HoNuts 2 - Pituitary Gland and the Neuroendocrine System

Diagnosis of functional endocrine abnormalities - Normal Range

"Normal range" for most hormones is quite wide Imagine normal range for hormone X is 9-25 units: - this means that when level of hormone X was determined in 100, or 1000 normal pts, there was a normal distribution, w/ 95% of the pop falling between 9-25 - also means that "normal" and appropriate level of X for some individuals will be 10 while for others normal level might be twice as high Whatever the correct level is for that individual, their hypothalamic-pituitary-endocrine gland axis will continually monitor and adjust, to maintain this level

Prolactin (PRL)

*Direct effector. Induces lactation* - Simple protein w/ some structural homology w/ GH MW ~ 22,000.

Somatostatin (SS)

*Inhibits GH and TSH release*. *Widespread distribution and actions (including GI tract and pancreas)* outside of hypothalamus - contains a disulfide bridge - *14a.a. single-chain and 28a.a. double-chain* (hypothalamic and systemic respectively) forms exist

Sellar Tumor

*Primary Tumor*: - Adenoma (most common) - Carcinoma (rare) *Secondary Tumor*: - Metastatic tumor (rarely causes pituitary deficiency)

Treatment of Hypopituitarism (Lecture - KNOW!)

*Synthetic Hormone replacement* 1.) ACTH Deficiency: Cortisol replacement 2.) TSH Deficiency: LT4 replacement 3.) FSH/LH deficiency: - Men:Testosterone - Women: Estrogen/Progesterone - Fertility: FSH/LH 4.) GH Deficiency - Children: rhGH - Adults: Controversy

Prolactin Excess (Hyperprolactinemia): Pharmacologic Causes

- Antihypertensives - GI Drugs - *Antipsychotics* - Antidepressants

IGF-1 (Somatomedin-C) [KNOW]

- Protein of 70 a.a.'s - A and B Chains have 50% homology w/ Insulin - Interacts w/ specific IGF-1 Receptor and Weakly w/ Insulin receptor - Mitogenic effect at tissue level --> stimulation of cell cycle

Secondary Hypo-X-ism

1.) Disease process in anterior pit gland --> levels of XSH begin to fall 2.) Even though endocrine gland producing hormone X is normal, it does not receive sufficient stimulation from XSH --> levels of hormone X begin to fall 3.) Low X detected in the hypothalamus --> decreased "negative feedback", --> levels of XRH begin to rise, in an effort to stimulate the anterior pit gland even more, to produce more XSH 4.) Diseased anterior pit gland unable to respond Biochemical pattern causes confusion because level of XSH may be w/in the normal range, and therefore interpreted as normal, when in fact it should be elevated because the level of hormone X is low --> Though *XSH is "normal" it is RELATIVELY (and abnormally) low given the low level of X*

Reasons to treat hyperprolactinemia fall into 3 categories

1.) Reduce mass effect if cause of hyperprolactinemia is a macroprolactinoma 2.) Reverse hypogonadism and promote fertility 3.) Diminish galactorrhea

Treatment of GH Excess

1.) Surgery 2.) Radiotherapy 3.) Dopamine Agonists 4.) Somatostatin Analogs 5.) GH Receptor Antagonists *In treating pituitary tumors, combinations of several treatment modalities are often necessary to attain cure.*

In any pituitary tumor, clinical features are determined by 3 factors:

1.) local tumor growth 2.) destruction of normal pituitary tissue 3.) production of excessive amounts of hormone

GH Changes with Age

Changes in GH decrease with age

Bone Changes in GH Overproduction

Changes in appearance may occur *slowly over a long period of time* - Overgrowth of mandible can cause *wide gaps between teeth and an "underbite"* - pt may notice that he/she requires increased size of rings, shoes, or hats, which had been stable through earlier adult life - Other bones such as *mandible and membranous bones of the skull grow in all dimensions* - Because of bony distortion around weight-bearing joints and in the spine, a *painful degenerative arthritis is a prominent clinical feature*

Hypothalamic Peptides: Overview (Lecture)

Chart

Hypothalamus

Composed of several groups of neurons ("nuclei") that perform a similar function (w/in each nuclei) and numerous fiber tracts entering and leaving the area - nuclei named according to anatomic position - Structures near the hypothalamus are the 3rd ventricle, optic chiasm, and structures of the limbic system Many hypothalamic neurons are neurosecretory cells that send axons to terminate in the *median eminence* where they release both *stimulatory and inhibitory hormones to the proximal hypothalamic-pituitary portal vessels*

Structure and Biosynthesis of Hypothalamic Hormones

Considerable variation in structure among the peptide releasing hormones. All are *small peptides*, however, and synthesized as *short sequences from longer prohormone molecules* that undergo post-translational cleavage to liberate the active peptide - Some have unique features

Angiotensin II (not covered in lecture?)

Formed in hypothalamus for regulation of BP, drinking behavior and ADH secretion - Also formed in lung and kidney to act as a pressor agent - 8 amino acids

Measuring GH Levels [KNOW!]

GH levels vary throughout the day --> little value in measuring a random blood sample to diagnose GH excess or deficiency - *Hyperglycemia will suppress normal GH secretion but will not suppress an autonomous GH-secreting tumor* (cause *acromegaly and gigantism*) --> glucose can be used to *dx conditions of GH excess* *Clinical test for autonomous GH secretion*: 75g oral glucose tolerance test [oral glucose tolerance test (OGTT)], w/ GH measured 2hrs after the glucose load

GH Periodic Secretion [KNOW - esp Bold!]

GH secreted in periodic pulses - secretory pulses originate from *pulse generator in the CNS* and *basic pattern of secretory pulses can be modulated!* - *2-3 hours between pulses; Each pulse lasts ~1hr* - Quiet interpulse intervals (ave 2-3hrs) during which plasma concentrations of GH fall to near zero levels followed by relatively long secretory episodes lasting about 1hr

Diagnosing Acromegaly

Glucose Tolerance Test

Hypothalamic Peptides [KNOW!]

Hypothalamic peptides are small molecules secreted in tiny amounts. It is NOT clinically useful to measure them in the peripheral (systemic) circulation. - Have been sequenced and synthesized and so can be injected to stimulate the anterior pituitary to test the function of various anterior pituitary cell types.

Hypopituitarism: Diagnosis - Insulin tolerance test

If you suspect that one or more of the hormones of the anterior pituitary gland is low, you could try to stimulate it *Insulin tolerance test*: If a pt is rendered hypoglycemic (via an IV injection of insulin) this Should stimulate production of GH and ACTH *"gold standard" to test these pituitary axes*

Hyperprolactinemia - Important to Distinguish Between 2 Causes [KNOW!]

Important clinical distinction: - Hyperprolactinema due to pituitary tumor of lactotrophs secreting Prolactin --> Responds to Meds! OR - Tumor not making prolactin but big enough to inhibit Dopamine --> Requires Surgery!

Connections between the pituitary and hypothalamus: Neural

Nuural connection through 2 neurosecretory tracts: - *supraoptico*hypophyseal nerve tract - *paraventriculo*hypophyseal nerve tract These carry neurosecretory axons from neurons in the 2 nuclei to their endings in the neural lobe (posterior pit)

Regulation of Prolactin Secretion [Know!]

Regulated from the hypothalamus; unlike the other anterior pit hormones, prolactin secretion is under *tonic inhibitory control via dopamine!*: Dopamine secreted from neurons of median eminence of the hypothalamus is a known prolactin inhibitory factor (PIF) - Prolactin is the only anterior pit hormone elevated by pituitary stalk obstruction (inhibiting dopamine access to lactotrophes) - Prolactin levels greatly affected by agents that alter dopaminergic secretion or action

Connections between the pituitary and hypothalamus: Vascular

Vascular connection via primary vascular plexus and portal hypophyseal vessels that together make up the *portal system* which carries blood from the median eminence to the anterior pit - Primary plexus composed of *fenestrated capillaries* and therefore *lacks a blood/brain barrier function* Anterior pit hormones reach peripheral circulation through venous drainage - Variability in venous drainage exists but usually occurs *posteriorly through the cavernous sinus into the superior and inferior petrosal sinuses to the jugular vein*

Neurosecretory Cells

neurons with the capacity to secrete peptides and hormones

Pituitary Anatomy and Functions

*Anterior Pit*: Adenohypohysis - Endocrine secretion of FSH, LH, TSH, ACTH, GH, PRL *Intermediate Lobe*: Pars Intermedia - No Known Function *Posterior Pit*: Neural Lobe or Neurohypophysis - Neuroendocrine storage and release of oxytoxin and ADH

Production of Excess GH

*Autonomous GH-producing adenoma* --> accelerated growth of bones and soft tissues - Gigantism in kids - Acromegaly in adults Rare; estimated incidence of 3-4 per million/yr

Multiple Sites of *Direct* GH Action: Bone and Linear Growth

*Bone* - Increases osteoclast differentiation & activity - Increases osteoblast activity - Increases bone mass by endochondral bone formation *Linear Growth* - Promotes epiphyseal growth (IGF-1) - "Dual Effector" theory: GH stimulates the differentiation of prechondrocytes and the local expression of IGF-1, which increases clonal expansion of chondrocytes

Hyperprolactinemia: Diminished dopaminergic inhibition of lactotrophes [KNOW!]

*Diminished dopaminergic inhibition usually results in prolactin levels between 50-150ng/ml* Inhibition of inhibitory effects of dopamine on lactotrophes will lead to an increase in prolactin levels: - Injury to hypothalamic neurons from tumor, infection, AVMs, etc can lead to diminished dopamine production - Pharmacologic agents which lead to depletion of central dopamine stores (reserpine, methyldopa) - Dopamine receptor antagonists (phenothiazines, butyrophenones, metoclopramde, domperidone) - Any insult that reduces portal blood flow will block dopamine access to lactotrophes --> Common causes of stalk compression are trauma, sellar and suprasellar tumors metastatic tumors, and inflammatory processes

β-lipotropin (β-LPH)

*Direct effector. Stimulates melanin. Promotes lipolysis* - Simple peptide which arises as a post-translational product of pro-opiomelanocortin (POMC). Has close homology with ACTH and MSH.

Melanocyte stimulating hormone (MSH)

*Direct effector. Stimulates melanin. Stimulates SATIETY (not appetite...)* - Simple peptide which arises as a post-translational product of pro-opiomelanocortin (POMC). Has close homology with ACTH and β-LPH.

Synthesis and release of IGF-I:

*GH stimulates synthesis and release of IGF-I by Liver* - IGF-I circulates in association w/ a group of binding proteins and is slowly cleared from plasma, w/ a t1/2 of 5hrs *Production*: affected by nutritional state of pt and by availability of insulin - Caloric deprivation and insulin deficiency reduce IGF-I production

Somatostatin Analogs - Specific Analogs (Lecture)

*Human somatostatin* - inhibit multitude of hormones - t1/2 =3min - binds all 5 receptor sub-types *Octreotide*: - t1/2 100 min - more specific *Lanreotide* - Octreotide and lanreotide are very effective but require daily subcutaneous injection or monthly intramuscular injection. - Side effects include fat malabsorption, impaired glucose tolerance (IGT) or diabetes, gallstones...

Diagnosis of functional endocrine abnormalities: Quantities of the various hormones that are present in the circulation

*Hypothalamic peptides*: produced in tiny quantities, and only secreted into local portal circulation --> *NOT normally detectable in systemic circulation* *Anterior pituitary hormones (like XSH) and all the hormones from endocrine glands (like X)*: produced in much larger quantities and released into the systemic circulation to travel to distant target tissues --> *systemic blood levels of both XSH and X can be measured easily in the lab*

Dopamine (main Prolactin inhibitory factor or PIF)

*Inhibits PRL*. Also a *major neurotransmitter* throughout the body - *1 amino acid!*

Growth hormone dependent growth factors

*Insulin-like growth factors (IGF) or Somatomedins* - Belong to an insulin gene superfamily containing genes encoding for proinsulin, IGF-I, IGF-II and relaxin - *IGF-1 (also known as Somatomedin C) is the main effector of GH!!* - IGF-I has a structure resembling the precursor for pancreatic insulin (proinsulin) but acts on peripheral tissues through its own specific receptor

Hormones of the anterior pituitary

*Larger, more complex molecules* than hypothalamic peptides - Made in specific cells in the ant pit and travel throughout body via systemic circulation to act on specific cells in the target endocrine gland - Most act as *trophic hormones*, which means that they are specific for a target endocrine gland (TSH), where they stimulate growth of the gland and release of an effector hormone - Others act as *direct effectors*, acting on many peripheral tissues directly (GH) *Anterior pit hormones released into peripheral (systemic) circulation in large amounts that can be measured clinically in peripheral venous blood samples!*

Hyperprolactinemia: Lactotrophe cell tumors or *Prolactinomas* [KNOW!]

*Most common functional pituitary tumor* - further classified by size, Microprolactinomas <1cm in maximal diameter; Macroprolactinomas 1cm or greater *Prolactin levels directly proportional to tumor size* - *Macroprolactinomas: serum prolactin levels 200ng/ml to levels in the thousands* - Macroprolactinomas can present w/ similar clinical manifestations as *other forms of hyperprolactinemia* but may also present w/ *compressive symptoms* due to tumor expansion from the sella, such as visual loss or cranial nerve defects

Multiple Sites of *Direct* GH Action: Muscle and Metabolic

*Muscle* - Increases a.a. transport - Increases nitrogen retention - Increases lean tissue & increases energy expenditure *Metabolic*: Counter-regulatory insulin effect: - Increased lipolysis - Inhibited lipoprotein lipase (LPL) - Stimulated hormone sensitive lipase (HSL) - Decreased glucose transport into muscles - Promotes hepatic gluconeogenesis - Decreased lipogenesis

Hyper-X-ism: Measuring XSH

*Normal*: Normal XSH *Tumor in Primary Endocrin Gland*: XSH Low due to increased negative feedback *Tumor in Ant Pit*: XSH high *Tumor Elsewhere*: Depends on tumor *Immune System Mimicing XSH*: XSH low due to increased negative feedback *Exogenous Ingestion of XSH*: XSH low due to increased negative feedback

Treatment of GH Excess: Somatostatin Analogs

*Octreotide, lanreotide, and pasireotide* ("-reotide" I'm real ti'de of growin'") Very effective in reducing GH secretion in acromegaly and have longer half-life than endogenous somatostatin - Must be given by SubQ or IM injection - Will have an impact on tumor growth, causing decrease in tumor size or arresting growth in nearly 85% of tumors but usually only to a modest degree

Pituitary Tumors: ACTH deficiency

*Oral Hydrocortisone (or other steroids) BID w/ a larger dose in the morning to mimic diurnal variation of ACTH and cortisol secretion* - pt should carry a steroid card and wear "Medicalert" bracelet to alert health care workers that they are steroid users - Instruct how to increase dose of cortisol in times of stress - Assess hypothalamic-pituitary-adrenal axis; may be fatal if a deficiency is undiagnosed - Timing of hormone replacement in a pt w/ complete hypopituitarism is critical

Pituitary Tumors: Women with LH and FSH deficiency

*Oral estrogen, alone or in combo w/ progestins* - will tx most symptoms, but pt will remain infertile while on tc - If pregnancy is contemplated, it is necessary to stop the estrogen and progestins and to use a more complex strategy involving *injections of drugs w/ LH/FSH activity* to stimulate the woman's ovaries directly

Treatment of GH Excess: GH Receptor Antagonists

*Pegvisomant* ("take them down a Peg!") Acts via *GH receptor inhibition --> GH levels rise in response to falling IGF-1* - In 12-wk trials in acromegalics who were either untreated or only partially cured, pegvisomant caused *significant reduction in circulating IGF-1 levels and improvement in many signs and symptoms* of acromegaly - Because of mechanism of action, *GH levels cannot be followed to assess cure* - Rarely (2% of cases) this agent *may cause tumor growth! (similar to Nelson's Syndrome)*

Pituitary Tumors: Primary vs Secondary [KNOW!]

*Primary Tumors*: - Carcinomas are very rare. - Histological examination does NOT correlate with biological activity *Secondary Tumors*: - Very rarely cause hypopituitarism - Usually occur in the setting of end-stage metastatic disease - BREAST >> bronchus, prostate, colon

Corticotropin releasing hormone (CRH)

*Releases ACTH (corticotropin)*, LPH, and β-endorphin - Longer (41 a.a.) peptide, shares a.a. sequences w/ other established hormones --> CRH has some *homology w/ angiotensinogen* (both increase BP!)

Growth hormone releasing hormone (GHRH)

*Releases GH* (stimulates *Somatotropes of Ant pit*!) Longer (*44 a.a. single-chain) peptide*, shares a.a. sequences w/ other established hormones --> GHRH has homology w/ the secretin-glucagon family of GI hormones

Ghrelin

*Releases GH; synergizes w/ GHRH* - *28 a.a.'s* (acylated) - Identified and purified from rat stomach but also found elsewhere (including hypothalamus) - Suggests some nutritional regulation of GH (orally-active analogs under development!)

Gonadotropin releasing hormone (GnRH)

*Releases LH and FSH* - 10 amino acids

Thyrotropin releasing hormone (TRH)

*Releases TSH and PRL and, to some extent, GH* - Only 3 amino acids (TRH = Tits Really Hurt = stimulates prolactin release)

Final Common Pathway for Neuroendocrine Control of the Anterior Pit

*Releasing factor neurons w/ their endings in the median eminence* --> *hypothalamic releasing peptides travel via the portal circulation to the anterior pit where each binds its specific receptor displayed on the surface of its target cell*

Control of Anterior Pituitary Secretion

*Secretion of each anterior pit hormone controlled by specific releasing and/or inhibiting factors*: 1.) Factors produced in neurons w/in hypothalamic nuclei --> transported via axons to median eminence --> released into capillaries of primary plexus in response to nerve impulses 2.) Factors then traverse portal system and interact via specific receptors on surface of target anterior pituitary cells Control of this system is by means of *positive and negative feedback loops*

Basic pattern of *GH* secretory pulses can be modulated by a number of factors: [KNOW - esp Bold!]

*Sleep*: onset of sleep usually induces a prominent pulse of GH *Exercise*: stimulates GH secretion *Stress*: increase secretion *Hypoglycemia*: potent stimulus for GH secretion - *Hyperglycemia*, therefore glucose loading - will INHIBIT GH secretion Amino acids, esp Arginine: stimulate secretion *Adrenergic agonists* - *α-agonists stimulate* (phentolamine, α-antagonist, inhibits GH secretion) *just α-growin' away* - *β-agonists inhibit* (Propranolol, augments GH secretion) *Beta makes me itty-Bitty*

Gonadotropins: Luteinizing hormone (LH), and follicle stimulating hormone (FSH)

*Stimulate ovaries and testes* - Glycoproteins of MW ~30,000 TSH, FSH and LH are from a related gene family, have a common alpha-chain, but a specific beta-chain.

Corticotropin, or adrenocortical stimulating hormone (ACTH)

*Stimulates adrenal cortex* - Simple peptide which arises as a post-translational product of pro-opiomelanocortin (POMC). Has a close homology with β-lipotropin and *MSH*

Growth hormone (GH)

*Stimulates growth and/or synthetic function in bone, cartilage, liver, and many soft tissues and connective tissues (CT)* - Simple protein w/ some structural homology w/ prolactin - MW ~ 22,000

Thyrotropin, or thyroid stimulating hormone (TSH)

*Stimulates thyroid* - Glycoproteins of MW ~30,000. TSH, FSH and LH are from a related gene family, have a common alpha-chain, but a specific beta-chain.

Pituitary Tumors: Men with LH and FSH deficiency

*Testosterone - either as a gel applied to skin or IM injection every 7-14 days* - potent stimulator of RBC production in marrow; overproduction can become a problem. *Regular checks of Hct, dosage may need adjustment to avoid polycythemia* - Men w/ LH and FSH deficiency will be *infertile*. If he wants to father a child, it is necessary to stop testosterone and to use a more complex strategy involving *injections of drugs with LH/FSH activity* to stimulate sperm production.

Pituitary Tumors: TSH deficiency

*Thyroxine* - orally, once a day

Treatment of GH Excess: Surgery [KNOW!]

*Trans-sphenoidal selective adenomectomy (TSA) can remove tumors directly* - *safe and effective if surgeon is good and tumor has no suprasellar extension (~80% cure, <15% hypopituitary)* - Larger tumors with *suprasellar and lateral extension*, rarely an *open craniotomy* is required. *Mortality, morbidity and subsequent hypopituitarism are higher* in this situation. Successful cure is based on surgeon expertise and tumor size and location.

If you think a gland is under-secreting...

*Try to stimulate it! Failure to stimulate confirms under secretion* - inject XRH and measure XSH at defined time afterwards (XSH often measured immediately before injection of XRH and 10-30min after) - assays used to measure anterior pit hormones (XSH) are sensitive and accurate = XRH stimulation tests rarely used

Hypothalamic Peptides (Hypothalamic Factors): Synthesis and Release [KNOW, esp bold]

*Very small peptides Made in discrete groups of cells in the hypothalamus (called "nuclei") named for their anatomic location* - *Released into the Median Eminence* and travel down *portal circulation (running from median eminence to anterior pit)* and *act on specific cells in the anterior pit* - are released in extremely small amounts and are difficult to measure in the peripheral circulation - Other hypothalamic peptides act as more *generalized hormones* in distant sites throughout the body, or as *neurotransmitters*

Example typical biochemical pattern of secondary hypo-X-ism

*X* = 2 ng/ml (normal 6-12 ng/ml) *XSH*= 10 ng/ml (normal 8-25 ng/ml) *Though XSH is "normal" it is relatively (and abnormally) low given the low level of X*

Pituitary Adenomas va Carcinomas

- *Invasion of neighboring structures*: 5-10% of all pit tumors; designated as "invasive adenomas" rather than as carcinomas - *Pituitary carcinoma*: designation limited to tumors w/ metastasis distant to the sella; carcinomas are rare

GH Deficiency: Lecture Points [KNOW!]

- Clinical diagnosis based on auxologic data (growth charts) - Confirmed biochemically: IGF-1, IGFBP3 - Severe growth retardation, decreased bone age, low IGF-1, IGFBP3 and GH - Confounding cases should undergo dynamic tests: ITT or GHRH-arginine stimulation - Confirmed cases should undergo MRI

Hypothalamus serves as the integrating center for many major physiologic functions

- Energy balance, including feeding behavior - Biologic clocks - Growth - Water balance and maintenance of vascular volume - Reproduction - Metabolic efficiency and emergency stress responses - Temperature regulation

Radiation Therapy Limitations for Pituitary Tumors

- Gamma knife takes several years to cure secreting tumor - risk of hypopituitarism almost 100% following radiotherapy but may take up to 10yrs to develop --> need chronic monitoring of pituitary function - Secondary malignancy possible late complication; average latency period 10yrs and only in pts who received very high radiation doses

Learning Objectives: Pituitary Tumors/Hypopituitarism

1. To be able to describe the most common causes of hypopituitarism. 2. To be able to describe the likely symptoms and signs that a patient might present with hypopituitarism (both male and female) 3. To be able to describe the main elements in the clinical workup of hypopituitarism. 4. To be able to describe the rationale for the treatment of hypopituitarism 5. To be able to describe the local symptoms and signs that would result from a tumor in the pituitary fossa enlarging above and lateral to the diaphragm sella.

Learning Objectives: Acromegaly

1. To be able to describe the most common signs and symptoms of acromegaly. How does the age of the patient at the time of dx effect the clinical findings? 2. To be able to describe the diagnostic evaluation of an individual with suspected growth hormone excess. 3. To be able to describe the common causes of GH excess. 4. To be able to describe the rationale for the treatment of GH excess. Describe the types of treatment available.

Learning Objectives: Hyperprolactinemia

1. To be able to describe the symptoms and signs that would result from prolonged elevations in prolactin levels. 2. To be able to describe the main elements in the clinical workup of a patient suspected of having hyperprolactinemia. 3. To be able to describe the rationale for the treatment of hyperprolactinemia. Describe the types of treatment available.

Summary of diagnosing functional endocrine problems: Pt comes to you w/ symptoms suggesting that they don't have enough hormone X. Normal range for hormone X is 9-25. Pr has a value of 10. How can you distinguish between: A.) Someone who has been sitting at 10 all their life (so is normal and whose symptoms must be due to something else). B.) Someone who has been at 20 all their life but has recently dropped from 20 to 10 due to some disease (true Hypo-X-ism)?

1.) *Defect at level of X*: Primary Hypo-X-ism --> loss of Negative feedback --> *Rise in XSH and XRH* 2.) *Defect at Pituitary : Secondary Hypo-X-ism (low XSH)* --> low X --> loss of negative feedback would effect hypothalamus but NOT anterior pit bc it can't make XSH to begin with --> *Rise in XRH, but not XSH*

Hypofunction: Level of hormone X could fall below normal in 3 ways

1.) *Primary Hypo-X-ism*: Disease process in endocrine gland that produces hormone X 2.) * Secondary Hypo-X-ism*: Disease process in the pituitary gland that produces XSH, so that, although the endocrine gland producing X is normal, it does not receive the appropriate trophic stimulation from XSH 3.) *Tertiary Hypo-X-ism*: Disease process above the level of the pituitary (in hypothalamus or pituitary stalk), so that, even though the anterior pituitary gland is normal, it does not receive the appropriate stimulation from XRH - tertiary problems often *occur concurrently w/ secondary hypofunction*, so the *main clinical distinction required is between primary and secondary hypofunction*

Afferent Pathways to the Hypothalamus: Neural

1.) *Rapid input via direct neural connections* from sensory and other areas of the nervous system - Stimuli such as visual perception of threat may initiate a reflexive stress response w/in seconds 2.) Hypothalamic responses can be initiated or modulated through slower inputs from *specialized local neuronal receptors* e.g. temperature, osmo- and chemoreceptors located w/in regions of the hypothalamus or in regions outside the hypothalamus connected neurally - several specialized receptor neurons located *adjacent to the circumventricular organ regions where blood borne signals have ready access*

2 other important regulators of GH secretion [KNOW]

1.) *Somatostatin (SS)*: made in hypothalamus, inhibits release of GH - SS secretion stimulated by GH and IGF-1 2.) *Stimulating receptors on somatotroph cells*: distinct from GHRH receptors - these receptors are the site of action for *Ghrelin* - Ghrelin abundant in the stomach and is a GH secretogogue, raising possibility of nutritional regulation of GH secretion - Ghrelin plays a role in appetite stimulation

Prolactin-releasing factors (PRFs) [Know!]

1.) *Thyrotropin releasing hormone (TRH)* 2.) *Vasoactive intestinal polypeptide (VIP)* 3.) *Estrogen* has a direct stimulatory effect on lactotrophe growth and secretion, thus increasing prolactin production 4.) *Suckling* of the breast stimulates prolactin secretion via neural afferent pathway 5.) *Stress* - Can all lead to Hyperprolactinemia

Hyperfunction: 6 ways in which the level of hormone X could become higher than normal (1-3)

1.) Autonomously functioning tumor in endocrine gland that makes hormone X - seen in thyroid, adrenals, pancreas, gonads, and other endocrine glands 2.) Autonomously functioning tumor in cells of anterior pit which make hormone XSH - most often seen for cells making GH, PRL, and ACTH 3.) Hypothalamus (or some ectopic site) could secrete an excessive amount of XRH, either because of an autonomously functioning tumor, or in response to stimulation from drugs - e.g. Hypothalamic hamartomas that secrete GnRH

Hypothalamus Negative Feedback Loop [KNOW!!!!]

1.) Blood level of effector hormone (X) becomes too high 2.) Rate of secretion of a specific hypothalamic peptide, or *releasing hormone* (let's call it XRH) and the related specific anterior pituitary *stimulating hormone* (XSH) receive a negative influence 3.) *Secretion of both XRH and XSH drop* --> effector gland receives fewer stimuli to produce X, and *blood level of X falls* 4.) Converse is true if the levels of effector hormone, X is too low (*decreased X induced negative feedback* w/ resultant *increase in XSH and XRH*)

Primary Hypo-X-ism

1.) Decreased level of hormone X in systemic circulation 2.) Low X detected in hypothalamus and anterior pituitary --> produces *decreased "negative feedback"* to those glands --> levels of *XRH and XSH begin to rise*, in an effort to stimulate the endocrine gland even more, to produce hormone X, and restore it to the correct level 3.) Endocrine gland is unable to respond so hormone X continues to fall, and XRH and XSH continue to rise (often to levels 10-100X above basal levels)

Hormones of the anterior pituitary: List

1.) Gonadotropins: Luteinizing hormone (LH), and follicle stimulating hormone (FSH) 2.) Thyrotropin, or thyroid stimulating hormone (TSH) 3.) Growth hormone (GH) 4.) Prolactin (PRL) 5.) Corticotropin, or adrenocortical stimulating hormone (ACTH) 6.) β-lipotropin (β-LPH) 7.) Melanocyte stimulating hormone (MSH)

Limitations of Plasma IGF-I Measurements

1.) IGF-1 is a less reliable marker than GH during OGTT for following acromegalic subjects after treatment 2.) IGF-1 levels can be decreased in the malnourished and malnutrition can stunt growth --> IGF-1 levels do not clearly discriminate between normal and reduced GH secretion

Importance of locally produced IGF-1 can be illustrated in 2 ways: [KNOW!]

1.) In mice that lack only hepatic IGF-1, circulating levels of IGF-1 fall dramatically yet they grow and develop normally 2.) Laron dwarfism: autosomal recessive inactivation GH receptor; characterized by short stature, weak musculature and increased visceral fat - Treatment w/ IGF-1 leads to some increase in linear growth but does not reverse all their problems. Their fat distribution and fat free mass remain abnormal - Although treated pts have adequate circulating IGF-1 levels their tissue levels of IGF-1 remain less than normal

Efferent pathways of the Hypothalamic control systems: Neural

1.) Neural connections to *higher brain centers*: hypothalamus can evoke *behavioral responses such as food seeking, suckling or sexual behavior* 2.) Neural connections to *structures of the limbic system*: hypothalamus can evoke *affective responses such as fear, rage or hedonia (pleasure)* 3.) By *activating the motor centers for the SNS and Parasympathetic NS*: Hypothalamus can evoke *patterned autonomic responses such as shivering, pressor vasomotor responses or copulatory reflexes*

Prolactin Excess (Hyperprolactinemia): Causes [KNOW!]

1.) Physiologic changes leading to increased prolactin production or decreased prolactin clearance - *stress, pregnancy, breast stimulation* 2.) Diminished dopaminergic inhibition of lactotrophes 3.) Lactotrophe cell tumors producing prolactin 4.) *Extra-Pituitary* - Renal - Hypothyroidism 6.) *Pitutary* - Prolactin secreting adenoma - Non-PRL secreting adenoma-stalk compression

Treatment of GH Deficiency

1.) Recombinant Human Growth Hormone (rhGH) 2.) Ghrelin Analogs

Hypothalamic Peptides: List

1.) Thyrotropin releasing hormone (TRH) 2.) Gonadotropin releasing hormone (GnRH) 3.) Corticotropin releasing hormone (CRH) 4.) Somatostatin (SS) 5.) Growth hormone releasing hormone (GHRH) 6.) Ghrelin 7.) Dopanine (main Prolactin inhibitory factor or PIF) 8.) Angiotensin II 9.) Enkephalins and Endorphins 10.) Vasointestinal peptide (VIP)

Control of the secretion of the GH-producing cells of the anterior pituitary

2 main regulators (*GHRH and SS*) control secretion of the *GH-producing cells of the anterior pit*; these cells are 35-45% of the gland and contain 5-10mg of GH in total - Pattern of pulses more prominent during active phase of growth during late childhood and early adolescence, in part due to increased sex hormones - Normal patterns susceptible to disruption by psychogenic, nutritional and metabolic disturbances --> emotional deprivation may cause low GH levels and growth failure in children - Daily GH secretory rates fall steadily from a peak in puberty to much lower levels after age 55

Hyperfunction: 6 ways in which the level of hormone X could become higher than normal (4-6)

4.) Tumor in another part of the body may produce secretory product that mimics XSH, or hormone X - Most common w/ certain types of lung cancer, known to produce ACTH 5.) Immune system may produce Ig's that stimulate production of hormone X - seen in hyperthyroidism due to Grave's disease 6.) Pt may be taking excessive amounts of hormone X - seen in pts who take excessive amounts of anabolic steroids to enhance muscle bulk for sports and in those who take excessive amounts of thyroid hormone to facilitate weight loss

Portal Circulation - Definition

A "portal" circulation is one which carries important constituents in the blood from one part of the body (where they are produced) to another part of the body (where they are used) with two capillary beds in series.

Regulation of GH secretion [KNOW!]

Achieved by a modification of the basic feedback loop (pic): 1.) GHRH from hypothalamus attaches to GHRH receptor on somatotroph cells of the anterior pituitary 2.) *Somatotroph* cells release GH into systemic circulation where it travels to many sites and attaches to GH receptors causing release of *insulin-like growth factor-1 (IGF-1 also known as somatomedin C)* - Almost all circulating IGF-1 comes from liver 3.) IGF-1 and Somatomedin inhibit further release of GHRH and GH via negative feedback loop

pituitary somatotroph adenoma

Acromegaly caused by a pituitary somatotroph adenoma may cause symptoms from compression of nearby CNS structures and symptoms of hypopituitarism

Adrenal vs Thyroid Steroid Replacement

Adrenal steroid replacement takes precedence esp prior to thyroid hormone replacement as achievement of euthyroidism may hasten metabolic clearance of cortisol and provoke adrenal crisis

Treatment of GH Excess: Radiotherapy [KNOW!]

All forms of radiotherapy are only slowly and incompletely effective. The risk of hypopituitarism is almost 100% over time. 1.) *External beam irradiation*: single source of radiation directed to a location inside the pt's head in a series of arcs. - *only slowly and incompletely effective (with almost 100% risk of hypopituitarism). Used after other things have failed* 2.) *Gamma knife*: radiation housed in a large shielded dome. Pt's skull immobilized in metal frame clamped to the skull and locked into a helmet that lines up w/ the radioactive sources inside the dome. Pt can be guided/moved inside the dome to allow precise delivery of radioactivity - *allows more precise excision without craniotomy (but can't be used within 3-5 mm of optic chiasma*due to risk of optic neuritis) 3.) *Seeds of Yttrium can be implanted at the time of the surgery if the tumor is large, invasive and incompletely excised (not used much now)*

Growth Hormone (GH)

Although *GH is an essential factor, growth also depends upon several other hormones acting in concert. Thus GH, thyroid hormone, cortisol, the sex steroids and insulin are all "growth hormones" necessary for full growth and development* - Once fully-grown, GH is not essential for life BUT even in adulthood GH does continue to function as a *counter-regulatory hormone to protect against hypoglycemia* - Adults who are GH-deficient lose muscle mass and strength, gain excess intraabdominal fat, and lose bone density

Rathke's Pouch

An evagination from the foregut in the region of the developing *3rd ventricle* w/in the diencephalon - Endodermal cells

Hypopituitarism: Progression of Hormone Deficiency

Any combo of hormone deficiencies can occur but there is often a characteristic progression: - *GH is lost first, followed by LH, FSH, and TSH* - *ACTH secretion usually maintained longest* *Posterior pituitary dysfunction, leading to diabetes insipidus* is usually a result of *hypothalamic injury --> vasopressin deficiency* - hypothalamus is site of vasopressin synthesis while posterior pit is only storage; destruction of the posterior pit therefore will not lead to vasopressin deficiency

Hypopituitarism: Causes [KNOW!]

Any of these conditions can lead to *partial or complete hypopituitarism*: - *Pituitary tumors* - *Parapituitary tumors* (e.g. craniopharyngioma) - *Trauma* (including surgery) - *Radiotherapy* - *Infiltrations* (e.g. sarcoidosis, hemochromatosis) - *Infections* (e.g. TB, syphilis, mycoses) - *Infarction* (e.g. *Sheehan's syndrome*) - *Developmental defects* (septo-optic hypoplasia) - *Functional defects of unknown etiology (most common cause of GH deficiency in childhood)* - *Empty Sella Syndrome*

Hypothalamic Neurons

Are Neurosecretory!

Infundibulum

As the pituitary forms, it moves inferiorly to lie at the end of a stalk, termed the *infundibulum*, in a bony cavity beneath the brain, called the *sella turcica*, formed from the sphenoid wings at the base of the skull.

Treatment of GH Excess: Dopamine Analogs

Bromocriptine, pergolide and cabergoline - very effective in the treatment of prolactin-secreting tumors - less effective in acromegaly - Advantage of being oral drugs, but much less effective than somatostatin analogs - side effects include headahce, nausea - rarely used now

Prolactin Excess (Hyperprolactinemia): Clinical Manifestations [KNOW!]

Causes *Hypogonadotropic Hypogonadism via alterations in GnRH pulse frequency* --> leads to gender and age specific clinical sequelae Women: - *Oligomenorrhea or amenorrhea and galactorhhea* - *Decreased fertility in premenopausal women* Note: Estrogen needed to promote prolactin-induced lactation, explaining the very low prevalence of galactorrhea in postmenopausal women and men w/ hyperprolactinemia Men: - Elevated PRL leads to low FSH, low LH and low testosterone w/ resultant *decrease in libido and sometimes ED* - Often *decreases fertility* due to decreased sperm production - *Gynecomastia* - *Glactorrhea* - *Osteopenia* *MASS EFFECTS - compression of nearby structures if tumor is the cause*

Acromegaly

Causes a distorted pattern of bony overgrowth w/ widening and thickening instead of simple elongation of the long bones - Prolonged prolonged excessive circulating levels of GH - Usually caused by a GH secreting pit tumor - Onset often Insiduous!

Pituitary Neoplasms

Constitute *~10% of all intracranial tumors* - *majority arise from endocrine cells of the adenohypophysis and are designated as Pituitary adenomas* - most found w/in the confines of the sella turcica *Ectopic adenohypophyseal cells* are known to occur in the infundibulum, pituitary stalk, floor of 3rd ventricle, and in the sphenoid bone between the nasopharynx and pituitary fossa --> pituitary adenomas in one of these locations occurs very rarely - *Usually secrete Prolactin, GH, or Both!*

Acromegaly and Mortality [KNOW!]

Decreased Lifespan of ~10 years after onset

GH Deficiency

Deficient secretion or activity of GH - Leads to *growth failure in children* and a number of *metabolic irregularities (hyperlipidemia, decreased lean muscle mass, decreased bone mineral content) in adults* Acquired *adult GH deficiency usually due to pituitary dysfunction from injury, surgical manipulation, or an expanding sellar mass* - Usually associated w/ deficits in other pituitary hormones and symptoms associated w/ these deficiencies are manifest

Hyperprolactinemia: Diagnosis [KNOW!]

Detailed hx and physical including a med profile accompanied by *Serum Prolactin levels and imaging of the pituitary* can usually differentiate the cause of prolactin excess - *Prolactin levels much higher in pituitary tumors (Prolactinomas)* - Significant differences in tx options and prognosis depend on an accurate dx

Cumulative Percentage of Patients with Normal Axes Following Radiotherapy

Diminishment of Anterior Pituitary over time - MUST follow patient!

Distinctions between states of endocrine hypofunction: XRH Stimulation Test

Does pt has a "low-normal" level of hormone, or has a truly low (abnormal) value, and if so, is it primary or secondary *Normal*: All levels normal, XSH rises w/ stimulation *Primary Hypo-X-ism*: Low X, High XSH, Exagerated rise in XSH w/ stim *Secondary Hypo-X-ism*: Low X, Relatively Low XSH, No or less than normal rise in XSH w/ stim

Embryological origin of the pituitary-hypothalamic unit: Circulation

During maturation a specialized portal circulation develops connecting the protruding base of the brain (*median eminence*), and the anterior pituitary. At the base of the brain, neuropeptides are manufactured in the hypothalamus, secreted into portal circulation, and carried from the median eminence, down the pituitary stalk, to the anterior pituitary *Hypothalamus --> Portal Circulation of Median Eminence --> down Pituitary Stalk --> Anterior Pituitary*

Hypopituitarism: Diagnosis

Dx of secondary hypogonadism and secondary hypothyroidism can be established by a *concomitant random sampling of the pituitary (LH, FSH, TSH) and effector gland hormones (estrogen, testosterone, thyroid hormones)* - However given random secretion of cortisol and GH, random serum tests are not as helpful to diagnose deficiency, rather a *stimulatory test such as the insulin tolerance test is still used and considered the "gold standard" to test these pituitary axes*

Direct metabolic effects of GH

Effects are both *anabolic and catabolic*; GH is one of the *"counterregulatory" hormones* - effects of GH probably contribute to overall fuel and endocrine pattern optimal for growth of tissues *Major metabolic effects of GH*: 1.) Promotes protein synthesis and positive balances of nitrogen, K+, and phosphate 2.) Stimulates lipolysis and ketogenesis 3.) Antagonizes the action of insulin on glucose metabolism in peripheral tissues, esp in skeletal muscle 4.) Causes compensatory hyperplasia and increased secretion by β-cells of pancreatic islets 5.) Promotes hepatic glucose production

Why don't we measure XRH levels?

Even though XRH levels might be increased 10X in capillaries of the median eminence they are still present in amounts *too small to be detectable in the peripheral circulation*

Treatment of pituitary tumors for Very Large Tumors Extending Above the Diaphragma Sellae

Frontal craniotomy may be needed - traumatic and dangerous Functional macroadenomas: sometimes possible to treat w/ dopamine agonists or somatostatin analogs prior to sx in order to shrink the tumor to make sx easier

Pituitary Adenomas: Gross Path

Grossly, pituitary adenomas are usually a mixture of solid and soft - color varies from gray to red according to degree of vascularity - Cystic and hemorrhagic changes may occur in the larger tumors Characteristic gross appearance is that of a tumor occupying both the intrasellar and suprasellar areas, w/ a central constriction produced by the diaphragm sellae

Local Tumor Growth (Pituitary Tumors): *Tumor extends outside the pituitary fossa*

Growth of tumor w/in a small bony cavity can cause pressure on important nearby structures - If tumor extends outside the pituitary fossa it may put *pressure on the optic chiasm* which lies directly above. Since fibers of the optic chiasm are crossing over, coming from the medial parts of both retinae, the *outer parts of the visual fields are lost first*

Functional heterogeneity of hypothalamic peptides

Hypothalamic peptides *may have multiple actions*: - TRH stimulates secretion of TSH, but also GH and prolactin - GnRH stimulates both LH and FSH secretion - SS inhibits secretion of GH and TSH, and when secreted in non-hypothalamic organs it inhibits multiple hormones (eg insulin) and functions - CRH stimulates secretion of ACTH and β-lipotropin. and may also centrally stimulate the SNS

Efferent pathways of the hypothalamic control systems: Endocrine

Hypothalamus evokes endocrine responses through *modulation of the secretion of hormones from the anterior and posterior pit* e.g. stimulation of ovulation, release of ADH during dehydration, secretion of prolactin in response to suckling, etc.

Basic Feedback Loop

Hypothalamus releases XRH --> stimulates Ant Pit to release XSH --> Stimulates Endocrine Gland to release X into systemic circulation

GH: Action on Peripheral Tissues

IGF-I and insulin do cross react weakly w/ each other's receptor. Major action of IGF-I is mitogenic --> stimulates the cell cycle in many tissues during periods of active growth: *Growth promoting effect is particularly strong for bone but in the presence of excess GH (and IGF-I), virtually all of the soft tissues grow at a more rapid rate than normal*

IGF-1 Actions on CNS

IGF-I exerts negative feedback effect on GH secretion by anterior pituitary, thereby helping to regulate the overall set point of the GH regulating system

Local Tumor Growth (Pituitary Tumors): tumor extends above pituitary fossa*

If suprasellar extension of tumor is asymmetrical, then visual field defect may be more noticeable on one side than the other - Often pt is completely unaware of visual problem until very late, but defect can be picked up by formal testing of visual fields - Since the *lower parts of the optic chiasm are affected first*, and these fibers contain neurons from the lower part of the retina, *upper parts of the visual field are lost first*

Gigantism

If untreated, pt may gain great height - Long bones able to reach enormous lengths because growth is occurring before closure of epiphyseal plates, a process triggered by increased gonadal steroids in puberty.

Afferent Pathways to the Hypothalamus: Endocrine

Info about status of the endocrine effector systems reaches hypothalamus and the pit via *circulation* - hormonal signals may exert either positive or negative feedback to the system

GH is Unique because... [KNOW]

It is an Anterior Pit hormone that has a direct effect on the end effector organ (and multiple end effector organs)!

Local Tumor Growth (Pituitary Tumors): CSF Effects

Local growth of a pituitary tumor may interfere w/ normal flow of CSF w/in the skull, leading to raised intracranial pressure, causing headache, nausea, mental changes, and impaired vision.

Relationship between hypothalamic releasing peptides, pituitary gland, and effetor organs

Maintenance of level of hormone X is maintained at the correct level for any individual: 1.) Basic rate of pulsatile secretion of XRH, from hypothalamus is "set" for each individual 2.) Secretion of XRH determines rate and magnitude of XSH secretion from anterior pit, which in turn determines the level of X in the blood

Treatment of GH Deficiency: Recombinant Human Growth Hormone (rhGH) [KNOW!]

Manufactured synthetically and given as a daily SubQ injection *Very effective treatment for childhood GH deficiency* - growing trend to include rhGH in the *treatment of adults with hypopituitarism* - *More controversial is the tx of normal children who are of short stature or older adults who have a natural decline in their GH*

Functional integration of hypothalamic inputs and outputs [KNOW]

Many hormones secreted in a series of pulses, the rate and magnitude of which is "set" for that organism - innate rate and amplitude of hormone secretion may be modulated by many neural and endocrine inputs that are responsive to stress, sleep, season or daylight - *rate and amplitude of hormone secretion modulates the downstream effector response* *Hypothalamus functions w/ specific patterned responses. Mix of inputs and outputs is characteristic for each response* - e.g. temp regulation - inputs and outputs mostly neural; reproduction - both a mixture of endocrine and neural events; growth - both primarily endocrine

Prolactin Deficiency

May be a consequence of any event leading to *hypopituitarism* - Infiltrative (sarcoidosis, fungal infection) processes or tumors invading the sellar region may produce pituitary compression and diminished function accompanied by a decrease in anterior pituitary hormonal secretion Only known consequence is a *lack of milk let-down in postpartum period* - hallmark of pituitary vascular infarction following OB hemorrhage known as *Sheehan's syndrome*

Pituitary Adenomas: Clinical Presentation [KNOW!]

May become clinically evident as a result of increased secretion of a specific hormone by tumor cell, signs of hypopituitarism secondary to compressive destruction of the normal gland, and/or by symptoms or signs resulting from compression of adjacent structures - *Suprasellar extension*: present in 10-20%, results in visual symptoms from compression of optic chiasm - *Extraocular tumor palsies*: occurs in 5-10% of the patient - *Pituitary apoplexy*

Hypothalamic Peptides: Neuronal Regulation of Release

May employ any of the *classic neurotransmitters* - Modulation of rate of release of hypothalamic factors into portal circulation may also involve *multiple neural inputs* *Releasing factor neurons w/ their endings in the median eminence* constitute the *final common pathway for neuroendocrine control of the anterior pit* --> hypothalamic releasing peptides travel via the portal circulation to the anterior pit where each binds its specific receptor displayed on the surface of its target cell

General principles of diagnosing functional endocrine problems: Pt comes to you w/ symptoms suggesting that they have too much hormone X. Normal range for hormone X is 9-25. Pt has a value of 24. 1._ How can you distinguish between someone who has been at 24 all their life and someone who has gone from 10 to 24 in recent months because of some problem? 2.) How can you distinguish between overproduction of X from - the primary endocrine gland? - A tumor in the anterior pituitary oversecreting XSH? - A tumor elsewhere? - Immune stimulation mimicking XSH? - Exogenous ingestion of X?

Measure XSH! *Normal*: Normal XSH *Tumor in Primary Endocrin Gland*: XSH Low due to increased negative feedback *Tumor in Ant Pit*: XSH high *Tumor Elsewhere*: Depends on tumor *Immune System Mimicing XSH*: XSH low due to increased negative feedback *Exogenous Ingestion of XSH*: XSH low due to increased negative feedback

Measurement of GH

Measurement of GH during OGTT remains the "gold standard" for diagnosis and follow-up of patients with acromegaly (Key Point!!)

GH Deficiency: Diagnosis

Measurement of low serum IGF-1 levels and lack of GH stimulation to various stimuli, the *Gold Standard of which is insulin induced hypoglycemia (the insulin tolerance test)*

Hyperfunction: Distinguishing between Conditions

Measuring both X and XSH, it is possible to distinguish between different conditions (See Chart!) - additional tests sometimes necessary to make a definitive diagnosis *If you think gland is over-secreting try to suppress it! Failure to suppress confirms oversecretion.*

Treatment of pituitary tumors

Medical therapy, surgical excision and radiation therapy - choice of therapy depends on clinical circumstances and tumor type 1.) *Prolactinomas*: dopamine agonists = initial tx of choice 2.) Small non-functioning pituitary tumors that do not extend w/in 3-5 mm of optic chiasm or impact pituitary function: watchful waiting 3.) Tumors secreting hormone (GH, ACTH): surgical resection; meds and radiation if surgery fails or tumor recurrence - transphenoidal resection = quick cure, but modest risk

Extrahepatic IGF-1 Production [KNOW!]

Most circulating IGF-1 comes from the liver, but other tissues (including bone, adipose, skeletal muscle, heart muscle, neurological tissue, reproductive organs) contain GH receptors and produce their own IGF-1

Pathologic classification of endocrine tumors

Neuroendocrine tumors exhibit many similar histological, immunohistochemical and ultrastructural features - neoplasms are composed of uniform cells - *Histological appearance does NOT correlate w/ biological activity of pituitary tumors* Currently pituitary tumors are classified according to *Size and Hormone Production* KNOW: *< 1 cm = microadenomas* * >1cm = macroadenomas* e.g. a prolactin secreting tumor measuring 1.2cm would be classified as a *macroprolactinoma*

Episodic Function

Neuronal circuits controlling neuroendocrine systems characteristically function w/ an episodic pattern w/ secretion occurring in bursts at intervals of minutes or hours Pulse frequency of secretion is *regulated, system specific, and a critical mechanism for modulation of the output of each hormone's effects*

Pituitary Adenomas: Epidemiology

Occur more frequently in adults w/ slight predilection for males - small % of pts, the pituitary tumor is one of the components of the multiple endocrine neoplasia (MEN) syndrome Type 1

Dual Embryological Origin of the Pituitary

Pituitary gland has *dual embryological origin* (Pi-"two"-itary) *Adenohypophysis/Anterior Pituitary*: arises from Rathke's pouch; endodermal cells become the hormone producing cells *Neurohypophysis/Posterior Pituitary*: an evagination of neural tissue of the embryo comes to lie over the posterior surface of the anterior pituitary, giving rise to the posterior pit *Pars Intermedia/Intermediate Lobe*: the cuboidal cells lining the small cleft at the opposed margins of the post/anterior pit. become the cells of the pars intermedia

Anatomical Location of the Pituitary Gland [Know - esp Bold]

Pituitary lies on the end of the stalk (infundibulum) w/in the *sella turcica*, behind the sphenoid sinus, separated from the base of the brain by the diaphragm *sellae*, a fibrous membrane bridging between the anterior and posterior clinoids of the sphenoid bone - Structures near the sella include the *optic chiasm superiorly* (lateral visual fields), the *carotid sinuses laterally*, the *sphenoid sinus anteriorly* and the *3rd ventricle posteriorly* - *Cavernous sinus nearby (houses carotid artery, CN 3,4,6,and 2 branches of 5)*

Plasma IGF-I [KNOW!]

Plasma levels of IGF-I fluctuate much less than GH itself --> measurement of plasma IGF-I has become a *common and useful clinical test for diagnosing GH excess*, and can be used to *follow responses to treatment of GH disorders* - IGF-1 levels can be accurately used to determine appropriate GH replacement in established GH-deficient individuals

Pituitary Adenomas: Histology

Poor correlation between microscopic appearance and biologic behavior is poor - Some invasive or metastasizing neoplasms have an obviously malignant cytologic appearance but most do not appreciably differ from a benign pituitary adenoma.

Post-Treatment Care of Pituitary Tumors

Post-surgery or radiation *imaging studies (MRI or CT) and functional studies* are done at *intervals for several years* to track pt progress *Functional studies*: - tests to see if a functional (secreting) tumor has been cured or whether it has re-grown and is producing excessive hormone again - stimulation tests of HPA and GH axes - determination of sex hormone and thyroid sufficiency via measurement of serum TSH, gonadotropins, thyroid hormone and sex hormone levels to evaluate which anterior pit hormones need to be replaced

Posterior pituitary dysfunction, leading to diabetes insipidus

Posterior pituitary dysfunction, leading to diabetes insipidus is usually a result of hypothalamic injury - hypothalamus is site of vasopressin synthesis while posterior pit is only storage; destruction of the posterior pit therefore will not lead to vasopressin deficiency

Prolactin (PRL) - Overview

Protein hormone secreted from *lactotrophe cells of the anterior pit* Necessary for breast development prior to nursing - Normal serum level 15-20 ng/ml in women; 10-15 ng/ml in men - Serum levels significantly elevated during pregnancy due to stimulatory effects of estrogen on lactotrophes - Receptor binding sites for prolactin found in multiple tissues but little is known about its function beyond its role in lactation - Elevated serum levels can lead to an altered GnRH pulse frequency and hypogonadotropic hypogonadism

Pituitary Tumors: Posterior Pituitary Deficiency

Pts w/ evidence of posterior pit deficiency (diabetes insipidus), polyuria, polydypsia and possible hypernatremia may develop: - Replacement of vasopressin via intranasal, oral or SubQ routes will relieve symptoms

Pituitary Apoplexy

Rare complication of adenomas - represents a massive hemorrhagic infarct w/in the tumor - most often seen in macroadenomas - Clinical diagnosis w/ the constellation of a hemorrhagic sellar mass, pituitary dysfunction and cranial nerve defects as a cause of tumor compression

Pituitary Tumors: Children with GH Deficiency (repeat info!!!!)

Regular injections of recombinant human GH (rhGH) until they are through puberty and fully-grown. - Some adults with GH deficiency may also benefit from rhGH tx

Vasointestinal peptide (VIP) (not covered in lecture?)

Releases PRL Found throughout the brain, intestine, and pancreas - May affect BG, BP, and water excretion - 28 amino acids

GH Replacement Therapy in Adults

Replacement of GH in adults w/ GH deficiency is controversial - improves fat free mass, bone density and general well-being in deficient adults - replaced as a daily SubQ injection and titration of the hormone dose is based on serum IGF-1 levels

Mechanism of Action of hypothalamic peptides

Several of the hypothalamic peptides act through *stimulation of adenylate cyclase and generation of cAMP* following receptor binding - *(SS does not)*

Soft Tissue Changes in GH Overproduction [KNOW!]

Soft tissues *grow and become distorted in appearance* - *earliest changes are coarsening of facial features and widening of feet and hands* - *Sweating is excessive*, sebaceous activity increases, and lips and tongue become enlarged - *Skeletal and Cardiac muscles grow*, but hypertrophy of muscles is accompanied by *myopathy, causing weakness and fatigue* - *Heart Disease* - Sodium retention manifests as *HTN in 35% of acromegalics*, and the *insulin resistant properties of GH as diabetes mellitus in 20%* - *Arthritis* - *Cerebrovascular events and headaches* - *Sleep Apnea*

Neuroendocrinology

Study of the interaction between the two great control systems of higher organisms, the endocrine and the nervous systems - During evolution of the endocrine and nervous systems, *genes encoding the structure of peptide and protein intercellular messages (and the structure of their specific receptors) have been remarkably conserved, while mode of transmission of the signal from one cell to another has undergone great diversification*. - Neuroendocrinology is primarily focused on the complex *interplay between the hypothalamus (nervous system) and the pituitary gland (endocrine system)*; the site where neural activity merges with hormonal physiology.

Enkephalins and Endorphins (not covered in lecture?)

The enkephalins and endorphins react with endogenous opiate receptors in various brain sites - Leu-enkephalin - Met-enkephalin - α-endorphin - β-endorphin - ϒ-endorphin

Hypothalamic Peptides (Hypothalamic Factors)

Those known to act as hormones where the *target is the anterior pit* are called *hypothalamic or hypophysiotropic hormones* Factors and hormones can have primarily releasing or inhibitory functions Examples: - *Prolactin inhibitory factor* (main one being dopamine) - *Tyrotropin releasing hormone (TRH)*

Local Tumor Growth (Pituitary Tumors): Sinus Invasion

Tumors may erode nearby bones and can extend into sphenoid or cavernous sinuses - If a tumor erodes into the sphenoid sinus it is possible that cerebro-spinal fluid may leak out into the nasal cavity causing CSF rhinorrhea, and raising the possibility that bacteria may gain access, causing meningitis *If a tumor extends into the cavernous sinus, palsy of the cranial nerves (II, III, IV, VI-3) traversing the sinus may be seen* - degree of local tumor growth can be detected with best resolution through MRI scanning

Hyperprolactinemia: Treatment [KNOW!]

Tx dependent on cause; Prolactinomas are amenable to medical management w/ *Dopamine agonists*: 1.) *Bromocriptime* 2.) *Cabergoline* - Only if fails or is not tolerated should surgical resection of tumor be considered

Treatment of GH Deficiency: Ghrelin Analogs

Under development - Offer promise of an orally active drug that can stimulate GH secretion

Hypopituitarism: Clinical Presentation

Underproduction of any or all of the hormones of the anterior and posterior pituitary; can lead to a variety of clinical presentations - pts present w/ symptoms of *diabetes insipidus, hypothyroidism, hypoadrenalism, growth failure and hypogonadism*

Destruction of normal pituitary tissue

causes hypopituitarism - complete assessment of pituitary hormone function and timely replacement of hormones is critical to survival in the patient w/ suspected hypopituitarism

Hypothalamus functions w/ specific patterned responses. Mix of inputs and outputs is characteristic for each response

e.g. temp regulation where inputs and outputs are mostly neural; reproduction where both are a mixture of endocrine and neural events; and growth where both arms are primarily endocrine.

Physiologic hyperprolactinemia

w/ exception of pregnancy and renal failure, levels of prolactin *rarely exceed 50-60ng/ml* from physiologic causes 1.) *Pregnancy*: elevated estrogen levels that stimulate lactotrophe growth and prolactin secretion 2.) *Renal failure*: via diminished clearance of the hormone 3.) *Primary hypothyroidism*: induces an increase in TRH that in turn has a stimulatory effect on lactotrophes 4.) *Chest wall injuries and nipple manipulation*: create stimulatory afferent signals similar to suckling