Development Team. Department of Zoology, University of Delhi. Department of Zoology, University of Delhi

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1 Paper Module : 06 : 17 Development Team Principal Investigator : Prof. Neeta Sehgal Department of Zoology, University of Delhi Co-Principal Investigator : Prof. D.K. Singh Department of Zoology, University of Delhi Paper Coordinator : Prof. Rakesh Kumar Seth Department of Zoology, University of Delhi Content Writer : Dr. Meena Yadav Maitreyi College, University of Delhi Content Reviewer : Prof. Neeta Sehgal Department of Zoology, University of Delhi

2 Description of Module Subject Name Paper Name Module Name/Title Module Id Keywords Zool 006 Neuro-endocrine Physiology M17 Brain-pituitary-target organ axis, hypothalamic-hypophysial portal system, arcuate nucleus, paraventricular nucleus, prepubertal hiatus, pre-ovulatory LH surge, positive feedback regulation, negative feedback regulation Contents 1. Learning Outcomes 2. Introduction 2.1. Types of feedback regulation 2.2. The Hypothalamic-Hypophysial Portal System 3. The neuroendocrine axis for growth (The Somatotropic Axis) 3.1. Factors influencing the Somatotropic Axis 4. The neuroendocrine axis for reproduction (The Brain-Pituitary-Gonadal Axis) 4.1. Oxytocin: Positive feedback regulation 4.2. Factors affecting Brain-Pituitary-Gonadal Axis 5. The neuroendocrine axis for Metabolism (The Brain-Pituitary-Thyroid Axis) 6. The neuroendocrine axis for lactation (The Lactotrophic Axis) 7. The neuroendocrine axis for stress (The Brain-Pituitary-Adrenal Axis) 7.1. Factors affecting CRH secretion from hypothalamus 8. Summary

3 1. Learning Outcomes After studying this module, you should be able to: Discuss the hypothalamus-hypophysial portal system The somatotropic axis and its regulation The Brain-pituitary-gonadal axis and its regulation The Brain-pituitary-thyrotropic axis and its regulation The Brain-pituitary-adrenal axis and its regulation The lactotrophic axis and its regulation The regulation of oxytocin secretion Various factors influencing the brain-pituitary-target organ axes 2. Introduction Hypothalamus secretes several hormones which act on respective target organs. These hormones act in a synchronized manner and involve a relay of the flow of signal from hypothalamus to target organs via various axes like hypothalamic-pituitary-gonadal axis, hypothalamic-pituitary-adrenal axis, hypothalamic-pituitary-thyroid axis, hypothalamicpituitary-liver axis etc. Though it appears that hypothalamic hormones are the primary regulators of these axes but a more complex role is played by central nervous system (CNS). The release of releasing or inhibiting hormones from hypothalamus is regulated by signals from other neurons or glial cells in brain. It is the synchronized regulation of the secretion of these neurohormones which drives the various metabolic and developmental activities in the body and helps in maintaining the homeostasis Types of feedback regulation The feedback regulation of neurohormones can occur at various levels like at gene transcription, translation, post-translational modifications or the release of hormones. The feedback regulation can be of broadly two types:

4 1. Positive feedback regulation: Sometimes, the action of the hormone on a target tissue causes surplus secretion of hormone. For example, secretion of luteinizing hormone (LH). The action of estrogen on the anterior pituitary causes release of LH, before ovulation. The secreted LH further acts on the ovaries to secrete more estrogen, which in turn stimulates the secretion of further LH from anterior pituitary. This action causes a heightened release of LH, also called as LH surge. After this, there is negative feedback regulation of the hormone. 2. Negative feedback regulation: The majority of the hormones secreted by brain are regulated by the negative feedback mechanism. When the levels of a hormone increase in the blood, the hormones inhibit the release of themselves by inhibiting the secretion of releasing and inhibiting hormones from the hypothalamus and which subsequently inhibits the release of hormones from the pituitary gland. For example, brain-pituitarythyroid axis, brain-pituitary-growth hormone axis etc The Hypothalamic-Hypophysial Portal System The secretion of hormones from the pituitary gland is under control of signals from hypothalamus. There can be two types of these signals: hormonal or neural. The posterior pituitary secretions are under control of nerve signals from hypothalamus. These neurons originate from various nuclei in hypothalamus and extend their axons such that they terminate in posterior pituitary. However, in case of anterior pituitary, the signals come in the form of hormones from the hypothalamus. These signals are called as releasing hormones/factors or inhibiting hormones/factors and are secreted within the hypothalamus. They are carried to the anterior pituitary via a rich capillary network called hypothalamic hypophysial portal system, primarily located in the median eminence. These hormones from hypothalamus then act on specific target secretory cells in the anterior pituitary and cause the release of respective hormones in the general blood circulation. The hypothalamus receives signals from various neurons within the nervous system:

5 i. Pain ii. Powerful thoughts (exciting or depressing) iii. Olfactory stimuli (pleasant and unpleasant): Signals are transmitted directly or through amygdala iv. Levels of electrolytes, nutrients, other hormones and water Thus, hypothalamus is a center which collects signals from all over the body and regulates the secretion of various hormones from pituitary to maintain the homeostasis inside the body. The minute blood vessels of the portal system penetrate the anterior pituitary and form a rich network. These capillaries originate from the median eminence, the lowermost part of the hypothalamus, and run into the anterior pituitary via the pituitary stalk. Hypothalamus contains specialized neurons which synthesize and secrete various releasing and inhibitory hormones into the median eminence to control the secretion of pituitary gland. Unlike other neurons, the hypothalamic secretory neurons do not propagate signals from one neuron to another, instead they secret releasing and inhibiting hormones into the tissue fluid in median eminence which are then absorbed into the capillaries and are carried to the sinuses in the anterior pituitary. The control of secretion of hormones from pituitary is regulated by pathways/axis which includes flow of signals in a loop including brain, pituitary and target organs. There are five neuroendocrine axes which regulate growth, reproduction, metabolism, lactation and stress. Let us discuss these axes one by one in the following sections. 3. The neuroendocrine axis for growth (The Somatotropic Axis) The growth hormone (GH) promotes the growth of the body by influencing synthesis of proteins, cell proliferation and differentiation. This axis is involved in regulating the growth of the organisms and works through the following hormones: a. Hypothalamus: Secretes growth hormone releasing hormone (GHRH) and growth hormone inhibiting hormone (GHIH) or somatostatin.

6 b. Anterior Pituitary: Secretes growth hormone (GH), also called somatotropin c. Primary target organ (liver): Secretes insulin-like growth factor-1 (IGF-1). There is a unique feature of this axis as GH and IGF-1 both can produce the growthpromoting effects either alone or together. However, both the hormones are required for the complete growth-promoting function as absence of any one of these, due to mutations, may result in dwarfism. The hormones secreted in somatotropic axis are different in nature than the hormones in other axes because hypothalamus secretes GHRH which stimulates the secretion of Growth Hormone (GH) from specialized cells in anterior pituitary called somatotropes and promotes growth and it also secrets GHIH which inhibits the secretion of GH and thus, inhibits the growth. The GHRH is secreted by neurons in the arcuate nucleus in hypothalamus. This nucleus also responds to changes in the blood glucose levels and causes satiety if blood glucose levels are high and hunger if the blood glucose levels are low. Further, GH interacts with GH receptors in liver and stimulates the secretion of IGF-1. The GH and IGF-1 have common target organs like bone and muscles and promote their growth, regeneration and metabolic homeostasis. GH and IGF-1 both are a part of feedback regulation of somatotropic axis.

7 Fig. 1: Feedback regulation in somatotropic axis: Hypothalamus secretes two hormones which regulate the secretion of GH i.e. GHRH (Stimulates GH secretion) and GHIH (Inhibits GH secretion). GH stimulates release of IGF-1 from liver and both synergistically act on the target tissues. IGF-1 has inhibitory effect on anterior pituitary as well as hypothalamus under proper stimuli. Additionally, ghrelin also has a positive effect on secretion of GH. GH Growth hormone; GHRH growth hormone releasing hormone; GHIH growth hormone inhibiting hormone; IGF-1 insulin-like growth factor -1; GH is released more during night as compared to day and is under hypothalamic control. In addition to GHRH and GHIH, ghrelin also controls the secretion of GH. It is produced in hypothalamus and stimulates the secretion of GH. Although there are several factors which influence the secretion of growth hormone but the most important factor is GHRH and not somatostatin. GHRH binds to its receptors present on somatotropes in anterior pituitary and stimulates secretion of GH. The binding of GHRH to receptors causes activation of adenylyl cyclase which causes an increase in the levels of camp. camp causes an increase in the levels of intracellular calcium which causes the secretory vesicles to fuse with the cell membrane and release GH into the blood. camp also induces transcription of gene for synthesis of more GH.

8 GH regulates GHRH secretion from hypothalamus by negative feedback (Fig. 1) but it induces the expression of somatostatin gene. Thus, if the GH is lacking or its levels are low the somatostatin gene will not be expressed to produce somatostatin. IGF-1 also acts in the similar way as GH and is a negative feedback molecule for GHRH and stimulates expression of somatostatin gene. The GHRH neurons are located in arcuate nucleus in hypothalamus and release GHRH in the portal capillaries in median eminence and other hypothalamic regions too where it may control feeding behaviour. Thus, GHRH neurons may get stimuli from other neurons in the CNS like α-adrenergic, dopaminergic, serotonergic and encephalinergic neurons. The cell bodies of GHRH neurons are densely located in arcuate nucleus whereas cell bodies of somatostatin neurons are dispersed throughout the CNS. However, cell bodies of somatostatin neurons which are involved in growth are concentrated in periventricular nucleus. Most of the neurons from hypothalamus have their axonic projections into the median eminence but somatostain neurons also interact with the GHRH neurons and thus inhibit them Factors influencing the Somatotropic Axis There are several factors which stimulate the release of growth hormone from anterior pituitary and have been summarized in Table 1. Table 1: Factors influencing secretion of growth hormone from anterior pituitary S.No. Factors that stimulate secretion of GH Factors that inhibit secretion of GH 1 Starvation or fasting Obesity 2 Hypoglycemia Aging 3 Low levels of free fatty acids Hyperglycemia 4 Depression or excitement High levels of free fatty acids 5 Exercise Exogenous GH 6 Testosterone and estrogen Somatomedins (insulin-like growth factors) 7 Early 2 hours of deep sleep GHIH or somatostatin 8 GHRH REM sleep 9 Glucagon Cortisol

9 10 Increase in circulating levels of certain amino acids 11 Apomorphine and dopamine receptor agonists 12 Protein meal Further, there are substances which are metabolically active and influence the somatostatin system: i. Amino acids stimulate somatostatin secretion whereas fatty acids and glucose inhibit somatostatin secretion. ii. Neurotransmitters: Catecholamines like dopamine, norepinephrine, acetylcholine, GABA affect somatostatin secretion. iii. Neuropeptides: Neurotensin, substance P, bombesin iv. Substances involved in glucoregulation like glucose, glucoregulatory enzymes and hormones 4. The neuroendocrine axis for reproduction (The Brain-Pituitary-Gonadal Axis) The brain-pituitary-gonadal axis plays a very important role in the propagation and survival of the species. The gonadotropins LH and FSH control the growth of testis and ovaries and their further development and hormonal activities. The hormones which are secreted and play role in this axis include: a. Hypothalamus and preoptic area: Secrete Gonadotropin Releasing Hormone (GnRH), also called as Luteinizing Hormone Releasing Hormone (LHRH). b. Anterior pituitary (gonadotropes): Secretes gonadotropins i.e. Luteinizing Hormone (LH) and Follicular Stimulating Hormone (FSH) c. Gonads (Testis in males and ovary in females):secrete sex steroid hormones like estrogens, progestins and androgens The GnRH neurons in hypothalamus extend their terminals in the median eminence and release GnRH in a pulsatile manner. The GnRH acts on its target cells in anterior pituitary i.e.

10 gonadotropes, and stimulates them to secrete gonadotropins i.e. Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH). These gonadotropins are secreted into the general circulation from where they reach their target cells in the testis and ovary which further stimulate steroidogenesis and spermatogenesis in males and oogenesis in females. The binding of the gonadotropins on the receptors of target cells in gonads leads to the synthesis and secretion of sex steroids from the gonads i.e. estrogens and progestins from ovary and androgens from the testis. However, ovaries also produce certain amounts of androgens and testes produce estrogens and progestins. The sex steroid hormones, once they are released from the gonads enter the general circulation and bind to the receptors on the target cells scattered throughout the body. The target tissues respond by producing secondary sex characteristics and other adult reproductive functions. Certain regions in the brain have receptors for sex steroid hormones including hypothalamus and the interaction shows several effects on the CNS. The most important effect of sex steroids is in the feedback regulation of GnRH secretion from the hypothalamus (Fig. 2). The regulation of reproductive axis changes as the function of the reproductive system changes over a period of time during development. For example, during the late embryonic period in development or just after birth, the activity of brain-pituitary-testicular axis increases while there is less activity of brain-pituitary-ovarian axis. However, shortly after birth the reproductive system goes dormant, may be due to the inhibition of the GnRH or due to lack of stimulation of this axis. This stage is called prepubertal hiatus where there are low levels of GnRH, gonadotropins and sex steroid hormones. In males, the sex steroids secretion and inhibition is controlled by negative feedback mechanism (Fig. 2). The release of GnRH stimulates secretion of gonadotropins. LH further stimulates the release of testosterone which in turn inhibits the release of LH by negative feedback loop. The main process by which testosterone shows negative feedback on hypothalamus is by inhibiting the release of GnRH and thus stops further release of LH and FSH by anterior pituitary. This results in the inhibition of secretion of testosterone by the testis and thus completes the negative feedback chain. Whenever there is excess secretion of

11 testosterone, this negative feedback ensures the levels of testosterone are reduced to normal levels by inhibiting the secretion of hormones at two levels: Hypothalamic hormones and Anterior pituitary hormones. Conversely, when the testosterone levels are too low, the hypothalamus secretes GnRH which in turn stimulates secretion of LH and FSH and further secretion of more testosterone from testis. Fig. 2: The brain-pituitary-gonadal axis: GnRH is secreted by GnRH neurons in hypothalamus and preoptic area. GnRH stimulates gonadotropes in anterior pituitary to secrete gonadotropins i.e. LH and FSH. Gonadotropins act on the gonads i.e. testis and ovary which secrete sex steroids like androgens, estrogens and progestins. The sex steroids, under proper stimulus, show negative feedback on anterior pituitary, hypothalamus and preoptic area during most of the cycle. But during some stages as in menstrual cycle, sex steroids may also show positive feedback on anterior pituitary and hypothalamus, causing hormonal surge. The Inhibin B secreted by the Sertoli cells in testis show negative feedback on anterior pituitary and hypothalamus. GnRH Gonadotropin releasing hormone; LH Luteinizing hormone; FSH Follicle stimulating hormone; In testis, when there is low production of sperms within seminiferous tubules, there is increase in the production of FSH by anterior pituitary. Also, if there is too high production of sperms, the FSH secretion slows down. This phenomenon of regulation of FSH secretion is

12 controlled by a hormone secreted by the Sertoli cells within the testis called as inhibin. Inhibin directly acts on anterior pituitary for negative feedback of FSH while it also slightly influences the GnRH secretion from hypothalamus. In females, in addition to the negative feedback regulation by sex steroids, like in males, there also occurs positive feedback regulation at certain times. In females, estradiol and progesterone act on hypothalamus to inhibit the release of GnRH and on anterior pituitary to inhibit release of gonadotropins i.e. negative feedback regulation. Thus, in major part of the reproductive cycle, estradiol and progesterone act on the brain and anterior pituitary via negative feedback to inhibit the release of GnRH and gonadotropins. However, in primates, during mid to late follicular stage and in rats on the day of proestrous (estrous cycle of 4-5 days), the estrogens show positive feedback effect on GnRH release. This effect of estradiol causes a preovulatory GnRH surge followed by preovulatory LH surge resulting in the release of ovum from the ovary and maturation of corpus luteum. After the ovum has been released, the effect of ovarian sex steroids again becomes inhibitory on hypothalamus i.e. negative feedback, until ovulation in next cycle. In case of brain-pituitary-gonadal axis, the main site of feedback regulation by sex steroids is not GnRH neurons as they express only Estrogen Receptor β (ERβ) and no other receptors like ERα, androgen receptors (AR), or progesterone receptors (PR). The presence of only ERβ does not satisfactorily explain the feedback regulation of GnRH secretion by estrogens, indicating that there are some other stimuli from central nervous system which also contribute in regulation of GnRH cells. These stimuli may lie in hypothalamus or other regions which contain sex steroid hormone receptors. Thus, the hypothalamic-pituitarygonadal axis may more appropriately be called as brain- pituitary-gonadal axis. The same logic may be applied to other axes as the feedback regulation does not entirely depend on the hormones from the target cells only. Thus, there are other afferent neurons having these receptors, which supply to and influence the GnRH neurons and thus play an important role in the feedback regulation of the GnRH neurons by sex steroid hormones.

13 The propagation of stimulus by sex steroids through afferent neurons carrying ERα to GnRH neurons may account for the shift between negative and positive feedback regulation. So there may be some neurons which respond to the higher levels of estrogens by following the negative feedback during most of the reproductive cycle while some others may respond to higher estrogen levels via positive feedback loop causing preovulatory surge Oxytocin: Positive feedback regulation Oxytocin (OT) is secreted by the dendrites and cell bodies of supraoptic and magnocellular neurons from paraventricular nucleus (PVN) in hypothalamus into the posterior pituitary. Along with this, oxytocin may also be secreted by uterus, placenta and fetal membrane during parturition. During childbirth when the uterine contractions start, more oxytocin is released which stimulate more contractions and as a result still more oxytocin is released. Due to this the strength of contractions increase which help in propelling the baby out. Once, the baby has been delivered, contractions stop and hence, the release of oxytocin also stops. Thus, oxytocin secretion increases due to stimulation by neural signals from contracting uterus and cervix as the fetus pass through them. Certain drugs inhibit the secretion of OT and thus slow down or stop the parturition. These drugs include µ-receptor agonists like morphine and pethidine and κ-agonist Another important role of OT is in the release of milk in nursing mothers. Suckling of mother s breast by the baby results in the secretion of oxytocin in the mother s milk. This causes milk to flow in the mammary glands and if the baby stops suckling, the milk is not released. The OT receptors are expressed in lactotropes in anterior pituitary. Together with prolactin, OT helps in ejection of milk from the mammary glands Factors affecting Brain-Pituitary-Gonadal Axis The GnRH neurons are functionally regulated by several neurotransmitters and neurotrophic factors, reflecting that GnRH neurons are integrative. Neurotransmitters which provide input

14 to GnRH neurons include GABA, glutamate, catecholamines and monoamines; neuropeptide include CRH, kisspeptin, β-endorphin, neurotensin, vasopressin etc. 5. The neuroendocrine axis for Metabolism (The Brain-Pituitary-Thyroid Axis) The brain-pituitary-thyroid axis is involved in regulation of metabolism which is needed for survival and development of the organisms. The rates of most of the intracellular reactions are regulated by thyroid hormones. The hormones which are a part of this axis are listed below: a. Hypothalamus: Secretes Thyrotropin Releasing Hormone (TRH), produced by neurons in paraventricular nucleus. b. Anterior Pituitary: Secretes Thyroid Stimulating Hormone (TSH). c. Thyroid gland: Secretes Thyroxine (T 4 ) and Triiodothyronine (T 3 ) The large axons of the TRH neurons, like other hypothalamic neurons, terminate in the median eminence. The high capillary network of the median eminence carries TRH to the anterior pituitary. The receptors for TRH are located in the specialized cells in anterior pituitary called as thyrotropes, which when stimulated by TRH will secrete TSH. From the anterior pituitary TSH is released in general circulation and reaches its target organ i.e. thyroid gland, located in neck, having receptors for TSH. The thyroid gland secretes two potent hormones i.e. Thyroxine (T 4 ) and Triiodothyronine (T 3 ) in general circulation. The target organs of T 3 and T 4 are located throughout the body.

15 Fig. 3: The brain-pituitary-thyroid axis: The TRH neurons in the PVN of hypothalamus stimulate thyrotropes of anterior pituitary to secrete TSH. TSH stimulates thyroid gland to secrete thyroid hormones T3 and T4. Thyroid hormones act on various target tissues in the body. Thyroid hormones show a negative feedback by acting on anterior pituitary and hypothalamus, when the levels of thyroid hormones increase more than required. TRH Thyrotropin releasing hormone; PVN paraventricular nucleus; TSH- thyroid stimulating hormone T 3 and T 4 are also involved in feedback regulation of TRH and TSH by acting on hypothalamus and anterior pituitary respectively (Fig. 3). The brain-pituitary-thyroid axis is an example of the negative feedback regulation. The precise regulation of these hormones is important as the lower or higher levels of these hormones may have drastic influence on the metabolism and other events of development. The thyroid hormones exist in two forms after being secreted from the thyroid gland: free form and bound form, when they are bound to globulins. The free form of thyroid hormones, which constitutes <1% of the total thyroid hormones participates in the negative feedback regulation by acting on the TRH neurons, thyrotropes and also acting on the target tissues.

16 6. The neuroendocrine axis for lactation (The Lactotrophic Axis) There is no releasing factor from hypothalamus for lactation and only the anterior pituitary secretes prolactin (PRL) which is the major regulator of lactation in mammals. Prolactin promotes the development of mammary glands and production of milk. However, there is an inhibiting factor for lactation i.e. dopamine, present in hypothalamus. The prolactin is released by the lactotropes in anterior pituitary in to the general circulation from where prolactin goes to its target cells in the mammary gland and promotes the synthesis and release of milk into the alveoli of mammary glands when stimulated by suckling (Fig. 4). Prolactin and oxytocin, together are needed during the period of lactation. Fig. 4: The LactotrophicAxis: The lactotrophs in anterior pituitary are stimulated by suckling action of the baby to release PRL in the general circulation. Along with this TRH, oxytocins, VIP etc. also have positive effect on the secretion of PRL. However, there are other neurons which secrete dopamine which has a strong inhibitory effect on PRL secretion. Thus, in the absence of suckling, the action of dopamine prevails, thereby preventing secretion of milk from the breasts. TRH Thyrotropin releasing hormone; VIP vasoactive intestinal peptide; PRL prolactin Dopamine is the only molecule which inhibits the release of prolactin from anterior pituitary and since it is present in hypothalamus in high amount, we can call it as the inhibiting factor for prolactin. It is also present in high quantity in median eminence form where it is

17 transported to the anterior pituitary via portal capillary network. There are several factors which contribute to the secretion or inhibition of prolactin from anterior pituitary: a. Drugs which increase dopamine levels in pituitary portal capillaries influence the PRL secretion. b. External application of dopamine influences the release of prolactin from anterior pituitary. The lactotropes in the anterior pituitary contain receptors for dopamine such that the increase or decrease in the portal dopamine is directly correlated with the changes in secretion of prolactin from anterior pituitary. Though there is no true prolactin releasing hormone in hypothalamus but factors like TRH, vasoactive intestinal peptide (VIP) and oxytocin influence the stimulation of prolactin release. 7. The neuroendocrine axis for stress (The Brain-Pituitary-Adrenal Axis) Stress is an important physiological and psychological phenomenon to which the organisms must adapt or react properly in order to survive. There could be several reasons of stress like: a. Escaping predation b. Escaping chronic stress of a disease c. Escaping from social influence The response to stress is mediated by brain-pituitary-adrenal axis which works by secretion of following hormones: a. Hypothalamus: Secretes corticotropin-releasing hormone (CRH), mainly from medial parvocellular part of paraventricular nucleus and arginine vasopressin (AVP) b. Anterior Pituitary: Secretes adrenocorticotropic hormone (ACTH), 8-lipotropin, 3- endorphin; catecholamines c. Adrenal cortex: Secretes glucocorticoids (cortisol, corticosterone etc.) The cell bodies of CRH neurons are located in the PVN of the hypothalamus. CRH neurons receive input from various other neurons in limbic system and lower brain stem. The axons from CRH neurons in hypothalamus reach the external layer of median eminence and from

18 here CRH neurons go to anterior pituitary where they target the corticotropes, which secrete ACTH. Another hypothalamic hormone produced by magnocellular neurons in PVN, called arginine vasopressin (AVP) or antidiuretic hormone (ADH), also acts on the corticotropes of anterior pituitary and shows a synergistic effect. The corticotropes have receptors for both the hypothalamic hormones i.e. CRH and AVP and respond by promoting synthesis and release of adrenocorticotropic hormone (ACTH) from anterior pituitary (Fig. 5). ACTH is released from the pituitary gland in the general circulation from where it reaches its target organ adrenal gland (adrenal cortex). ACTH activates adenylyl cyclase in cell membrane of adrenocortical cells which forms camp. camp induces the synthesis of adrenocortical hormones. Thus, adrenal cortex responds by secreting glucocorticoids. The glucocorticoids show negative feedback regulation of brain and pituitary and thus, inhibit the synthesis of CRH and ACTH respectively. Glucocorticoids also inhibit the transcription of precursor protein pro-opiomelanocortin (POMC) in the corticotropes in anterior pituitary. Thus, the brain-pituitary-adrenal axis is an example of a negative feedback regulation. The PVN is an important center as it gets input from various regions of the brain like the brain stem, the mid brain, the limbic system and other hypothalamic nuclei.

19 Fig. 5: The brain-pituitary-adrenal axis: The PVN of hypothalamus contains two types of neurons which re associated with stress i.e. CRH neurons and AVP neurons.crh stimulates corticotropes in anterior pituitary to secrete ACTH. ACTH acts on adrenal cortex and stimulates secretion of glucocorticoids which act on the target cells. The glucocorticoids show a negative feedback effect on anterior pituitary and hypothalamus. Stress is one of the stimulant for secretion of CRH and after the target cells have been relieved of stress, the secretion of CRH, ACTH and glucocorticoids goes down. PVN paraventricular nucleus; CRH- corticotropin releasing hormone; AVP arginine vasopressin; ACTH adrenocorticotropin hormone; 7.1. Factors affecting CRH secretion from hypothalamus There are several factors which may affect the secretion of CRH from hypothalamus like: 1. Physiologic stress: Any type of mental or physical stress can increase the secretion of ACTH and cortisol. If there is any physical stress, the signal is transmitted via brain stem to hypothalamus and median eminence. Then CRH is secreted in to the portal system in median eminence which ultimately results in secretion of cortisol in blood. Similarly, if there is any mental stress the signal is transmitted through limbic system (amygdala and hippocampus) which then transmit the signal to hypothalamus. 2. Cortisol: Cortisol shows direct negative feedback on hypothalamus and pituitary gland. Thus, cortisol decreases the secretion of CRH and ACTH respectively. 3. Adrenal steroids use feedback loop to inhibit secretion of CRH and ACTH. In this type of feedback loop, there is a specific point which is called as steady state where the secretion of releasing factors to stimulate secretin of hormone is balanced by the end products to inhibit the secretion of hormones. The steady state, however, changes over time in sync with the circadian rhythm. At some times more ACTH may be required to inhibit the release of more ACTH. Other than these factors, some more have been summarized in Table 2 below. Table 2: Factors affecting secretion of CRH from hypothalamus Factors which up regulate secretion of Factors which down regulate secretion of CRH from hypothalamus CRH (via negative feedback) i. Serotonergic system i. Opiates ii. Cholinergic system ii. γ aminobutyric acid (GABA)

20 iii. Catecholaminergic system iii. glucocorticoids iv. ACTH 8. Summary Hypothalamus secretes several hormones which act on respective target organs via several pathways which are called as brain-pituitary-target organ axes. Hypothalamus secretes various signals in the form of either hormones or neurotransmitters. The feedback regulation of neurohormones can occur at various levels like at gene transcription, translation, post-translational modifications or the release of hormones. The feedback regulation of the neurohormones is of two types: Positive feedback regulation, when the presence of high levels of hormones stimulates secretion of more hormone and negative feedback regulation, when the presence of high levels of hormones inhibits the secretion of hormone. The hormonal signals from the hypothalamus are released into the hypothalamichypophysial portal system, a rich network of minute blood vessels in the median eminence, just below the hypothalamus. From the median eminence, the hormonal signals go to the sinuses in the anterior pituitary. The somatotropic axis includes secretion of following hormones: Hypothalamus: Secretes growth hormone releasing hormone (GHRH) and growth hormone inhibiting hormone (GHIH) or somatostatin. Anterior Pituitary: Secretes growth hormone (GH), also called somatotrophin Primary target organ (liver): Secretes insulin-like growth factor-1 (IGF-1). Somatotropic axis is an example of negative feedback regulation as excess of GH and IGF- 1 inhibit the release of hormones from hypothalamus and anterior pituitary. The brain-pituitary-gonadal axis secretes following hormones:

21 Hypothalamus and preoptic area: Secrete Gonadotropin Releasing Hormone (GnRH), also called as Luteinizing Hormone Releasing Hormone (LHRH). Anterior pituitary (gonadotropes): Secretes gonadotropins i.e. Luteinizing Hormone (LH) and Follicular Stimulating Hormone (FSH) Gonads (Testis in males and ovary in females): Secrete sex steroid hormones like estrogens, progestins and androgens During most of the time, this axis shows negative feedback regulation as sex steroids inhibit the secretion of anterior pituitary and hypothalamus. But, in primates, during preovulatory stages, the sex steroids adopt positive feedback mechanism to increase the levels of LH to cause LH surge which is required for ovulation. After, ovulation the axis again adopts negative feedback regulation. The brain-pituitary-thyroid axis secrets following hormones: Hypothalamus: Secretes Thyrotropin Releasing Hormone (TRH), produced by neurons in paraventricular nucleus. Anterior Pituitary: Secretes Thyroid Stimulating Hormone (TSH). Thyroid gland: Secretes Thyroxine (T 4 ) and Triiodothyronine (T 3 ) This axis follows the typical negative feedback mechanism for regulating the secretion of TRH and TSH. The thyroid hormones when present in higher levels in the tissues exert an inhibitory effect on anterior pituitary and hypothalamus. The lactotrophic axis does not have any releasing hormone from the hypothalamus. However, hypothalamus has dopamine which inhibits the secretion of prolactin (PRL) from anterior pituitary. Suckling by the baby stimulates the lactotropes in the anterior pituitary to release PRL which acts on the mammary gland and stimulates production and secretion of milk. PRL and oxytocin together stimulate release of milk form the mammary gland.

22 In the absence of suckling stimulus, dopamine inhibits the secretion of PRL from anterior pituitary. The brain-pituitary-adrenal axis secretes following hormones: Hypothalamus: Secretes corticotropin-releasing hormone (CRH), mainly from medial parvocellular part of paraventricular nucleus and arginine vasopressin (AVP) Anterior Pituitary: Secretes adrenocorticotropic hormone (ACTH), 8-lipotropin, 3- endorphin; catecholamines Adrenal cortex: Secretes glucocorticoids (cortisol, corticosterone etc.) This axis is also an example of a typical negative feedback regulation. The glucocorticoids show inhibitory effects on anterior pituitary and hypothalamus, when the glucocorticoid levels become higher. Stress is the main stimulant for secretion of CRH from hypothalamus and then the pathway follows. Thus, the homeostasis within the body is maintained by the above explained brainpituitary-target organ axes which are regulated either by positive feedback mechanism or negative feedback mechanism.