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HYPOTHALAMUS AND PITUITARY The hypothalamus is arranged symmetrically on either side of the 3rd ventricle.

Its primary functions are in the regulation of homeostasis and behaviour. It works by integrating signals from the CNS, PNS and endocrine system. It has a co-ordinated response from the visceral ANS i.e. a neural output and also a neuroendocrine function in the form of an endocrine output.

There are many control centres/nuclei located in the hypothalamus including the ventromedial nucleus which is NB in satiety and neuroendocrine control, the arcuate nucleus and periventricular zone which both play roles in neuroendocrine control, the paraventricular nucleus is responsible for oxytocin release and water conservation and the supraoptic nucleus controls vasopressin release. The hypothalamic pituitary axis plays a very important role in the normal functioning of several homeostatic processes in the body. Several of the hypothalamic nuclei mentioned above have connections with the pituitary gland. The supraoptic nucleus and the paraventricular nucleus connect to the posterior pituitary while the periventricular nucleus, dorso/ventromedial nucleus and arcuate nucleus connect to the anterior pituitary. The pituitary gland sits in the depression of the sphenoid bone. It is connected to the hypothalamus via a stalk known as the infundibulum. There is a dense capillary plexus at the top of this stalk. The pituitary consists of 3 lobes; anterior (pars distalis/adrenohypophysis), posterior (pars nervosa/neurohypophysis), intermediate (pars intermedia). The hypothalamic neurons can be classified as peptidergic neuroendocrine cells and neuroendocrine cells. The peptidergic neuroendocrine cells neuroendocrine peptide hormones into the circulation via the posterior pituitary vasculature and local hypophyseal portal circulation. The neuroendocrine cells can be subdivided into magnocellular neurons and parvocellular neurons. Magnocellular neurons originate in the PVH and SON and terminate in the posterior pituitary. They are responsible for the transfer of vasopressin and oxytocin. The parvocellular neurons originate in the PeVH and ARC and terminate at the median eminence. They also transfer hormones such as TRH, GnRH and dopamine via the hypophyseal portal circulation to the anterior pituitary. The neurosecretion of hormones

Hypothalamus and anterior pituitary The hypothalamus controls the endocrine system via the secretion of regulatory hormones (hypophysiotrophic hormones) that control activity in the pars distalis/anterior lobe of the pituitary gland. These hormones bind to cell membrane receptors in corresponding endocrine cell types in the anterior pituitary and stimulate/inhibit hormone synthesis and secretion from them. Hormones secreted from the anterior pituitary control other endocrine organs. The relationship between the hypothalamus and anterior pituitary is facilitated by hypophyseal portal circulation which consists of fenestrated capillaries. This circulation is rapid and sensitive. Neurons synthesizing trophic hormones in the hypothalamus release them into capillaries in the portal system. The portal vessels then carry the trophic hormones directly to the anterior pituitary. The endocrine cells of the AP then release their hormones into a second set of capillaries for distribution to the rest of the body. It is important to note that the anterior pituitary is not innervated by the hypothalamus.

The anterior pituitary hormones can be classified into three groups melanocortinsACTH, lipotropin, melanocyte stimulating hormone (MSH) all of which are derived from POMC somatomammotropinsgrowth hormone, prolactin glycoprotein hormonesLH, FSH, TSH

As a result of the hypophysiotrophic hormones and their influence on the actions of the pituitary axis several hypothalamic-pituitary axes can be identified. 1. Hypothalamus pituitary adrenal axis In response to stress corticotrphin releasing hormone (CRH) secretion from the PVN of the hypothalamus is increased. This in turn increases secretion of adrenocorticotrophic hormone (ACTH) from the corticotrophs of the anterior pituitary. The increased plasma ACTH stimulates cortisol secretion from the zona fasiculata of the adrenal cortex. This pathway is activated by stress (neural and hormonal input) and regulated by negative feedback inhibition by cortisol on CRH and ACTH. Cortisol is extremely important in the endocrine response to stress (fight or flight). It acts on liver and muscle tissue to mobilize glucose/energy source. It can be referred to as a glucose counter-regulatory

hormone. Efferent output from the PVN also activates the sympathetic branch of the autonomic nervous system thus increasing epinephrine. The overall response is vasoconstriction, increased heart rate and respiratory rate, enhanced arousal and alertness There is daily variation in the relationship between ACTH and cortisol. This is due to the cortisol awakening response. This response is characterized by a circadian rhythm that is mediated by the suprachiasmatic nucleus and visual and light/dark cues. It is an adaptation to anticipated stress that is specifically related to night time sleep. The response is enhanced by rising earlier and in light. While continuous low level noise attenuates the response. 2. Hypothalamic pituitary thyroid axis

3. Hypothalamic pituitary gonadal axis GnRH from the hypothalamus stimulates LH and FSH secretion from the gonadotroph cells of the anterior pituitary. They are regulated by negative feedback by estrogen, testosterone or inhibin. LH acts on leydig cells in the testes and thecal cells in the ovary. FSH acts on sertoli cells of the testis and granulose cells of ovary. Both of these hormones are necessary for fertility and reproduction.

Physiological role in females

Actions in the testis

4. DA Prolactin mammary glands Prolactin is the only pituitary hormone that is not a trophic hormone. It is produced by the lactotrophs of the anterior pituitary. It is regulated by estrogen and progesterone (so is increased in pregnancy), its release is inhibited by dopamine. It plays a major physiological role in lactation and stimulates mammogenesis (glandular breast development) and lactogenesis (milk production).

5. Growth factor and IGF-1 axis

Hypothalamus and Posterior pituitary The neurohypophysis consists of unmyelinated nerve axons of neurons whose cell bodies are located in the hypothalamus and that terminate in the posterior pituitary. The neurons are pituicytes/glial cells. Secretory granules containing oxytocin and vasopressin hormones are stored along the length of the neurons in axonal dilations known as Herring Bodies. The secretory granules are released by exocytosis at the pituitary end of the neuron. Vasopressin is also known as antidiuretic hormone. It is a 9 amino acid peptide with an internal S-S bond giving it a cyclical structure. It is structurally related to oxytocin. It is secreted by peptidergic neuroendocrine cells in the PVH and SON. It is secreted in response to dehydration i.e. reduced central venous pressure that is sensed by baroreceptors in veins, atria and carotid arteries and increased plasma osmotic pressure due to water loss sensed by osmoreceptors in the hypothalamus. It acts on V2 receptors in the basolateral membrane of the distal tubular epithelium. The receptor activates cAMP second messenger system, the cell increases aquaporin water pores in apical membrane and thus water is absorbed by osmosis into the plasma. It plays a physiological role in the regulation of plasma

osmolarity by allowing for increased water reabsorption at the collecting ducts and regulation of vascular tone.

Vasopressin resistance or deficiency can result in Diabetes Insipidus. The features of this disease include the excretion of large volumes of dilute urine/day which cannot be reduced by reducing fluid intake, the inability of the kidney to reabsorb H20 and dehydration. It can either be classified as neural DI (hypothalamus, pituitary lesion) or nephrogenic DI (renal resistance to vasopressin). Nephrogenic can either be inherited or acquired. Inherited results from mutations in the V2 receptor or in aquaporin 2. While acquired may be drug induced or due to polycystic kidney disease. Oxytocin is also secreted by the peptidergic neuroendocrine cells in PVH and SON. It has a weak antidiuretic action but also plays a physiological role in parturition, lactation and social/mating/emotional behaviour. In lactation, it stimulates myoepithelial contractions to expel milk from mammary alveoli into ducts/collecting chamber. In parturition, it stimulates uterine contractions and can be used to induce labour.

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