Pituitary and Hypothalamic Physiology

Lawrence S. Kirschner, MD, PhDDivision of Endocrinology, Diabetes and MetabolismLawrence.Kirschner@osumc.edu

Learning Objectives

Explain the function of the hypothalamus and anterior pituitary Describe hypothalamic hormones, their actions and dysfunction. Illustrate the importance of continuous vs. pulsatile secretion Describe the synthesis, secretion and action of each of the anterior pituitary’s hormonal axes

Hypothalamus-Pituitary-Adrenal Hypothalamus-Pituitary-Thyroid Hypothalamus-Pituitary-Gonad Hypothalamus-Pituitary-Growth hormone Hypothalamus-Pituitary-Prolactin

For each axis above, describe the physiologic roles of each end-organ hormone. For each axis, describe the short and long feedback loops that govern normal function of these

hormones

 

Describe the function of the posterior pituitary (Neurohypophysis) List the physiologic functions of ADH Describe the regulation of ADH secretion, storage and metabolism Describe the mechanism of thirst Describe oxytocin secretion, storage, action and feed back regulation

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Hypothalamus-Pituitary Unit(3 players) Hypothalamus

Anatomic subset of CNS neurons

Anterior pituitary (adenohypophysis) Epithelial origin, arising from roof of mouth (Rathke’s

pouch)

Posterior pituitary (neurohypophysis) Neural origin. These are actually cells of the CNS

whose axons extend down to meet the cells of the anterior pituitary. The bundle of axons = pituitary stalk

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The Master Regulator (?)

The pituitary is a central control gland affecting the function of many downstream endocrine glands It takes input from higher centers via the

hypothalamus It provides input to target glands via endocrine

signaling However, rather than a single gland, it functions more

like a central location where many pathways cross, but interact only minimally

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A P

AP

A

P

A

P

Anatomic development of the Pituitary Gland

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A= Anterior Pituitary

P = Posteriorpituitary

Brain MRI (for orientation)

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Important stuff

Pituitary anatomy (coronal view)

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Upper jaw

Sphenoid sinus

Sellaturcica

Cavernous Sinus

Pituitary MRI

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Carotid artery

Tumor

Cavernous sinus(cranial nerves,

etc.)

Sella turcica

Anterior Pituitary(6 hormones, 5 cell types)

Cell type Stimulates…

ACTH Corticotroph Adrenals

TSH Thyrotrophs Thyroid

Prolactin Lactotrophs Mammary

LH/FSH Gonadotrophs Gonads

GH Somatotrophs Liver + others

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POMC LH/FSH

GH

PRL

TSH

Prop-1Pit1

Rpx

Lhx2,3

Tpit Sf1

Pituitary development

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Loss of the appropriate transcription factors can cause defects in the corresponding downstream hormone systems. Clinical mutations are known for many of these proteins

The H-P-x system(s)

The hypothalamus is an anatomical subset of the CNS which provides integration for higher order signals from the brain to the endocrine system. E.g., do not reproduce under conditions of nutritional deficiency

These signals are passed locally to the anterior pituitary gland, which relays the signal in endocrine fashion to target endocrine glands distributed throughout the body

However, each of these systems functions more or less independently of the others

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The hypothalamus is composed of anatomically and functionally distinct sets of cells (nuclei)

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Hypothalamus

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• Receives neural and hormonal input from multiple sources

• Communicates to pituitary gland via H-P portal system

+ -

Hormone

-Lon

g F

ee

dba

ck

- -

Short F

eedback

+S

hort

Fee

dbac

k

Hypothalamus-pituitary signaling Hypothalamus secretes hormones, which travel via

portal circulation to the pituitary. Specificity is achieved by means of differential receptor

expression

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Hypothalamus

Somatotroph

Gonadotroph

Corticotroph

GHRH

GHRHreceptor

CRHreceptor

GnRHreceptor

GH

GH GH

GHTo body

The H-P-x systems

H-P-A hypothalamus-pituitary-adrenal

H-P-G hypothalamus-pituitary-gonad

H-P-T hypothalamus-pituitary-thyroid

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Other H-P-effector systems not as clearly defined Growth hormone axis

Prolactin axis

(Posterior pituitary)

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Hypothalamic Hormones

Most are small peptides Rapidly degraded

Makes clinical measurement tricky sometimes Secreted in pulsatile fashion Can regulate their own release (short feedback

loop)

Stimulate release and synthesis of anterior pituitary hormones

Stimulate growth of anterior pituitary cells

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Major Hypophysiotropic Hormones

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Evaluation of pituitary function

Pituitary hormone hormones are typically highly dynamic, so random measurements may not provide good evaluation of function

At a minimum, pituitary hormone function CANNOT be evaluated unless target hormone levels are also measured

In order to assess pituitary function, testing typically relies on exogenously stimulating or suppressing the pituitary gland to make sure it is behaving normally

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H-P-A axis

Hypothalamus

Pituitary

Adrenal

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Adrenal-Pituitary Feedback Regulation

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HPA: HypothalamusCorticotropin Releasing Hormone (CRH)

41 amino acid peptide, derived from cleavage of 191 AA preprohormone

Secreted in response to neural inputs and stress Relatively long half life (60 minutes) Stimulates secretion of ACTH from corticotrophs Also stimulated by ADH and angiotensin II Inhibited by cortisol and oxytocin

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HPA: Anterior Pituitary ACTH

Secreted by corticotrophs in response to CRH POMC precursor Stimulates secretion of cortisol and sex steroids

from the adrenal glands Stimulates growth of adrenal cortex Cortisol exerts negative feedback on anterior

pituitary and hypothalamus Inhibits CRH release Diurnal pattern, usually highest early AM

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POMC (Pro-opiomelanocortin)

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POMC (Pro-opiomelanocortin)

POMC is a precursor polypeptide to a number of hormones. ACTH adrenals adrenal steroids MSH Melanocytes skin pigment Endorphins and enkephalins Other assorted peptides with unclear function

(lipotropins ,CLIP, etc) Situations where ACTH levels are abnormally

high (e.g., adrenal insufficiency) will tend to result in release of all of these peptides, with physiologic consequences (e.g., increased skin pigment)

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HPA: End organAdrenal steroids ACTH stimulates production of cortisol from the adrenal

cortex. In fact, production of ALL adrenal steroids is stimulated by ACTH

(e.g., aldosterone)

Cortisol is responsible for negative feedback to pituitary and adrenal

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H-P-G axis

Hypothalamus

Pituitary

Gonads

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Gonadotropin Actions and Feedback - Male

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H-P-G: HypothalamusGonadotropin-Releasing Hormone (GnRH) Also known as LHRH 10 AA peptide, cleaved from 92 AA precursor Stimulates LH and FSH from gonadotrophs Inhibited by sex hormones and prolactin Secretion differs in relation to life cycle

Pre-pubertal Pubertal Adult Post-menopausal (women)

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GnRH – Role of pulsatile secretion

Regulation of FSH and LH release depends on frequency and concentration of GnRH Pulsatile secretion LH/FSH release Continuous secretion NO LH/FSH release

When GnRH is secreted continuously (or administered exogenously), it causes suppression of LH/FSH release and gonadal steroidogenesis

Anterior Pituitary HormonesGonadotropins (LH, FSH) Secreted by gonadotrophs in response to GnRH Composed of identical -subunits (same as TSH

and HCG), but β-subunit provides signaling specificity

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(LH) (FSH)(TSH)

HPG: End organ Sex steroids, inhibin LH stimulates sex steroidogenesis: estrogen,

progesterone and testosterone Leydig cells (male) Theca cells (female)

Female endocrinology more complex with 2-cell system LH Theca cells (A-dione); FSH granulosa cell (E2)

FSH stimulates growth of ovarian follicles, sperm production and inhibin secretion

Inhibin, estrogen (low concentrations), progesterone and testosterone all provide negative feedback E.g. Depot-Provera (progestin) as birth control

High concentrations of estrogen stimulate secretion of LH and FSH (ovulatory surge)

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Hormonal Profiles of the Ovarian (Menstrual) Cycle

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H-P-T axis

Hypothalamus

Pituitary

Thyroid

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Thyroid-Pituitary Feedback Regulation

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H-P-T: HypothalamusThyrotropin-Releasing Hormone (TRH)

Tripeptide (glu-his-pro) Stimulates TSH secretion from thyrotrophs Also stimulates prolactin secretion from lactotrophs Inhibited by thyroid hormone

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H-P-T: Anterior Pituitary TSH (Thyroid stimulating hormone)

Secreted by thyrotrophs in response to TRH Alpha subunit same as LH, FSH and HCG Stimulates secretion of T4, T3 and growth of thyroid

gland Inhibited by thyroid hormone via short-feedback loop

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HPT: End organThyroid hormone TSH stimulates production of thyroid hormones (T4 and

T3) from the thyroid gland Active hormone is T3 (binds to thyroid hormone receptor

to cause effects) Good correlation between T4 and T3 levels, so

measurements of T4 usually sufficient Note: usually (exceptions exist)

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Growth Hormone (GH) axis

Hypothalamus

Pituitary

GH target organs (liver, bone, others)

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Feedbacks of GH Secretion

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GH axis: HypothalamusGrowth Hormone-Releasing Hormone (GHRH)

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44 AA peptide Relatively long half life (50 min) Stimulates release of GH by somatotrophs Inhibited by GH, IGF-1, and somatostatin

Somatostatin

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Inhibits multiple hormones in various tissues In the anterior pituitary, inhibits GH and TSH

secretion But also inhibits things like insulin as well

Stimulated by GH and IGF-1

GH Axis: Anterior Pituitary Growth Hormone

Secreted by somatotrophs in response to GHRH Pulsatile - difficult to measure

Normal GH is very low most of day (<0.5 ng/ml) but has 3-5 large spikes (10 ng/ml) per day, often at night

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GH

GH Axis: Anterior Pituitary Growth Hormone Highest in puberty and decreases with age

Stimulated by hypoglycemia Inhibited by hyperglycemia Regulation

GH inhibits GHRH secretion IGF-1 inhibits GH and GHRH IGF-1 also stimulates somatostatin secretion Somatostatin inhibits GH secretion

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Growth Hormone function

Stimulates production of IGF-1 (insulin-like growth factor-1) and somatostatin

Anabolic effects, linear bone growth, organ size and lean body mass

Most effects are thought to be mediated via IGF-1, but GH receptors found in many organs, suggesting a direct role in physiologic processes

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Growth Hormone has direct and indirect effects (via IGF1)

IGF-1 dependent Protein synthesis AA transport Muscle mass Bone growth Cartilage growth Nucleic acid synthesis

IGF-1 independent Anti-insulin (IR) Lipolysis Ketogenesis Hyperglycemia Na, water retention

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Prolactin axis

HypothalamusPituitaryProlactin target organs (mammary tissue, others)

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Anterior Pituitary HormonesProlactin

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Prolactin: Hypothalamus Dopamine

Provides tonic inhibition of prolactin secretion Stimulated by serotonin and VIP No long feedback (no target organ hormone)

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Anterior Pituitary HormonesProlactin

Control is INHIBITORY (Dopamine) More dopamine less prolactin

Secreted by lactotrophs Stimulates breast development and milk

production Increases with pregnancy, lactation, stress, high

estrogen, and certain meds Also is stimulated by TRH, oxytocin and

estrogen Inhibits GnRH

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Pharmacology affecting PRL

Drugs that affect dopaminergic neurons can affect prolactin Neuroleptics and many atypical anti-psychotics are DA

antagonists, and frequently lead to elevated PRL levels Blockade of DA at the pituitary occurs irregardless of CNS effects Elevated PRL levels are sometimes clinically significant in patients on

neuroleptics Conversely, DA agonists will lower PRL

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Overview of Anterior Pituitary Hormone Functions

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Posterior Pituitary Hormones

Synthesized in PVN and SON in the hypothalamus

Bound by neurophysins Transported down axons into neurohypophysis

and stored until released Release occurs when cell membrane

depolarizes

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Title

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Posterior Pituitary HormonesAnti-diuretic Hormone (ADH) Also called arginine vasopressin (AVP) Stimulated by osmoreceptors – increasing

plasma osmolality to >280 mOsm/kg Stimulated by baroreceptors – decreasing

plasma volume – 10% drop Conserves body water by increasing

permeability of collecting ducts (kidney) Also binds to receptors in blood vessels to raise

BP

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Plasma Osmolarity and ADH

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Absence of ADH

In the absence of ADH, the kidney is unable to concentrate urine = diabetes insipidus (urine is NOT sweet) Patients may excrete >8-10 liters/day

Patients lose excessive free water, and plasma osmolality (and Na+) go UP

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Posterior Pituitary HormonesOxytocin Similar structure to ADH (only 2 AA difference) Stimulated by suckling and dilation of the uterus during

childbirth Increases smooth muscle contraction – milk ejection and

uterine contraction ? Role in male ejaculation

Positive feedback mechanism

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Summary

In the anterior pituitary (adenohypophysis) The Hypothalamus-Pituitary-End Organ systems maintain hormone homeostasis by a series of short- and long-feedback loops

In the posterior pituitary (neuro-hypophysis), hormone secretion is regulated by neurophysiologic stimuli

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Pituitary and Hypothalamic Physiology Quiz

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Questions? Contact me at Lawrence.Kirschner@osumc.edu

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