Endocrinology Physiology Flashcards
endocrinology
-study of signaling between organs in the body —> hormones and metabolites travel through the blood to act on target tissues
-contrasts GI system that interacts with outside world
endocrine glands
use hormones to regulate other organs and organ functions directly to blood
clinical endocrinology
-deals with diseases that affect the “classic” endocrine organs like the thyroid, parathyroid, pituitary, adrenals, pancreatic islets, and gonads (ovaries and testes) as well as osteoporosis, lipid disorders and hypertension, and obesity
-overlaps with other specialties: ENDO pancreas (islets) vs EXOCRINE pancreas (digestion) managed by GI
basic science
-study of hormones and their actions
-receptors, intercellular signalling, transcriptional regulation, intracellular communication within a tissue or between organs
-leads to the discovery of new hormones, newly recognized functions of known hormones, and emergence of diseases
endocrine vs nervous systems
-endocrine relies on release of hormones into bloodstream @ a distance that is indirect
-with nervous system, the release is localized and has direct communication
-endocrine targets all tissues, while the nervous targets neurons, muscles, some endocrine gland cells, and fat cells
-the effect onset of the nervous is immediate/rapid, whereas the effect onset for the endocrine is gradual
-the effect duration for the nervous is very short and for the endocrine short to long
-the effect recovery for the nervous is fast, while the effect recovery for the endocrine is variable
hormone
chemical signal secreted into the bloodstream to act on distant tissues to regulate function of a target cell
what are the two types of hormones?
-act on nuclear receptors
-act on cell surface receptors
nuclear receptors
-“classic” hormones
-thyroid hormones (derived from tyrosine)
-steroid hormones (derived from cholesterol) —> with intact steroid nucleus (gonadal and adrenal steroids) and with broken steroid nucleus (vitamin D)
cell surface receptors
-require signal transduction via second messengers intracellularly
-polypeptides —> some are small (TRH is 3 amino acids), some are big (GH is ~200 amino acids), and some are glyosylated (TSH, FSH, LH, and hCG)
-monamines and derivatives (serotonin, dopamine, norepinephrine, epinephrine)
-prostaglandins
nuclear receptor hormones structures
multiple ring structure with substitutions that define how they bind
nuclear receptor superfamily
comprised of:
-steroid hormone receptors (estrogens, progesterone, androgen, glucocorticoids, mineralcorticoids)
-heterodimeric receptors (retinoic acid, thyroid hormones, vitamin D, oxysterols, bile acids, xenobiotics)
-orphan receptors (SF-1, LRH-1, SHP, TLX)
cell surface receptors
peptide hormones and amine derivatives
mechanism of nuclear receptor hormones
nuclear receptors reside inside the cell —> binding of the ligand will translocate the nucleus —> regulate transcription
mechanisms of cell surface receptor hormones
growth factor receptors like receptor tyrosine kinases and G-protein coupled like the seven membrane spanning domain receptor like E, NE, TRH, GnRH, LH, FSH
where do endocrine hormones act?
hormone is secreted into the bloodstream —> transported to another site (target), where it it exerts its function (stimulatory or inhibitory)
where do paracrine hormones act?
hormone acts locally on nearby cells (sex steroids in the ovary)
where do autocrine hormones act?
hormone acts locally on the cell that produced it (insulin)
where do hormones come from?
-several endocrine glands that make specific hormones that could be studied
-ductless (do not have a duct system like liver or pancreas) and highly vascularized
-there are “classical” endocrine glands
-many “non-classical” endocrine organs have primary functions
“classical” endocrine glands
discrete organs with hormone secretion as their primary functions
how do hormones get where they are going? hormone synthesis and release (secretion)
-cells generating hormones will secrete from pool of precursors in regulated fashion to the bloodstream
-tonic/basal secretion @ low levels then stimulated secretion in response to stimulus measured by cell
-populations of hormone levels in the blood can vary —> stochastic spitting out in relation to environment and cycles that are periodic especially during the day Ex. circadian rhythm
how do hormones circulate?
-free or bound hormones with their carriers
-need equilibrium between bound and free fraction hormones
free hormones
-the active fraction for cellular action and feedback
-amines and polypeptide hormones usually circulate free in the bloodstream with a shorter half-life since they are water soluble
-EXCEPT insulin-like growth factors bound to IGFBPs
bound hormones and their carriers
-steroid and thyroid hormones are not very water soluble —> need carrier proteins
-fraction that is bound to the carrier protein, the largest one, is inactive
-specific: TBG for T4 and T3, SHBG for T and E2, CBG for cortisol
-non-specific- albumin and pre-albumin
-EXCEPT the minerlcorticoid steroids (aldosterone) don’t have a carrier protein
-hormones that are heavily protein bound are cleared more slowly from the circulation by the liver and kidneys —> longer half-life
how to measure free and bound hormones?
-ideally in the lab one should measure the free hormone, but this is not always possible
-if you measure the total hormone and there is a carrier protein abnormality, the total hormone may not reflect accurately the free hormone
hormonal pharma: action, metabolism, and clearance
-agonist, partial agonist, antagonist
-only a small fraction of the circulating hormone is taken up by the target tissue
-the bulk clearance is done by kidneys and liver
-only a small fraction is excreted intact in urine or feces
-if the hormone is acting like a ligand, it can act as ligand for target receptor
hormonal regulation
-most organs secrete hormones then have another hormone regulating it —> stimulatory (trophic) and inhibitory
feedback
interaction between hormones
negative feedback loop
endocrine cells secrete hormones to target cells —> target cells release hormone to tell endocrine cells to stop producing
positive feedback loop
target cells are telling endocrine cells to keep secreting (amplifies signals)
what are the 6 classical endocrine organs?
pituitary, thyroid, parathyroid, adrenal, pancreatic islets, and gonads
functional categorization of hormones
-sex and reproduction, lactation, development and growth, metabolism, “stress” response, calcium homeostasis, electrolytes, blood pressure, and energy homeostasis
-some overlap with what hormones do
what are the three functional categorizations of the endocrine diseases? (in relation to the target gland)
hypofunction (hormone deficiency), hyperfunction (hormone excess), and hormone “resistance” syndromes (no clear hyper or hypo but response to target hormone is not robust)
hypofunction
-primary: the primary (or target) gland is defective)
-secondary: the trophic hormone in the pituitary is defective
-tertiary: the trophic hormone in the hypothalamus is defective
hyperfunction
-primary: the primary gland itself is hyperactive
-secondary: the trophic hormone in the pituitary is overproduced
-latrogenic or fictitious: administration of synthetic hormones, intentionally by physician or without physician knowledge
hormone “resistance” syndromes
-functionally defined: hormone is produced in substantial quantities but is inative or has reduced activity
-the hormone itself is abnormal
-receptor for the hormone is “blocked” by antibodies
-receptor itself is abnormal
-post-receptor pathway is abnormal
pituitary
-responds to hypothalamic control
-sits right behind the nasal passages sinuses
-highly vascularized- pituitary diseases can cause space occupying issues with nearby nerves
-stalk and posterior/anterior are very neuronal —> anterior secretes majority of hormones
-median eminence- where the hypothalamic releasing hormones are released to the anterior pituitary
hypothalamic hypophysiotropic hormones
growth hormone releasing hormone (GRH), somatostatin, corticotropin releasing hormone (CRH), gonadotropin releasing hormone (GnRH), thyrotropin releasing hormone (TRH), and prolactin inhibiting hormone (dopamine)
cytology of the pituitary
-each pituitary hormone is made by its own type of cell that secretes that type of hormone
-all mix together and regulate the pituitary
H-P-growth hormone axis
-pituitary somatotrophs secrete growth hormones that can act on different tissues and are critical for linear growth and development
-in adults, a lot of growth hormone functions are mediated by growth hormone action on the liver —> triggers action of IGF-1
-very pulsatile
excess growth hormone syndromes
-gigantism- causes you to be really tall
-acromegaly- can’t have excess growth in your bones —> enlarged hands, feet, facial features
prolactin (PRL)
-critical for lactation but may have other effects
-helps with pseudo vs real seizures (levels are acutely elevated in seizures)
-several circulating forms of PRL —> explains discrepancies between bioassay and immunoassay
functions of PRL
-evolutionary benefit to stop cycling when you are nursing, so that you don’t get pregnant too close together (inhibits pulsatile secretion of GnRH —> no midcycle surge —> no ovulation)
-main function is to stimulate milk synthesis in the post-partum period by inducing the final differentiation of milk cells, resulting in casein synthesis
thyroid gland
-largest endocrine gland
-primarily used to synthesize thyroid hormones (T4 and T3)
-thyroid hormones are unique in that they contain ~60% iodine
-thyroid hormones can regulate growth and development
-within the thyroid, cells surrounding follicles of thyroid hormones and you can see loss of stores where hormones are used
thyroid hormone synthesis
you need iodine and storage of pre-formed hormones
thyroid feedback
-thyroid gland is the target of the pituitary, which secretes TSH if it senses that the levels of thyroid hormone are too low —> TSH stimulates thyroid hormone regulation to increase —> increased T4 and T3 thyroid hormone circulates body —> acts on negative feedback loop on pituitary to decrease TSH
what drives thyroid disfunction?
immune system diseases
hypothyroidism (Hashimoto’s)
destruction of thyroid cells where you gain weight, dry skin, fatigue, not regular reproductive cycles
hyperthyroidism (Grave’s)
antibodies bind to and stimulate the receptor that churns out TSH —> high levels of thyroid hormone with large, swollen thyroid glands and weight loss
hashimoto’s thyroiditis
-infiltration of lymphocytes in the thyroid that release antigens
-autoantibodies NOT causal but evidence of immune autoreactivity
H-P-adrenal axis
hypothalamus secretes CRH —> pituitary, which secretes ACTH —> adrenal glands, which secretes cortisol and adrenalandrogen
adrenal anatomy
-retroperitoneal with a high amount of bloodflow
-above or medial to the upper poles of the kidneys
-90% of the weight is composed of the cortex and 10% is the medulla
what are the three classes of hormones?
- glucocorticoids
- androgenic hormones
- mineralic
aldosterone
-main hormone produced in the zona glomerulosa
-a significant percentage (30-50%) circulate free and the remaining majority circulates bound to albumin and in part to CBG
-rapidly inactivated in the liver
-small amount of free aldosterone filters in the urine and can be easily quantitated
aldosterone targets and actions
-regulates sodium and potassium concentrations in the blood
-regulated by renin-angiotensin system and kidneys sensing the volume and pressure of water
-feedback loop of sodium and potassium levels not directly regulated by pituitary
-major target tissues are kidneys, colon, salivary glands, and sweat glands
cortisol
-downstream ACTH production by pituitary and synthesized in different ways
-different enzymatic deficiencies can cause classic biochemical blocks
-circulating primarily bound to cortisol-binding globulin and can circulate to different cells in the body
-critical for fight/flight response, settings where bP is low, and severe levels of stress
when do cortisol levels fluctuate?
-in the circadian rhythm —> increase in the early morning that peaks then dissipates over the course of the day
-rhythm can be disrupted in people who are jet lagged or nightshift workers
cortisol metabolism
-after release from the cortisol cells, the majority of cortisol enters the circulation and binds mainly to CBG and to a lesser extent albumin
-about 10% of the circulating cortisol is free
-bound hormones are biologically inactive, while the free or unbound fraction is active
-cortisol is metabolized in the liver
addison disease
-adrenal insufficiency resulting in decreased levels of glucocorticoids, mineralcorticoids, androgens, and secondary elevation in ACTH
-adrenal cortex becomes infiltrated with lymphocytes and eventually atrophic
-autoimmunity is the most common cause of addison disease
what are the many organs that are targets of glucocorticoids?
liver, adipocytes, muscles, bones, gut, kidney, skin, heart, mood, appetite, granulocytes, lymphocytes
H-P-gonadal
hypothalamus secretes GnRH on the pituitary, which secretes FSH and LSH —> target gonads to produce eggs or sperm
glucose homeostasis and diabetes
-increase in glucose after meals during the day and influx of nutrients stimulate insulin secretion that moves glucose into cells
-in diabetes, difficult to maintain normal fasting blood glucose and excursions of blood glucose are pronounced —> excursions are occurring despite robust or larger increases of insulin
glucose sensing by beta cells leads to physiologic insulin secretion
-glucose transporter in beta cell is not regulated —> allows equilibrium of glucose intra- and extra-cellularly
-within the beta cell, glucose is phosphorylated by glucokinase, which traps glucose and in cellular respiration you get increase in ATP
-ADP as glucose goes up —> leads to depolarization of membrane to trigger ca2+ gated channel to trigger insulin exocytosis
-rapid insulin release upfront is first basilar response then longer chronic release
insulin structure
-pre-pro-polypeptide that looks back on itself with intramolecular disulfide bonds —> insulin pre-pro-polypeptide is cleaved and released in equimolar levels in C peptide
“basal-bolus” insulin therapy with long and rapid-acting analogs
-in clinical setting, type I or II diabetes we can recapitulate correct insulin response but difficult to do —> modify insulin peptide or add a fatty acid
-be more rapid acting you can alter the order of lysing the proline residues or add an aspartic acid residue to change interaction with subcutaneous tissue and causes it to be released quickly into the bloodstream
-for long acting, you can tether into the interstitial space with long fatty acid
-insulin action occurs on metabolic responsive tissues like the liver, muscles, and fat
insulin action on classically responsive tissues
-nutrient-rich —> release more insulin —> shut down catabolic processes and increase anabolic ones
-fasting state —> decline in insulin —> mobilizing or consuming stored precursors
insulin action on glucose uptake in fat and muscle @ cellular level
@ cellular level, tissues with insulin receptors through signal cascade will trigger downstream effect on anabolism and trigger translocation of glucose transporters from intercellular pools —> plasma membrane —> allow response to insulin
parathyroids and bones regulate calcium homeostasis
parathyroid glands —> thyroid glands —> regulate calcium and phosphate reabsorption from bone and gut
almost all organs have “non-classical” endocrine functions
-molecularly you will see every tissue and cell type is secreting substances in endocrine fashion
-endocrine aspects to tissues and cells like in the gut and the heart produces secreted peptides plus the brain regulates the heart
Ex. placenta has all types of peptides and nuclear receptor hormones
