Hypothalamus Pituitary Axis

The ______ system is a chemical messenger system comprising feedback loops of hormones released by internal glands of an organism directly into the circulatory system —> regulating distant target organs.

endocrine

In humans, the major endocrine glands are the ______ gland and the ______ glands.

adrenal, thyroid

Major functions of the endocrine system:

• Regulation of ______ storage, ______, and ______.

• Adaptation to ______ (new/old) environments and conditions of ______.

• Facilitation of  ______ and _______.

• ______ and ______ of reproductive system.

• energy, production, utilization

• new, stress

• growth, development

• maturation and function

Balancing two altered states of function:

• ______ —> inc. released or add agonist

• ______ —> dec. release or add antagonist

• deficiency

• excess

Anterior Pituitary Hormones (6)

• Growth hormone (GH)

• Prolactin (PRL)

• Thyroid Stimulating Hormone (TSH)

• Adrenocorticotropin Hormone (ACTH)

• Gonadotropins:

  • Lutenizing Hormone (LH)

  • Follicule Stimulating Hormone (FSH)

Posterior Pituitary Hormones (2)

• Oxytocin (OXY)

• Anti-diuretic Hormone (ADH, vasopressin)

Hypothalamus-Pituitary Axis

1. Anterior Pituitary

vs.

2. Posterior Pituitary

1. Hypothalamus —> Anterior Pituitary —> Organ/Gland —> Tissue —> DIRECT effect

2. Hypothalamus —> Posterior Pituitary —> Tissue —> INDIRECT effect

Two main MOA of Endocrine Hormones

• ______ receptors —> modulate ______ of genes in target cells (ex: tyrosine kinase receptors)

• ______ receptors —> exert ______ effect on signal transduction pathways (ex: GPCRs)

• nuclear, transcription

• membrane, rapid

Oxytocin Release

• Anterior or Pituitary?

• ______ secretion

• Sensory Stimuli:

  • Dilation of ______ and ______

  • ______

• MOA: oxytocin binds to ______ —> activates ______ release from SR. Ca2+ activates contractile proteins: ______ contraction.

• Receptor Locations:

  • ______ —> induction of labor

  • ______ —> milk ejection

• pituitary

• pulsatile

• cervix, vagina

• GPCR, Ca2+, muscle

• uterus

• breast

Oxytocin Agonist

• MOA —> activates oxytocin receptors to ______ (inc./dec.) Ca2+ release and ______ contractions.

• Uses —> induction and augmentation of ______, control ______ ______ after delivery

• increase, uterine

• labor, uterine hemorrhage

Oxytocin Agonist —> Adverse Effects (5)

• fetal distress

• placental abruption

• uterine rupture

• fluid retention

• hypotension —> when administered as IV bolus

Oxytocin

• Oxytocin is sometimes nicknamed the “cuddle hormone” because it ______ (enhances/reduces) bonding in emotional circuits with ______ (positive/negative) experiences.

• As a neuromodulator, oxytocin acts in the ________ to sharpen sensory signals by ______ (increasing/decreasing) background “noise.”

• enhances, positive

• hypothalamus, decreasing

Vasopressin

• anterior or pituitary?

• Stimulating Factors:

  • ______ (rise/fall) in blood pressure

  • ______ (rise/fall) in plasma osmolarity

• Main Effects: (2)

• Receptor Locations + Effects (2)

• pituitary

• fall

• rise

• vasoconstriction, fluid retention

• V1 in vascular smooth muscle = vasoconstriction, V2 in kidneys = fluid retention

V2 Receptor MOA

• effects ______ on water reabsorption

• V2 binds to ______ —> activates ______ _______ pathway

• phosphorylation aquaporin 2 (______) which is then inserted into ______ cell membrane

• ______ (increases/decreases) water reabsorption (anti-diuretic)

• kidney

• GPCRs, adenylyl cyclase

• AQP2, luminal

• increases

Vasopressin Receptor Agonists

• MOA —> activates ____ receptors >>>> ____ receptors

• acts in _______ to _______ water resorption

• Adverse Effects —> (4)

• Agents —> (2)

• Uses —> (2)

• V2, V1

• kidney, increase

• GI upset, hypervolemic, hyponatremia, allergic reactions

• desmopressin, vasopressin (arginine vasopressin)

• diabetes insipidus, polyuria (nasal spray for pts > 50 y/o)

______ ______ → deficiency in vasopressin that causes excretion of abnormally large volumes of dilute urine and excessive thirst

diabetes insipidus

Vasopressin Receptor Antagonists

• MOA —> block ____ receptors

• acts in ______ to ______ water resorption

• Uses —>  ______ and ______ in hospitalized patients

• Agents —> (2)

• V2

• kidney, decrease

• hypervolemic, hyponatremia

• Conivaptan, Tolvaptan

Growth Hormone Release

• Stimulating Factors —> (2)

• Inhibitory Factors —> (2)

• MOA —> GH binds to 2 ______ monomers —> recruits 2 ______ molecules (tyrosine kinases) —> activate downstream signaling —> ______ (increases/decreases) IGF-1 expression

• GHR also activates ______ —> may mediate the ______ (increased/decreased) expression of glucose transporters on the plasma membrane.

• growth hormone releasing hormone (GHRH), ghrelin

• somatostatin, feedback inhibition by GH and insulin-like growth factor (IGF-1)

• GHR, JAK2, increases

• IRS-1, increased

Growth Hormone

• anterior or pituitary?

• Physiological Effects:

  • ______ longitudinal bone growth

  • ______ bone mineral density

  • anabolic effects in ______

  • catabolic effects in ______

• Mixed effects in carbohydrate metabolism:

  • GH ______ (enhance/reduce) insulin sensitivity = ______ serum glucose.

  • IGF-1 = ______ serum glucose.

• Therapeutic consideration:

• anterior

• increase

• increase muscle

• fat

• reduce, increase

• decrease

• monitor blood sugar until you know which effect predominates

Growth Hormone —> Deficiency

• causes —> ______ and damage to ______ or ______

• adverse effects:

  • ______ (tall/short) stature

  • ______ (inc./dec.) BMD

  • ______ (inc./dec.) muscle mass

  • ______

• genetic, hypothalamus, pituitary

• short

• decrease

• decrease

• adiposity

Growth Hormone —> Excess

• causes —> ______ ______

• Children

  • ______ —> increased longitudinal growth

• Adults

  • ______ —> abnormal growth of cartilage, bone, and vital organs

  • results in….

• pituitary adenomas

• gigantism

• acromegaly

• HTN, glucose intolerance, carpal tunnel syndrome, sleep apnea, cardiovascular disease

Somatropin = ______ ______ ______ ______ 

• DNA sequences match ______

• route of administration —>

• MOA —> binds ______ and ______ the production of IGF-1

• Uses —> (2)

• recombinant human growth hormone (rhGH)

• GH

• subQ injection

• GHR, increases

• children of short stature with GH deficiency

• adults with demonstrated GH deficiency and/or deficiencies in 3 other pituitary hormones

Somatropin

• Adverse Effects:

  • children —>

  • adult —>

    • symptoms: (4)

• Contraindications: (2)

• rare

• more frequent in older or obese patients

  • carpal tunnel syndrome, peripheral edema, arthralgias, myalgias

• malignancy or other proliferative disorders

• acute critical illness (cardiovascular or respiratory)

Mecaserim = ______ ______ ______ ______

• MOA —> stimulates ______ receptors

• Adverse Effects:

  • ______ —> take with a meal or snack

  • ______

  • DO NOT use ______

• Uses: 

• recombinant insulin-like growth factor 1

• IGF-1

• hypoglycemia

• lipohypertrophy

• malignancy

• GH deficiency due to mutations in GHR or IGF-1 or antibodies against GH

Mecaserim Rinfabate = recombinant IGF-1 with ______

• MOA —> stimulates ______ receptors

• IGFBP-1 (binding protein)

• IGF-1

Tesamorelin = ______ ______ ______ ______ ______

• ______ (increases/decreases) GH and IGF-1 but clinical effects primarily to ______ visceral fat accumulation

• ______ effects on glucose regulation

• not approved for ______ ______

• used for ______ ______ lipodystrophy

• synthetic growth hormone releasing hormone (GHRH)

• increases, reduce

• minimal

• GH deficiency

• HIV associated

Somatostatin Analogues

• MOA —> mimics ______; inhibits ______ and ______ release to ______ GH and IGF-1

• Uses —> ______

• Intermediate-acting, immediate release —> ______

• Long-acting, slow release

  • ______ —> decreases tumor size

  • ______

  • ______ —> inhibits ACTH secretion; used in Cushing’s Syndrome

• SST, GHRH, GH, decrease

• acromegaly

• octreotide

• octreotide LAR

• lanreotide

• pasireotide

Somatostatin Analogues —> Adverse Effects

• ______ ______ (~50%) —> diarrhea, nausea, abdominal pain

• inhibitory effect on ______ and ______ (______)

• decreased insulin ______ and ______

• pasireotide also increases ______ secretion —> hyperglycemia

• GI upset

• TSH, ACTH, pasireotide

• secretion, resistance

• glucagon

Pegvisomant

• ______ antagonist

• MOA —> binds to ______ and blocks the action of ______

• Route of Administration/Dosing Interval:

• Uses: ______

• Adverse Effects —> (3)

• GHR

• GHR, GH

• SubQ injection daily or weekly

• acromegaly

• elevated liver enzymes, injection site reactions, monitor for pituitary adenomas

Prolactin Release

• Stimulating Factors

  • no ______ stimulatory release factor, but ______ and ______ can stimulate its release

• Inhibitory Factors

  • dopamine inhibits prolactin release by binding to ______ receptors on the anterior pituitary

• prolactin release is unusual because it has no ______ ______ control

• unique, thyrotropin-releasing hormone (TRH), suckling

• D2

• negative feedback

Prolactin

• MOA —> binds to ______ receptors —> structurally related to ______

• serum prolactin levels rise transiently after —> (6)

• prolactin levels rise and are sustained during ______ and ______

• the physiological effects of prolactin include:

  • ______ and ______ lactation

  • decreasing ______ function

  • suppressing ______ drive

• these functions ensure that maternal lactation is ______ and not ______ by pregnancy

• PRL, GHR

• exercise, meals, sexual intercourse, general anesthesia, myocardial infarction, and acute stress

• pregnancy, breastfeeding

• induce, maintain

• reproductive

• sexual

• sustained, interrupted

Hyperprolactinemia

• causes excess ______ production —> ______

• ______ (increase/decrease) in reproductive function

  • suppress hypothalamic ______ and ______ secretion

  • impairs ______ ______ synthesis in both women and men

  • women —> can lead to ______, ______, and decreased ______

• prolactin, lactation

• decrease

• GnRH, gonadotropin

• sex hormone

• menstrual irregularities, infertility, libido

Dopamine Agonists

• MOA —> activate ______ receptors more than ______ receptors

  • decrease in ______ secretion, ______ motor, and ______ control

• used for the treatment of ______, inhibition of ______ postpartum, and ______ disease

• two common dopamine agonists include ______ and ______

• adverse effects:

  • ______ upset

  • ______ hypotension

  • ______ disturbances 

  • ______ and ______ (at high doses)

• D2, D1

• PRL, CNS, behavior

• hyperprolactinemia, lactation, Parkinson’s

• Bromocriptine, Cabergoline

• GI

• orthostatic

• psychiatric

• vasospasm, pulmonary infiltrates

Gonadotropins

• the two main gonadotropins are ______ and ______

• release is stimulated by ______ secreted in a ______ manner

• continuous GnRH leads to ______ and ______ of GnRH receptors

• gonadotropin secretion is inhibited by feedback inhibition from ______ ______ and ______

• human chorionic gonadotropin (hCG) is produced by the ______ and is detected by a ______ pregnancy test

• luteinizing hormone (LH), follicle-stimulating hormone (FSH)

• GnRH, pulsatile

• desensitization, down regulation

• sex steroids, inhibin

• placenta, urine

Gonadotropins —> LH

• In men, LH stimulated de novo ______ synthesis in ______ cells of the testes.

• In women, LH triggers ______ and the development of the ______ _______.

• androgen, Leydig

  • ovulation, corpus luteum

Gonadotropins —> FSH

• In men, FSH stimulates ______ maturation.

• In women, FSH stimulates the growth of ______ in the ______.

• FSH induces expression of ______ receptors on theca and granulosa cells.

• FSH increases the expression of ______ in granulosa cells, stimulating ______ estradiol.

• sperm

• follicles, ovary

• LH

• aromatase, estradiol

Gonadotropins – Types of Hypogonadism

• In HYPOgonadotropic hypogonadism, deficient sex steroid production occurs due to ________ gonadotropin secretion.

• In HYPERgonadotropic hypogonadism, deficient sex steroid production occurs due to direct impairment of ________ function, which results in ________ gonadotropin secretion.

• decreased

• gonadal, increased

FSH analogs

• MOA —> activate ______ receptors to mimic the effects of FSH

• used to treat ______ and controlled ______

• Adverse effects of FSH analogs include:

  • ______ hyperstimulation syndrome

  • multiple ______

  • ______ in men

  • ______, ______, and ______

• FSH

• infertility, ovulation

• ovarian

• pregnancies

• gynecomastia

• headache, depression, edema

Types of FSH Analogs

• ________ alfa and ________ beta are recombinant FSH preparations.

• ________ is human FSH purified from the urine of postmenopausal women.

• ________ (hMG) is extracted from the urine of postmenopausal women and contains both ________ and ________ activity.

• Follitropin, Follitropin

• Urofollitropin

• Menotropin, FSH, LH

LH Analogs

• MOA —> stimulate ______ receptor to mimic the effects of ______

• used for the ______ of ovulation in fertility treatments and to treat ______

• Adverse effects of LH analogs include:

  • ______ hyperstimulation syndrome

  • multiple ______

  • ______ in men

  • ______, ______, and ______

• LH

• initiation, infertility

• ovarian

• pregnancies

• gynecomastia

• headache, depression, edema

Types of LH Analogs

• ________ (hCG) mimics LH activity and is often used to trigger ovulation.

• ________ alfa is a recombinant form of hCG.

• ________ is recombinant human LH.

• ________ are extracted from the urine of postmenopausal women and contain both ________ and ________ activity.

• human chorionic gonadotropin

• choriogonadotropin

• lutropin

• menotropins, FSH, LH

GnRH Receptor Agonists

• MOA —> binds to and stimulates ______ receptor

• With intermittent administration, GnRH agonists ________ LH and FSH secretion.

• With prolonged continuous administration, GnRH agonists ________ LH and FSH secretion.

• GnRH agonists are used for ________ treatments, ________ puberty, and ________ cancer.

• Adverse Effects —> (5)

• Drug Examples —> (5)

• GnRH

• increase

• decrease

• fertility, precocious, prostate

• headache, nausea, light-headedness, injection site reactions, symptoms of hypogonadism

• leuprolide, groserelin, histrelin, nafarelin, triptorelin

GnRH Receptor Antagonists

• MOA —> binds to and blocks ______ receptor

  • reduces ______ and ______ production and secretion

  • reduces production of ______ ______

• are used for ________ treatments, ________ cancer, and pain associated with ________

• interaction —> ______ the effectiveness of ______ ______

• adverse effects —> (5)

• drug examples —> (4)

• GnRH

• LH, FSH

• sex steroids

• infertility, prostate, endometriosis

• reduce, hormonal contraceptives

• s/s menopause, nausea, headache, CNS disturbances, hypersensitivity

• ganirelix, cetrolrelix, degarelix, elagolix