; IIIV = third ventricle.
Figure 7. Figure 7. GnIH projections to GnRH cells and to the neurosecretory zone of the median eminence. Panel A shows Z‐slices of GnRH cells (red) with GnIH fibers (green in close association (sheep); yellow arrows show close contacts. Panel B shows a single GnRH cell in the sheep brain immunostained in brown with a varicose GnIH fiber in close contact (black). Panel C shows immunostaining of a GnRH cell (green) with close contact (arrows) from a varicose GnIH fiber (red) in the rat brain. Panel D is staining (green) for GnIH in the sheep median eminence and the boxed area in D is shown at higher power in E. Note the arrows in E, which indicate dark areas being the primary capillary plexus of the portal blood system. Taken, with permission, from ().
Figure 8. Figure 8. Saggital view of the median eminence and the arcuate nucleus of the rat, showing vasculature that is designated as arterial or venous, by the two‐dye method (). The red vessels are arteries and the blue vessels are veins. The stippled area is the arcuate nucleus. The horizontal scales indicate the different zones of the arcuate nucleus (NA) and the numbers are relative to bregma. Abbreviations, according to the original are:Ai—artery infrachiasmaticaha—artery hypophysea anteriorhm—artery hypophysea mediaehp—artery hypophysea posteriorEM—median eminencen—artery neurophypophysea anteriorNA—arcuate nucleusP1—portal vein 1rr—region retrochiasmaticavta—vein tuberalis anteriorvtm—vein tuberalis mediaevtp—vein tuberalis posterior
Figure 9. Figure 9. Capillary loop from the hypophysial portal primary plexus that loops into the mediobasal hypothalamus, showing an ascending capillary (), a loop underneath the ependymal of the hypophysial recess of the third ventricle (), a descending loop (), and an anatomizing vessel (). RH = hypophysial recess of the third ventricle; EM = median eminence. Taken, with permission, from ().
Figure 10. Figure 10. Porous microvessels in the mediobasal hypothalamus in a rat. PV1‐labeling of some blood vessels in the ventromedial arcuate nucleus (vm). PV1‐labelling (green) and either (red) the panendothelial cell marker RECA1 (upper panel) or the neuronal marker HuC/D (lower panel) showing merged images (right panel). Some HuC/D‐ir perikarya are close to PV1‐ir subependymal capillaries (short arrows). icl, Intrainfundibular capillary loop; psp, primary superficial plexus; pv, long portal vessel; sep, subependymal plexus. *, Third ventricle. Taken, with permission, from ().
Figure 11. Figure 11. Labeling of porous blood vessels in the mediobasal arcuate nucleus in the mouse. Panels A‐D show examples from 4 animals with immunolabeling for MECA32 (green). The vessels labeled 1 to 3 in D are also shown at higher power in the lower panels. Scale bar 100 μm in A‐D and 5 μm in 1 to 3. ARC—arcuate nucleus, vm—ventromedial arcuate nucleus, ME—median eminence, *third ventricle. From ().
Figure 12. Figure 12. Porosity of the organum vasculosum of the lamina terminalis (OVLT) in the mice bearing green fluorescent protein‐GnRH transgenes. Panel A shows diffusion of intravenously injected horseradish peroxidase (HRP; pseudocolored in red) into the OVLT and 100 μm beyond its borders into adjacent parenchyma of the brain. The area into which the HRP penetrated included that of GnRH cell bodies and dendrites (green). Arrowheads = labeled blood vessels. The inset shows the OVLT of a saline injected animal devoid of HRP signal. Scale bar = 100 μm. Panel B shows a camera lucida‐like schematic of three GnRH neurons filled with dye and demonstrating projections of the three dendritic trees into the OVLT. The gray neurons are green fluorescent labeled GnRH cells adjacent to the OVLT. Scale bar = 50 μm. Inner dashed gray line outlines the OVLT, outer dashed line represents a distance of approximately 100 μm from the OVLT. Taken, with permission, from ().
Figure 13. Figure 13. Short‐form of the leptin receptor (transporter) in rat brain. Panel A. Measurement of mRNA for the short form of the leptin receptor by polymerase chain reaction. Panel B. Levels of the short form of the leptin receptor in microvessels. Panel C. In situ hybridization using a 35S‐labeled antisense probe to all forms of the leptin receptor mRNA, labeling a microvessel in the thalamus. bv, Brain vessel. Magnification bar 30 μm. Panel D Darkfield photomicrograph of the choroid plexus (chp). sm, Stria medullaris. Taken, with permission, from ().
Figure 14. Figure 14. Glial “end‐feet” are in close association with GnRH neurosecretory terminals in the median eminence. Electron micrographs showing plasticity of the relationship between GnRH nerve terminals and glial end‐feet in relation to the pericapillary space during the reproductive cycle in the rat. (Left panel) GnRH terminals (large arrowhead) in the external zone of the median eminence in close proximity of the fenestrated capillaries (Cap) of the primary plexus of the portal vasculature. Throughout most of the estrous cycle, GnRH nerve terminals (labeled with 15‐nm gold particles) are ensheathed by tanycytic end‐feet (Tan), preventing the projection to the pericapillary space (p.s.) delineated by the parenchymatous basal lamina (arrow). The small arrowhead indicates the endothelial basal lamina and the short arrow the fenestration of the endothelium. Scale bar: 0.5 μm. (Right panels) During proestrus, leading to the preovulatory GnRH/LH surge, GnRH nerve endings (large arrowhead) vome into close contact with the pericapillary space (p.s.) either through filopodial extension of the nerve terminal (arrows) (Bottom right panel) or (Top right panel) by evaginations of the parenchymatous basal lamina (small black arrowheads); this allows the pericapillary space (p.s., asterisk) to penetrate the parenchyma of the GnRH nerve terminal. The top right panel shows fusion of secretory granules (large‐sized black vesicles) with the axo‐plasmic membrane of the GnRH nerve terminal in direct apposition with the parenchymatous basal lamina (small arrows). The penetration of the pericapillary space into the nerve parenchyma on the day of proestrus may result from the morphological remodeling of tanycytic endfeets (tan) anchored to the parenchymatous basal lamina through hemidesmosomes seen as dark thickenings within the tanycytic processes in apposition with the basal lamina (small white arrowheads). Scale bar: 0.5 μm. Taken, with permission, from ().
Figure 15. Figure 15. GnRH secretion into the hypophysial portal blood, showing the rigid 1:1 relationship between major secretory pulses of GnRH from the hypothalamus and pulses of LH secreted by the pituitary gonadotropes. Taken, with permission, from ().
Figure 16. Figure 16. The “ram effect.” Panel A shows plasma LH profiles for representative anestrous ewes treated with artificial cerebrospinal fluid (aCSF) or a kisspeptin receptor antagonist (P‐271). The control ewes received an infusion of aCSF with no exposure to a ram. The ewes were held in isolation from rams for some months and then introduced to a ram. The timing of infusions is indicated by the arrowhead/bar and the shaded area indicates male exposure. Panel B shows GnRH neurons (brown), that were either colabeled for c‐Fos (arrows) or not colabeled (arrowheads); scale bar 100 μm. Panel C shows mean ± SEM c‐Fos labeled GnRH cells, *P < 0.05, **P < 0.01, ***P < 0.001, n = 4/group. Male introduction caused immediate pulsatile secretion of LH (reflecting GnRH secretion) and this was associated with an increase in the activity (c‐Fos labeling) of GnRH cells. The effect was diminished by treatment with a kisspeptin receptor antagonist, indicating the dependence of the response on kisspeptin action. Taken, with permission, from ().
Figure 17. Figure 17. Kisspeptin projections from KNDy cells into the median eminence (ovine). Panel A shows kisspeptin and GnRH fibers in intimate relationship in the neurosecretory zone of the median eminence and Panel B shows an electron photomicrograph of close association between a terminal that is stained for dynorphin (dense core immunoperoxidase labeled vesicles—arrowheads) and another that is stained for GnRH. Scale bar: 2 μm. Panel A is from () and Panel B is from ().
Figure 18. Figure 18. Model for neurokinin B (NKB) paracrine regulation of KNDy cells, showing possible explanation for the hypogonadotropic condition of patients with inactivating mutations of the gene or the NKB receptor. In normal individuals (left panel), NKB may originate from KNDy cells and have an autocrine effect to cause kisspeptin secretion and stimulation of GnRH cells, enabling secretion of GnRH, LH and FSH. In individuals with mutations in the NKB gene or receptor, the paracrine feedback is lost and GnRH, LH, and FSH secretion is severely compromised. Another explanation is that NKB from non‐KNDy cells may act on the KNDy cells to elicit function. Taken, with permission, from ().
Figure 19. Figure 19. Constant infusion of CRH allows the pulsatile secretion of corticosterone in rats. Animals were taken at a time of day when the HPA axis was relatively quiescent and given infusions (i.v.) of either saline (Panels A and B) or CRH at a rate of 0.5 mg/h (Panels C and D). Although the infusion of CRH was nonpulsatile, a pulsatile secretion of corticosterone ensued. Taken, with permission, from ().
Figure 20. Figure 20. GnRH secretion into the hypophysial portal blood in male sheep and the effect of castration. Note the increase in GnRH pulse frequency with time after castration. The “short‐term” animals were sampled 2 to 15 days after castration and the “long‐term” animals were sampled 1 to 6 months after castration. The interpulse interval of intact animals was 180 min and this was reduced to 70 and 36 min in short and long‐term castrates, respectively. Taken, with permission, from ().
Figure 21. Figure 21. GnRH surge caused by estradiol in ovariectomized females. Using hypophysial portal blood access to measure GnRH secretion and jugular venous sampling to measure LH secretion, the pattern of GnRH secretion at the time of the surge was deciphered by rapid sampling (2.5 min intervals). Ovariectomized ewes were given i.m. injections of 50 μg estradiol benzoate and sampled at the time of when the ensuing GnRH/LH surge was expected and two examples are shown. The arrows indicate pulses of GnRH. The dotted line indicates the onset of the LH surge, and the continuous vertical line in Panel B indicates the termination of the leading edge of the LH surge. Taken, with permission, from ().
Figure 22. Figure 22. The role of KNDy cells and preoptic kisspeptin cells in the induction of the estrogen induced GnRH/LH surge in the ewe. In panel A data from ovariectomized ewes shows c‐Fos labeling in KNDy cells is reduced by chronic estrogen treatment (estrogen implant‐negative feedback) but is increased by acute estrogen injection [1 h after 50 μg i.m. injection of estradiol benzoate—activation of the positive feedback mechanism (histology panels show brown kisspeptin cells and black c‐Fos labeling)]. Quantification for c‐Fos labeling is seen in the histogram for which mean ± SEM values are given for groups of four animals. The horizontal bars indicate statistical significance between groups and data are presented for the rostral, mid and caudal arcuate nucleus (ARC) and the preoptic area (POA). Panel B shows data from a similar model of surge induction in ovariectomized ewes that were primed with progesterone treatment. Data for GnRH (LHRH) neurons and preoptic kisspeptin (kp) neurons are shown. The time scale refers to the time after progesterone withdrawal and estrogen treatment and 26 h coincides with the onset of the GnRH/LH surge. At this time, there is an increase in the c‐Fos labeling of GnRH neurons and preoptic kisspeptin neurons. Taken, with permission, from () Panel A and () Panel B.
Figure 23. Figure 23. CRH and AVP secretion into the hypophysial portal blood in sheep in relation to the secretion of pro‐opiomelanocortin peptides from the pituitary gland. Statistically identified pulses are identified by ▾ and arrows indicate the imposition of stressors as indicated (large arrow—audiovisual stress; small arrows—insulin and ketamine). Taken, with permission, from ().
Figure 24. Figure 24. Levels of epinephrine, norepinephrine, and dopamine in the hypophysial portal blood of pregnant and lactating rats and concomitant levels in arterial blood. Taken, with permission, from ().
Figure 25. Figure 25. Effect of prolaction on TIDA cells. Figs. A‐C show cells from mice bearing a green fluorescent protein (GFP) gene driven by the tyrosine hydroxylase promoter. A shows GFP expression in green and B shows TH expression in red, with the merged images in C (white arrows indicating colocalization). The grey arrow indicates a cell that is GFP‐labeled but is not a TIDA neuron. Panel D shows electrophysiological firing rate of a TIDA neuron at the points indicated in Panel E, which is a plot of the average effect of prolactin on the normalized firing rate in six TIDA neurons. The numbers on Panel E relate to the three different firing patterns seen in Panel D. The dotted line in E is the normalized firing rate. From ().
Figure 26. Figure 26. TRH secretion into the hypophysial portal blood of a sheep, in relation to the levels of prolactin in jugular blood. The TRH levels are expressed as pmol/min and nmol/L. There is a lack of association between pulses of TRH and those of prolactin secretion. Taken, with permission, from ().
Figure 27. Figure 27. Secretion of GHRH and somatostatin (SRIH) into the hypophysial portal blood of sheep in relation to the secretion of growth hormone (GH) from the pituitary gland; see text for details. The horizontal dotted lines indicate assay sensitivity. Taken, with permission, from ().
Figure 28. Figure 28. Levels of GnIH in the hypophysial portal blood and jugular venous blood in sheep during the luteal phase (A) and follicular phase (B) of the estrous cycle and the anestrous period (C). * in A‐C indicate statistically identified pulses. Panels D‐F are mean ± SEM values for mean values, pulse amplitude and pulse frequency, respectively; *P < 0.05 versus luteal and follicular values. In Panel F, values with different notations (a, b, and c) are statistically different—*P < 0.05. Taken, with permission, from ().
Figure 29. Figure 29. Effect of aging on the level of expression of GnIH in rats. Transgenic animals bearing the enhanced green fluorescent protein (eGFP) gene driven by the GnIH promoter were studied. In Panels A and B eGFP‐labeled GnIH cells are seen in the dorsomedial nucleus of the hypothalamus and red labeling is c‐Fos. Arrows indicate double labeled cells. *P < 0.05. Taken, with permission, from ().


Figure 1. The neuroendocrine cells of the hypothalamus, that secrete neurohormones into the hypohysial portal system and stimulate or inhibit the function of the cells of the anterior pituitary gland are found in discrete nuclei. The peptides shown localized to various nuclei in this diagram are also produced in other regions of the hypothalamus/brain, but the distribution here relates specifically to neuroendocrine cells. POA = preoptic area; PVN = paraventricular nucleus; DMH = dorsomedial nucleus of the hypothalamus; ARC = arcuate nucleus of the hypothalamus GnRH = gonadotropin releasing hormone; AVP = arginine vasopression; CRH = corticotropin releasing hormone; SRIF = somatotropin release inhibitory hormone or somatostatin; TRH = thyrotropin releasing hormone; GnIH = gonadotropin inhibitory hormone; GHRH = growth hormone releasing hormone; DA = dopamine. NB. GnIH is not secreted into portal blood in rats or mice.


Figure 2. Schematic version of the hypophysial portal blood system to emphasize how multiple neuroendocrine factors travel together through the median eminence to the anterior pituitary gland. Blood enters the primary capillary bed of the hypophysial portal system from the superior hypophysial artery and then courses through the long portal vessels to the secondary capillary bed in the anterior pituitary gland. Neurohormones are released from effector neurons in the neurosecretory zone of the median eminence and travel to the anterior pituitary gland as an admixture. Each neurohormone acts on the relevant cells of the anterior pituitary gland that express the cognate receptors for the specific neurohormone. Secretion of neurohormones may be modulated by factors secreted from modulatory neurons within the neurosecretory zone.


Figure 3. Distribution of neuroendocrine peptides within the paraventricular nucleus of the rat. Animals were given systemic injections of Fast Blue dye, which is taken up by terminals of neuroendocrine cells and retrogradely transported to the soma of the cells. Immunostaining then identified neuroendocrine cells of various types within the paraventricular nucleus. In A, images are taken at three levels through the nucleus and the upper row shows Fast Blue (FB) labeling. The other panels show the regionality of distribution for vasopressin (VAS), corticotropin releasing hormone (CRH) and oxytocin (OXY), using fluorescence immunohistochemistry. The arrows in Series B indicate the same anatomical location for all three images. In B, paired sections were mapped for each peptide or transmitter, indicating which were neuroendocrine cells (blue dots) and which were non‐neuroendocrine cells (red dots). GRH = growth hormone releasing hormone SS = somatostatin; DA = dopamine; TRH = thyrotropin releasing hormone. Adapted, with permission, from ().


Figure 4. The GnRH neurosecretory terminal bed in the external zone of the median eminence as seen in the sheep. The fluorescent immunohistochemistry shown here indicates beaded fibers (in green) in close proximity to the vessels of the primary plexus of the hypophysial portal system, which are unstained (arrows). IIIV = third ventricle, EZ = external zone of the median eminence; PT = pars tuberalis.


Figure 5. The number of GnRH cells found in various regions of the hypothalamus of the ewe brain. dBB = diagonal band of Broca; POA = preoptic area; AHA = anterior hypothalamus; MBH = mediobasal hypothalamus. Adapted from ().


Figure 6. Location of GnIH cells in non‐human primates, sheep and rats. Panel A is taken from () and Panel B from (). In both cases, the GnIH cells are identified in the dorsomedial nucleus by in situ hybridization. Panel C is an image of the hypothalamus of a rat bearing a green fluorescent protein (GFP)‐GnIH transgene described by (). In Panel C, the area outlined in red is the dorsomedial nucleus and the area outlined in yellow is a smaller population of GnRH‐GFP labeled cells in the dorsotuberomammillary nucleus; IIIV = third ventricle.


Figure 7. GnIH projections to GnRH cells and to the neurosecretory zone of the median eminence. Panel A shows Z‐slices of GnRH cells (red) with GnIH fibers (green in close association (sheep); yellow arrows show close contacts. Panel B shows a single GnRH cell in the sheep brain immunostained in brown with a varicose GnIH fiber in close contact (black). Panel C shows immunostaining of a GnRH cell (green) with close contact (arrows) from a varicose GnIH fiber (red) in the rat brain. Panel D is staining (green) for GnIH in the sheep median eminence and the boxed area in D is shown at higher power in E. Note the arrows in E, which indicate dark areas being the primary capillary plexus of the portal blood system. Taken, with permission, from ().


Figure 8. Saggital view of the median eminence and the arcuate nucleus of the rat, showing vasculature that is designated as arterial or venous, by the two‐dye method (). The red vessels are arteries and the blue vessels are veins. The stippled area is the arcuate nucleus. The horizontal scales indicate the different zones of the arcuate nucleus (NA) and the numbers are relative to bregma. Abbreviations, according to the original are:Ai—artery infrachiasmaticaha—artery hypophysea anteriorhm—artery hypophysea mediaehp—artery hypophysea posteriorEM—median eminencen—artery neurophypophysea anteriorNA—arcuate nucleusP1—portal vein 1rr—region retrochiasmaticavta—vein tuberalis anteriorvtm—vein tuberalis mediaevtp—vein tuberalis posterior


Figure 9. Capillary loop from the hypophysial portal primary plexus that loops into the mediobasal hypothalamus, showing an ascending capillary (), a loop underneath the ependymal of the hypophysial recess of the third ventricle (), a descending loop (), and an anatomizing vessel (). RH = hypophysial recess of the third ventricle; EM = median eminence. Taken, with permission, from ().


Figure 10. Porous microvessels in the mediobasal hypothalamus in a rat. PV1‐labeling of some blood vessels in the ventromedial arcuate nucleus (vm). PV1‐labelling (green) and either (red) the panendothelial cell marker RECA1 (upper panel) or the neuronal marker HuC/D (lower panel) showing merged images (right panel). Some HuC/D‐ir perikarya are close to PV1‐ir subependymal capillaries (short arrows). icl, Intrainfundibular capillary loop; psp, primary superficial plexus; pv, long portal vessel; sep, subependymal plexus. *, Third ventricle. Taken, with permission, from ().


Figure 11. Labeling of porous blood vessels in the mediobasal arcuate nucleus in the mouse. Panels A‐D show examples from 4 animals with immunolabeling for MECA32 (green). The vessels labeled 1 to 3 in D are also shown at higher power in the lower panels. Scale bar 100 μm in A‐D and 5 μm in 1 to 3. ARC—arcuate nucleus, vm—ventromedial arcuate nucleus, ME—median eminence, *third ventricle. From ().


Figure 12. Porosity of the organum vasculosum of the lamina terminalis (OVLT) in the mice bearing green fluorescent protein‐GnRH transgenes. Panel A shows diffusion of intravenously injected horseradish peroxidase (HRP; pseudocolored in red) into the OVLT and 100 μm beyond its borders into adjacent parenchyma of the brain. The area into which the HRP penetrated included that of GnRH cell bodies and dendrites (green). Arrowheads = labeled blood vessels. The inset shows the OVLT of a saline injected animal devoid of HRP signal. Scale bar = 100 μm. Panel B shows a camera lucida‐like schematic of three GnRH neurons filled with dye and demonstrating projections of the three dendritic trees into the OVLT. The gray neurons are green fluorescent labeled GnRH cells adjacent to the OVLT. Scale bar = 50 μm. Inner dashed gray line outlines the OVLT, outer dashed line represents a distance of approximately 100 μm from the OVLT. Taken, with permission, from ().


Figure 13. Short‐form of the leptin receptor (transporter) in rat brain. Panel A. Measurement of mRNA for the short form of the leptin receptor by polymerase chain reaction. Panel B. Levels of the short form of the leptin receptor in microvessels. Panel C. In situ hybridization using a 35S‐labeled antisense probe to all forms of the leptin receptor mRNA, labeling a microvessel in the thalamus. bv, Brain vessel. Magnification bar 30 μm. Panel D Darkfield photomicrograph of the choroid plexus (chp). sm, Stria medullaris. Taken, with permission, from ().


Figure 14. Glial “end‐feet” are in close association with GnRH neurosecretory terminals in the median eminence. Electron micrographs showing plasticity of the relationship between GnRH nerve terminals and glial end‐feet in relation to the pericapillary space during the reproductive cycle in the rat. (Left panel) GnRH terminals (large arrowhead) in the external zone of the median eminence in close proximity of the fenestrated capillaries (Cap) of the primary plexus of the portal vasculature. Throughout most of the estrous cycle, GnRH nerve terminals (labeled with 15‐nm gold particles) are ensheathed by tanycytic end‐feet (Tan), preventing the projection to the pericapillary space (p.s.) delineated by the parenchymatous basal lamina (arrow). The small arrowhead indicates the endothelial basal lamina and the short arrow the fenestration of the endothelium. Scale bar: 0.5 μm. (Right panels) During proestrus, leading to the preovulatory GnRH/LH surge, GnRH nerve endings (large arrowhead) vome into close contact with the pericapillary space (p.s.) either through filopodial extension of the nerve terminal (arrows) (Bottom right panel) or (Top right panel) by evaginations of the parenchymatous basal lamina (small black arrowheads); this allows the pericapillary space (p.s., asterisk) to penetrate the parenchyma of the GnRH nerve terminal. The top right panel shows fusion of secretory granules (large‐sized black vesicles) with the axo‐plasmic membrane of the GnRH nerve terminal in direct apposition with the parenchymatous basal lamina (small arrows). The penetration of the pericapillary space into the nerve parenchyma on the day of proestrus may result from the morphological remodeling of tanycytic endfeets (tan) anchored to the parenchymatous basal lamina through hemidesmosomes seen as dark thickenings within the tanycytic processes in apposition with the basal lamina (small white arrowheads). Scale bar: 0.5 μm. Taken, with permission, from ().


Figure 15. GnRH secretion into the hypophysial portal blood, showing the rigid 1:1 relationship between major secretory pulses of GnRH from the hypothalamus and pulses of LH secreted by the pituitary gonadotropes. Taken, with permission, from ().


Figure 16. The “ram effect.” Panel A shows plasma LH profiles for representative anestrous ewes treated with artificial cerebrospinal fluid (aCSF) or a kisspeptin receptor antagonist (P‐271). The control ewes received an infusion of aCSF with no exposure to a ram. The ewes were held in isolation from rams for some months and then introduced to a ram. The timing of infusions is indicated by the arrowhead/bar and the shaded area indicates male exposure. Panel B shows GnRH neurons (brown), that were either colabeled for c‐Fos (arrows) or not colabeled (arrowheads); scale bar 100 μm. Panel C shows mean ± SEM c‐Fos labeled GnRH cells, *P < 0.05, **P < 0.01, ***P < 0.001, n = 4/group. Male introduction caused immediate pulsatile secretion of LH (reflecting GnRH secretion) and this was associated with an increase in the activity (c‐Fos labeling) of GnRH cells. The effect was diminished by treatment with a kisspeptin receptor antagonist, indicating the dependence of the response on kisspeptin action. Taken, with permission, from ().


Figure 17. Kisspeptin projections from KNDy cells into the median eminence (ovine). Panel A shows kisspeptin and GnRH fibers in intimate relationship in the neurosecretory zone of the median eminence and Panel B shows an electron photomicrograph of close association between a terminal that is stained for dynorphin (dense core immunoperoxidase labeled vesicles—arrowheads) and another that is stained for GnRH. Scale bar: 2 μm. Panel A is from () and Panel B is from ().


Figure 18. Model for neurokinin B (NKB) paracrine regulation of KNDy cells, showing possible explanation for the hypogonadotropic condition of patients with inactivating mutations of the gene or the NKB receptor. In normal individuals (left panel), NKB may originate from KNDy cells and have an autocrine effect to cause kisspeptin secretion and stimulation of GnRH cells, enabling secretion of GnRH, LH and FSH. In individuals with mutations in the NKB gene or receptor, the paracrine feedback is lost and GnRH, LH, and FSH secretion is severely compromised. Another explanation is that NKB from non‐KNDy cells may act on the KNDy cells to elicit function. Taken, with permission, from ().


Figure 19. Constant infusion of CRH allows the pulsatile secretion of corticosterone in rats. Animals were taken at a time of day when the HPA axis was relatively quiescent and given infusions (i.v.) of either saline (Panels A and B) or CRH at a rate of 0.5 mg/h (Panels C and D). Although the infusion of CRH was nonpulsatile, a pulsatile secretion of corticosterone ensued. Taken, with permission, from ().


Figure 20. GnRH secretion into the hypophysial portal blood in male sheep and the effect of castration. Note the increase in GnRH pulse frequency with time after castration. The “short‐term” animals were sampled 2 to 15 days after castration and the “long‐term” animals were sampled 1 to 6 months after castration. The interpulse interval of intact animals was 180 min and this was reduced to 70 and 36 min in short and long‐term castrates, respectively. Taken, with permission, from ().


Figure 21. GnRH surge caused by estradiol in ovariectomized females. Using hypophysial portal blood access to measure GnRH secretion and jugular venous sampling to measure LH secretion, the pattern of GnRH secretion at the time of the surge was deciphered by rapid sampling (2.5 min intervals). Ovariectomized ewes were given i.m. injections of 50 μg estradiol benzoate and sampled at the time of when the ensuing GnRH/LH surge was expected and two examples are shown. The arrows indicate pulses of GnRH. The dotted line indicates the onset of the LH surge, and the continuous vertical line in Panel B indicates the termination of the leading edge of the LH surge. Taken, with permission, from ().


Figure 22. The role of KNDy cells and preoptic kisspeptin cells in the induction of the estrogen induced GnRH/LH surge in the ewe. In panel A data from ovariectomized ewes shows c‐Fos labeling in KNDy cells is reduced by chronic estrogen treatment (estrogen implant‐negative feedback) but is increased by acute estrogen injection [1 h after 50 μg i.m. injection of estradiol benzoate—activation of the positive feedback mechanism (histology panels show brown kisspeptin cells and black c‐Fos labeling)]. Quantification for c‐Fos labeling is seen in the histogram for which mean ± SEM values are given for groups of four animals. The horizontal bars indicate statistical significance between groups and data are presented for the rostral, mid and caudal arcuate nucleus (ARC) and the preoptic area (POA). Panel B shows data from a similar model of surge induction in ovariectomized ewes that were primed with progesterone treatment. Data for GnRH (LHRH) neurons and preoptic kisspeptin (kp) neurons are shown. The time scale refers to the time after progesterone withdrawal and estrogen treatment and 26 h coincides with the onset of the GnRH/LH surge. At this time, there is an increase in the c‐Fos labeling of GnRH neurons and preoptic kisspeptin neurons. Taken, with permission, from () Panel A and () Panel B.


Figure 23. CRH and AVP secretion into the hypophysial portal blood in sheep in relation to the secretion of pro‐opiomelanocortin peptides from the pituitary gland. Statistically identified pulses are identified by ▾ and arrows indicate the imposition of stressors as indicated (large arrow—audiovisual stress; small arrows—insulin and ketamine). Taken, with permission, from ().


Figure 24. Levels of epinephrine, norepinephrine, and dopamine in the hypophysial portal blood of pregnant and lactating rats and concomitant levels in arterial blood. Taken, with permission, from ().


Figure 25. Effect of prolaction on TIDA cells. Figs. A‐C show cells from mice bearing a green fluorescent protein (GFP) gene driven by the tyrosine hydroxylase promoter. A shows GFP expression in green and B shows TH expression in red, with the merged images in C (white arrows indicating colocalization). The grey arrow indicates a cell that is GFP‐labeled but is not a TIDA neuron. Panel D shows electrophysiological firing rate of a TIDA neuron at the points indicated in Panel E, which is a plot of the average effect of prolactin on the normalized firing rate in six TIDA neurons. The numbers on Panel E relate to the three different firing patterns seen in Panel D. The dotted line in E is the normalized firing rate. From ().


Figure 26. TRH secretion into the hypophysial portal blood of a sheep, in relation to the levels of prolactin in jugular blood. The TRH levels are expressed as pmol/min and nmol/L. There is a lack of association between pulses of TRH and those of prolactin secretion. Taken, with permission, from ().


Figure 27. Secretion of GHRH and somatostatin (SRIH) into the hypophysial portal blood of sheep in relation to the secretion of growth hormone (GH) from the pituitary gland; see text for details. The horizontal dotted lines indicate assay sensitivity. Taken, with permission, from ().


Figure 28. Levels of GnIH in the hypophysial portal blood and jugular venous blood in sheep during the luteal phase (A) and follicular phase (B) of the estrous cycle and the anestrous period (C). * in A‐C indicate statistically identified pulses. Panels D‐F are mean ± SEM values for mean values, pulse amplitude and pulse frequency, respectively; *P < 0.05 versus luteal and follicular values. In Panel F, values with different notations (a, b, and c) are statistically different—*P < 0.05. Taken, with permission, from ().


Figure 29. Effect of aging on the level of expression of GnIH in rats. Transgenic animals bearing the enhanced green fluorescent protein (eGFP) gene driven by the GnIH promoter were studied. In Panels A and B eGFP‐labeled GnIH cells are seen in the dorsomedial nucleus of the hypothalamus and red labeling is c‐Fos. Arrows indicate double labeled cells. *P < 0.05. Taken, with permission, from ().
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I.J. Clarke. Hypothalamus as an Endocrine Organ. Compr Physiol 2014, 5: 217-253. doi: 10.1002/cphy.c140019