Hypothalamus and Pituitary

Hypothalamus and Pituitary The hypothalamus-pituitary unit is the most dominant portion of the entire endocrine system. The output of the hypothalamus-pituitary unit regulates the function of the thyroid, adrenal and reproductive glands and also controls somatic growth, lactation, milk secretion and water metabolism.

Hypothalamus and Pituitary Pituitary function depends on the hypothalamus and the anatomical organization of the hypothalamus-pituitary unit reflects this relationship. The pituitary gland lies in a pocket of bone at the base of the brain, just below the hypothalamus to which it is connected by a stalk containing nerve fibers and blood vessels. The pituitary is composed to two lobes-- anterior and posterior

Posterior Pituitary: neurohypophysis Posterior pituitary: an outgrowth of the hypothalamus composed of neural tissue. Hypothalamic neurons pass through the neural stalk and end in the posterior pituitary. The upper portion of the neural stalk extends into the hypothalamus and is called the median eminence.

Anterior pituitary: adenohypophysis Anterior pituitary: connected to the hypothalamus by the superior hypophyseal artery. The antererior pituitary is an amalgam of hormone producing glandular cells. The anterior pituitary produces six peptide hormones: prolactin, growth hormone (GH), thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH).

Hypothalamus and pituitary gland

Hypothalamus and pituitary gland

Regulation of Hypothalamus

Anatomical and functional organization

Hypothalamic releasing factors for anterior pituitary hormones Travel to adenohypophysis via hypophyseal-portal circulation Travel to specific cells in anterior pituitary to stimulate synthesis and secretion of trophic hormones

Hypothalamic releasing hormones Effect on pituitary Corticotropin releasing hormone (CRH) Stimulates ACTH secretion Thyrotropin releasing hormone (TRH) Stimulates TSH and Prolactin secretion Growth hormone releasing hormone (GHRH) Stimulates GH secretion Somatostatin Inhibits GH (and other hormone) secretion Gonadotropin releasing hormone (GnRH) Stimulates LH and FSH secretion Prolactin releasing hormone (PRH) Stimulates PRL secretion Prolactin inhibiting hormone (dopamine) Inhibits PRL secretion

Characteristics of hypothalamic releasing hormones Secretion in pulses Act on specific membrane receptors Transduce signals via second messengers Stimulate release of stored pituitary hormones Stimulate synthesis of pituitary hormones Stimulates hyperplasia and hypertophy of target cells Regulates its own receptor

Anterior pituitary Anterior pituitary: connected to the hypothalamus by hypothalmoanterior pituitary portal vessels. The anterior pituitary produces six peptide hormones: prolactin, growth hormone (GH), thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH).

Anterior pituitary cells and hormones

Hypothalamus and anterior pituitary

Anterior pituitary hormones

Feedback regulation of hypothalmus/pituitary A prominent feature of each of the hormonal sequences initiated by the hypothalamic releasing hormones is negative feedback exerted upon the hypothalamic-pituitary system by the hormones whose production are stimulated in the sequence.

Hypothalamus-pituitary axis

Feedback control

Feedback control of thyroid function

Feedback and restoration of homeostasis

Feedback control of growth hormone

Growth hormone vs. metabolic state When protein and energy intake are adequate, it is appropriate to convert amino acids to protein and stimulate growth. hence GH and insulin promote anabolic reactions during protein intake During carbohydrate intake, GH antagonizes insulin effects-- blocks glucose uptake to prevent hypoglycemia. (if there is too much insulin, all the glucose would be taken up). When there is adequate glucose as during absorptive phase, and glucose uptake is required, then GH secretion is inhibited so it won't counter act insulin action.

Growth hormone vs. metabolic state During fasting, GH antagonizes insulin action and helps mediate glucose sparing, ie stimulates gluconeogenesis In general, duing anabolic or absorptive phase, GH facilitates insulin action, to promote growth. during fasting or post-absorptive phase, GH opposes insulin action, to promote catabolism or glucose sparing

Growth hormone and metabolic state

ACTH: adrenocorticotropic hormone: synthesis and regulation of secrtion Produced in corticotrophs ACTH is produced in the anterior pituitary by proteolytic processing of Prepro-opiomelanocortin (POMC). Other neuropeptide products include b and g lipotropin, b-endorphin, and a-melanocyte-stimulating hormone (a-MSH). ACTH is a key regulator of the stress response

ACTH synthesis

ACTH ACTH is made up of 39 amino acids Regulates adrenal cortex and synthesis of adrenocorticosteroids a-MSH resides in first 13 AA of ACTH a-MSH stimulates melanocytes and can darken skin Overproduction of ACTH may accompany increased pigmentation due to a-MSH.

Addison’s Disease Disease in which patients lack cortisol from zona fasiculata, and thus lacks negative feedback that suppresses ACTH production Result: overproduction of ACTH Skin color will darken JFK had Addison’s disease and was treated with cortisol injections

b-endorphin Produced as a result of ACTH synthesis Binds to opiate receptors Results in “runner’s high” Role in anterior pituitary not completely understood One of many endogenous opiods such as enkephalins

Regulation of ACTH secretion

Regulation of ACTH Stimulation of release CRH and ADH Stress Hypoglycemia CRH and ADH both synthesized in hypothalamus ADH is released by posertior pituitary and reaches anterior pituitary via inferior hypophyseal artery.

ACTH Circadian pattern of release Highest levels of cortisol are in early AM following ACTH release Depends on sleep-wake cycle, jet-lag can result in alteration of pattern Opposes the circadian pattern of growth hormone secretion

Regulation of ACTH

ACTH Acts on adrenal cortex stimulates growth of cortex (trophic action) Stimulates steroid hormone synthesis Lack of negative feedback from cortisol results in aberrantly high ACTH, elevated levels of other adrenal corticosteroids– adrenal androgens Adrenogenital syndrome: masculization of female fetus

Glycoprotein hormones LH, FSH, TSH and hCG a and b subunits Each subunit encoded by different gene a subunit is identical for all hormones b subunit are unique and provide biological specificity

Glycoprotein hormones Glycoprotein hormones contain two subunits, a common a subunit and a distinct b subunit: TSH, LH, FSH and hCG.

Gonadotrophs Cells in anterior pituitary that produce LH and FSH Synthesis and secretion stimulated by GnRH– major effect on LH FSH secretion controlled by inhibin Pulsitile secretion of GnRH and inhibin cause distinct patterns of LH and FSH secretion

LH/FSH Pulsatile pattern of secretion LH pulses are biphasic (every 1 minute, then large pulse at 1 hour) FSH pulses are uniphasic Diurnal– LH/FSH more pronounced during puberty Cyclic in females– ovarian cycle with LH surge at time of ovulation Males are not cyclic, but constant pulses of LH cause pulses of testosterone to be produced

Pulsitile secretion of GnRH and LH

Regulation of LH/FSH Negative feed-back Inhibin produced by testes and ovaries Decreases FSH b-subunit expression Testosterone from Leydig cells– synthesis stimulated by LH, feedsback to inhibit GnRH production from hypothalamus and down-regulates GnRH receptors Progesterone– suppresses ovulation, basis for oral contraceptives. Works at both the level of pituitary and hypothalamus.

Regulation of LH/FSH Dopamine, endorphin, and prolactin inhibit GnRH release. Prolactin inhibition affords post-partum contraceptive effect Overproduction of prolactin via pituitary tumor can cause amenorrhea– shuts off GnRH Treated with bromocryptine (dopamine agonist) Surgical removal of pituitary tumor

Regulation of LH/FSH Positive feedback Estradiol at high plasma concentrations in late follicular phase of ovarian cycle stimulates GnRH and LH surge– triggers ovulation

Regulation of gonadotropin secretion

Thyrotrophs Site of TSH synthesis Pattern of secretion is relatively steady TSH secretion stimulated by TRH Feedback control by T3 (thyroid hormone)

Feedback control of thyroid function

Lacotrophs Site of production of prolactin Lactogenesis (milk synthesis) requires prolactin Tonically inhibited Of the anterior pituitary hormones, the only one Multifactoral control, balance favors inhibition Dopamine inhibits prolactin Prolactin releasing hormone is TRH Ocytocin also stimulates prolactin release Estradiol enhances prolactin synthesis

Prolactin Stimulates breast development and lactogenesis May be involved in development of Leydig cells in pre-pubertal males Immunomodulatory effects– stimulates T cell functions Prolactin receptors in thymus

Posterior pituitary hormones: ADH (AVP) and Oxytocin (really hypothalamic hormones) Both are synthesized in the cell bodies of hypothalamic neurons ADH: supraoptic nucleus Oxytocin: paraventricular nucleus Both are synthesized as preprohormones and processed into nonapeptides (nine amino acids). They are released from the termini in response to an action potential which travels from the axon body in the hypothalamus

Hypothalamus and posterior pituitary

Structures of ADH and oxytocin

Oxytocin: stimulates myoepithelial contractions In uterus during parturition In mammary gland during lactation

Oxytocin: milk ejection from lactating mammary gland suckling is major stimulus for release. sensory receptors in nipple connect with nerve fibers to the spine, then impulses are relayed through brain to PVN where cholinergic synapses fire on oxytocin neurons and stimulate release.

Oxytocin: uterine contractions Reflexes originating in the cervical, vaginal and uterus stimulate oxytocin synthesis and release via neural input to hypothalamus Increases in plasma at time of ovulation, parturition, and coitus Estrogen increases synthesis and lowers threshold for release

Oxytocin secretion is stimulated by nursing

ADH: conserve body water and regulate tonicity of body fluids Also known as vasopressin Regulated by osmotic and volume stimuli Water deprivation increases osmolality of plasma which activates hypothalmic osmoreceptors to stimulate ADH release

Regulation of ADH secretion

ADH increases renal tubular absorption of water

ADH and plasma osmolality

ADH and blood pressure