The Hypothalamic-Pituitary Axis andThe Hypothalamic-Pituitary Axis andPituitary HormonesPituitary Hormones

The hypothalamus, a region of the brain that controls an immense number ofbodily functions, is located at the base of the brain. The pituitary gland, also knownAs hypophysis, lies immediately below the hypothalamus. It rests in a depression at

The base of the skull, called sella turcica.

Pituitary gland

•Anterior pituitary (adenohypophysis) - cells secrete peptide/protein hormones

•Posterior pituitary (neurohypophysis) - is an extension of the hypothalamus - is composed largely of the axons of the hypothalamic neurons

•In many mammals, there is also an intermediate lobe (pars intermedia) between the anterior and posterior pituitary

•Based on histologic features, both the adenohypophysis and neurohypophysis are subdivided:

- Adenohypophysis - pars distalis - pars tuberalis (contains hypophyseal vessels) - pars intermedia (secretes melanocyte-stimulating hormone [MSH])

-Neurohypophysis -pars nervosa -median eminence (the upper section of neurohypophysis) -infundibular stalk (the “stem” that connects the pars nervosa to the bas of the brain)

•Secretion of hormones from anterior pituitary is under strict control of the hypothalamic releasing/inhibiting hormones which reach the anterior pituitary through

•Hypothalamic-hypophyseal portal vessels that branch again into a series of capillaries within the adenohypophysis.

Three distinct cell types are seen in the adenohypophysis:

•Acidophils (40%) - somatotrophs – produce growth hormone (GH)

- lactotrophs – produce prolactin (PRL)

•Basophils (10%) - thyrotrophs - produce thyroid stimulating hormone (TSH) – a glycoprotein - gonadotrophs – produce luteinizing hormone (LH) & follicle – stimulation

hormone (FSH) – glycoproteins - corticotrophs – produce adrenocorticotropic hormone (ACTH) – polypeptide

•Chromophobes (50%)

The major portion of the neurohypophysis contains unmyelinated axons from hypothalamic neurosecretory neurons:•Supraoptic nuclei – mainly produce antidiuretic hormone (ADH)/vasopressin (AVP) + neurophysin•Paraventricular nuclei – mainly produce oxytocine + neurophysin

Anterior pituitary hormones (six peptide hormones)

Growth hormone (GH/somatotropin)•Synthesized and secreted by somatotrophs•Stimulates body growth - GH liver/other tissues IGF1 (insulin-like growth factor-1) chondrocytes (cartilage cells) long bone growth - IGF1 also differentiation & prolifiration of myoblasts muscle growth•Metabolic effects (on protein, lipid & carbohydrate metabolism) - IGF1 amino acid uptake protein synthesis + oxidation of protein - IGF1 glucose synthesis in the liver - GH (direct action) adipocytes (fat cells) free fatty acids -GH (anti-insulin/direct action) uptake of glucose in peripheral tissues glucose in plasma insulin in plasma (hyperinsulinemia)

Control of GH secretion

•GHRH (growth hormone-releasing hormone), a hypothalamic peptide synthesis + secretion of GH•Stress, exercise, hypoglycemia, sleep GH•Ghrelin, a peptide secreted y stomach GH•Somatostatin (hypothalamic growth hormone inhibiting hormone) GH synthesis+release•IGF1 somatostatin GH•GH GH (autocrine negative feedback)•Release of hormone is pulsatile

Clinical (hyposecretion/hypersecretion)

•Site of lesion may be at the level of: - the hypothalamus - the pituitary - target cells

•Deficiency in GH/receptor defects growth retardation or dwarfism

• GH secretion in young children/adolescents (from tumor of somatotrophs) giantism

• GH secretion in adults acromegaly

Thyroid-stimulating hormone (thyrotropin/TSH)•Secreted by “thyrotrophs” of the anterior pituitary - a glycoprotein hormone - a compound of α and β subunits

•Thyrotropin-releasing hormone (TRH) from the hypothalamus thyrotrophs thyrotropin (TSH)

•TSH thyroid thyroid hormones (T3 & T4)

• T3 and T4 in plasma TRH action on thyrotrophs T3 & T4 levels negative feedback at anterior pituitary thyrotrophs) + hypothalamus

•Stress/dopamine/cortisol/somatostatin TSH

Adrenocorticotropic hormone (ACTH/corticotropin)

•Secreted by the anterior pituitary “corticotrophs”

•Corticotropin releasing factor (CRF) from the hypothalamus corticotrophs corticotropin (ACTH)

•CRF proopiomelanocortin ACTH + β-lipotropin + α-MSH

•ACTH adrenal glucocorticoids (cortisol)

• cortisol CRF ACTH (negative feedback)

•β -lipotropin – precursor of β-endorphin

•β -endorphin – opioid peptide that alleviates pain

•MSH – controls melanin pigmentation in the skin

•Corticotrophs adenomas ACTH cortisol secondary Cushing’s disease

Clinical

Gonadotropins (FSH and LH)

•Secreted by pituitary “gonadotrophs”•Hypothalamic GnRH gonadotrophs LH (luteinizing hormone) and FSH (follicle-stimulating hormone)•LH sex steroid (testosterone in males and estrogenes + progesterone in females)•LH follicle induces ovulation corpus luteum (luteinization) pro- gesterone + estrogenes•FSH maturation of ovarian follicles in females and spermatogenesis in males•FSH inhibin both in males and females•Inhibin FSH secretion at the pituitary level (negative feedback)•Estrogens/testosterone LH secretion (negative feedback)•LH & FSH secretions are pulsatile

Clinical

•Attenuated secretion of LH/FSH or both results in hypogonadism - in males low sperm count - in females cessation of reproductive cycles•Elevated blood levels of LH and FSH or both usually reflect lack of gonadal steroid negative feedback

Prolactin

•A single-chain protein hormone closely related to growth hormone•It is secreted by “lactotrophs” of the anterior pituitary•Also secreted by the “deciduas” of the pregnant uterus•Prolactin induces lobuloalveolar growth of the mammary gland (during pregnancy and lactation)•Prolactin stimulates lactogenesis after giving birth to a baby – in the presence of cortisol&insulin, prolactin produces milk proteins•In some mammals (rodents, dogs, skunks) prolactin is necessary to maintain pregnancy by maintaining their luteal function. In mice, prolactin deficiency blocks ovulation, fertilization, implantation and thus makes the animals infertile•Experimental evidences suggest that prolactin may act as autocrine/paracrine modulator of immune activity•Prolactin-inhibiting factor (PIF/dopamine) of the hypothalamus tonically suppresses prolactin secretion•TRH (thyrotopin-releasing hormone) prolactin secretion•Estrogenes prolactin synthesis and release•Stimulation of the nipple during breast feeding/nursing, leads to prolactin release

Clinical•Excessive secretion of prolactin (hyperprolactinemia), is a common disorder in humans due to microadenoma of the prolactin secreting cells•Common manifestations of hyperprolactinemia: in women: - lack of menstrual cycle - galactorrhea (excessive & spontaneous secretion of milk) in men: - hypogonadism - breast enlargement (gynecomastia) - decreased sex drive - rarely galactorrhea - low sperm count

Antidiuretic hormone (ADH)/Vasopressin (AVP)

•ADH is a nanopeptide, secreted mainly by the supraoptic nuclei of the hypothalamus and released from the posterior pituitary (its carrier protein, neurophysin is also released)•ADH conserves body water by reducing the volume of urine (antidiuresis)•It acts primarily on the collecting tubules of the kidney, forms “water channels” and promotes reabsorption of water from the glomerular filtrate back into the circulation•Reabsorption of this “solute-free” water plasma osmolarity and increase osmo- larity of urine•ADH/vasopressin widespread vasoconstriction arterial pressure•Osmoreceptors in the hypothalamus sense plasma osmolarity• plasma osmolarity (normal ~ 290 mOsm/L) ADH secretion• ADH H2O conservation by kidney H2O balance

• osmolarity of plasma thirst sensation (center in the hypothalamus) drinking H2O balance•Decrease in ECF/blood volume volume receptors (in atria) monitor ADH secretion•Nausea & vomiting ADH secretion

Clinical

•Diabetes insipidus (excessive loss of body H2O in urine)•Types: - Neurogenic (hypothalamic/central) - deficiency in secretion of ADH from the posterior pituitary (due to trauma, infections or tumors) - Nephrogenic (due to ADH receptor deficiency in kidney)

Diabetes insipidus urine production (10-16 L/day). However, the loss iscompensated by water intake.

Oxytocin

•Oxytocin is a nine amino acid peptide, synthesized mainly by paraventricular nuclei in the hypothalamus and transported down the axons to the posterior pituitary for secretion into blood•It is also formed in the ovaries and testes•Oxytocin stimulates contraction of myoepithelial cells of mammary gland alveoli, causing milk ejection (milk letdown)•Oxytocin is involved in facilitating sperm transport both in the females and in the males genital tracts•Oxytocin is released during labor - fetus stimulates the cervix & vagina stretch reflex oxytocin secretion prostaglandins contraction of uterine smooth muscle parturition (birth)•Physical stimulation of nipples/teats initiates oxytocin release (a neurohormonal reflex)•In males, oxytocin is released in pulses during ejaculation•Acute stress oxytocin secretion•Estrogen oxytocin receptor synthsis•Alcohol drink oxytocin secretion