- Conencted to the hypothalmus 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) 

- Corticotroph cells make up 15-20% of the pituitary population, produce ACTH, and target the Adrenal gland, Adipocytes, and Melanocytes.

- Thyrotroph cells make up 3-5% of the pituitary population, produce TSH, and target the Thyroid gland.

- Gonadotroph cells make up 10-15% of the pituitary population, produce LH and FSH, and target the gonads.

- Somatotroph cells make up 40-50% of the pituitary population, produce GH, and target all tissues and the liver.

- Finally, lactotroph makes up 10-15% of the pituitary population, produces PRL, and targets the breasts and gonads. 

- GH secretion controlled primarily by hypothalamic GHRH (growht hormone releasing hormone) stimulation and somatostatin (inhibits several hormones) inhibition.

- Neurotransmitters involved in control of GH secretion - via regulation of GHRH and somatostatin.

- Neurotransmitter systems that stimulate GHRH         and/or inhibit somatostatin

    - Catecholamines ating via alpha2-adrenergic         receptors

    -Dopamine acting via D1 or D2 receptors

    - Excitatory amino acids acting via both NMDA         and non-NMDA receptors 

- Beta Adrenergic receptors stimulate somatostatin release nad inhibit GH

- Beta-Adrenergic receptors inhibit hypothalamic release of GHRH 

- 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 adequte glucose as during absorptive phase, and glucose uptake is required, then GH secretion is inhibited so it won't counter act insulin action.   

- During fasting, GH antagonizes insulin action and helps mediate glucose sparing, ie stimulates gluconeogenesis

- In general, during 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 sparring.   

- Random serum samples not useful due to pulsatile pattern of release

- Provocative tests necessary

        - GH measurement after 90 min exercise

        - GH measurement immediately after onset             of sleep

- Definitive tests

        - GH measurement after insulin-induced                 hypoglycemia

        - Glucose supresses GH levels 30-90 min             after administration - patients with GH                 excess do not suppress

        - Measurement of IGF-1 to assess GH excess 

- Sleep (stages III and IV) (most growth may occur at night)

- Estrogensor Androgens (Puberty)

- Thyroid Hormones 

- Corticosteroids (high doses)

- Aging

- Hypothyroidism 

Bone - Proliferation of epiphyseal cartilage

Connective Tissue - Stimulates Proliferation

Viscera - Stimulation of growth

Adipose Tissue - Increase Lipolysis (Triglycerides -->  Free Fatty Acids)

Muscle - Increase Amino acid uptake; Increase           Protein synthesis

Liver - Increase Glucose output (Increase blood          glucose) 

- Children (Dwarfism) - Decreased growth velocity; retarded skeletal development; poorly developed musculature; excess subcutaneous fat

 - Adults - Decreased muscle strength; decreased bone density; increased body fat

- Children (Gigantism) - Increased growth velocity

- Adults (Acromegaly) - Connective tissue proliferation; dermal overgrowth; enlargement of the extremities; skull deformities; peripheral neuropathy; insulin resistance

*Note: 1st degree IGF-1 deficiency leads to short stature 

- Caused by eosinophilic adenomas of somatotrophs

- Excess GH leads to development of gigantism if hypersecretion is present during early life - a rare condition

    - Symmetrial enlargment of body resultin in true     giant with overgrowth of long bones, connective     tissue and viscera organs.

- Excess GH leads to acromegaly if hypersecretion occurs after body growth has stopped.

    - Elongation of long bones not possible so there     is over growth of cancellous bones - protruding     jaw, thickening of phalanges, and over growth         of visceral organs 

ACTH: Synthesis and Regulation of Secretion

- Produced in corticotrophs

- ACTH is produced in teh anterior pituitary by proteolytic processing of Preproopiomelanocortin (POMC)

- Other neuropetide products include Beta and Gamma lipotropin, Beta-endorphin, and alpha-melanocyte-stimulating hormone (alpha-MSH).

- ACTH is a key regulator of the stress response 

- ACTH is made up of 39 amino acids

- Regulates adrenal cortex and synthesis of adrenocorticosteroids

- alpha-MSH resides in first 13 AA of ACTH

- Alpha-MSH stimulates melanocytes and can darken skin

- Overproduction of ACTH may accompany increased pigmentation due to alpha-MSH 

- Disease in which patients lack cortisol from zona fasiculata, and thus lacks negative feedback that suppresses ACTH production

- Result: overproduction of ACTH

- Skin will darken

- JFK had Addison's disease and was treated with cortisol injections 

- Beta-endorphin is produced

- Binds to opiate receptors

- Results in "runner's high"; strenuous exercise takes a person over a threshold that activates endorphin production.  Endorphins are released during long, continuous workous, when breathing is difficult

- Role in anterior pituitary not completely understood.

- One of many endogenous opioids such as enkephalins 

- MSH peptides are produced

- alpha-MSH has antipyretic and anti-inflammatory effects; also inhibits CRH and LHRH secretion

- Four MSH receptors identified

- May inhibit feeding behavior

- ACTH has MSH-like activity

- However, MSH has NO ACTH like activity 

- Stimulation of Release

- CRH and ADH

- Stress

- Hypoglycemia

- CRH and ADH both synthesized in hypothalamus

- ADH (a.k.a vasopressin) is released by posterior pituitary and reaches anterior pituitary via inferior hypophyseal artery 

- Deficiency of vasopressin (ADH) in herditary diabetes insipidus is accompanied by decreased ACTH release.

- Vasopressin potentiates CRH at both hypothalamic and pituitary levels

- Many vasopressinergic neurons also contain CRH resulting in co-release of two peptides into portal blood. 

- 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 

- 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 

- LH, FSH, TSH, and hCG are examples

    - have alpha and beta subunits

    - each subunit is encoded by different gene

- alpha subunit is identical for all hormones

- Beta subunits are unique and provide biological specificity 

- Cells in anterior pituitary that produce LH and FSH

- Synthesis and secretion stimulated by GnRH-major effect on LH

- FSH secretion controlled by inhibin

- Pulsatile secretion of GnRH and inhibin cause distinct patterns of LH and FSH secretion. 

- 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. 

- Negative feed-back

    - Inhibin produced by testes and ovaries                 decreases FSH beta-subunit expression

    - Testosterone from leydigg 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 

- 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 

- Positive Feedback

    - Estradiol at high plasma concentrations in late     follicular phase of ovarian cycle stimulates GnRH     and LH surge - triggers ovulation.   

- Site of TSH synthesis

- Pattern of secretion is relatively steady

- TSH secretion stimulated by TRH

- Feedback control by T3 (Thyroid Hormone) 

- Hyperthyroidism caused by circulating antibodies to the TSH receptor

-Associated with diffuse goiter

- Autoantibodies bind to TSH receptor and mimic the action of TSH itself leads to persistent stimulation of thyroid and elevated levels of thyroid hormones. 

- 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

    - Oxytocin also stimulates prolactin release

    - Estradiol enhances prolactin synthesis 

- 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 

Clinical Assessment of PRL

- Single basal serum PRL measurement sufficient to determine excess

- PRL deficiency not a usualy clinical concern

- PRL is only anterior pituitary with predominant negative control by hypothalamus - often elevated by lesions that interfere with portal blood flow.

- Elevated by primary PRL adenomas of pituitary 

About Posterior Pituitary hormones: ADH (AVP) and Oxytocin (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