Exam 4 Practice Questions Flashcards
Hypothalamic-pituitary-adrenal axis hormones released at nerve terminals:
- Vasopressin (ADH)
- Oxytocin.
What is the target tissue of vasopresssin?
Kidney and vascular tissue.
What is the target tissue of oxytocin?
Mammary gland and uterus.
Vasopressin and oxytocin are released from the _________ _________, at the ______ ________.
- Posterior pituitary.
- Nerve terminals.
Hormones released from the anterior pituitary:
- Growth hormone. (GH)
- Prolactin (PRL)
- Thyrotropin (TSH).
- Follitropin (FSH).
- Luteotropin (LH).
- Corticotropin (ACTH).
- Melanocyte stimulating hormone. (MSH).
Hormones released from the anterior pituitary gland are released into the __________.
Blood.
Paraventricular nuclei (PVN) primarily secrete _____________.
Oxytocin.
Supraoptic neuclei (SON) primarily secretes _____________________, also called ______________________.
- Anti-diuretic hormone (ADH).
- Arginine vasopressin.
What is it called when oxytocin and vasopressin accumulate in axon dilations?
Herring bodies.
Oxytocin and vasopressin are transported along the _______ together, via the carrier protein _________.
- Axons.
- Neurophysin.
What is the hypothalamic-hypophyseal portal system?
Blood flow between the hypothalamus to the anterior pituitary, that transports hormones.
What is the hypothalamic-hypophyseal tract?
A nervous tract between the paraventircular nuclei (PVN) and supraoptic nuclei (SON), to the herring body, that stimulates release of hormones into the blood at the posterior pituitary.
Of GnRH, LH, and FSH, which hormone will start the pulsatile wave of release?
GnRH - gonadotropin releasing hormone. This makes sense because LH and FSH are both gonadotropins, that need GnRH to stimulate their release.
True or false: Hormone release is hgihly regulated by a intricate system of negative feedback controls, but does not utilize positive feedback mechanism.
FALSE - Hormone release can have positive and negative feedback.
What are the functions of oxytocin?
- Allows people to experience love and trust.
- Can be used for many other things - such as muscle maintenance and repair.
A mutation in the oxytocin receptor may cause:
An inability to trust people - single forever.
In normal function, what occurs when ADH binds to vasopressin II receptor?
- cAMP-mediated translocation of aquaporin-2 to the apical surface of the cell.
- Subsequent increase in water permeability.
If there is an abscence of ADH, and water cannot be reabsorbed due to a lack of aquaporins on the apical cell surface, what will occur?
- Hyperosmality.
- Hypernatremia - high plasma Na+ conc.
- Polyuria - excessive urination.
- Polydipsia - Increased thirst.
How does alcohol inhibit ADH?
- Alcohol will inhibit the release of ADH from the supraoptic nuclei (SON).
- Alcohol acts as an antagonist for ADH in the kidneys, preventing aquaporins from binding to the collecting ducts.
During pregancy, the placenta will secrete _______________, causing breakdown of ______, resulting in inability to reabsorb H2O.
- Vasopressinase.
- ADH/vasopressin.
SIADH stands for:
Syndrome of Inappropriate ADH secretion.
What condition is considered to be the opposite of diabetes insipidus?
SIADH
Diabetes insipidus is caused by:
A lack of ADH, causing decreased ability to reabsorb water.
In SIADH, patients will have abnormally _____ levels of ___________.
- High.
- Vasopressin/ADH.
In SIADH, what occurs due to high levels of ADH?
- Very highly urine osmolatlity.
- Kidneys salvage inappropriately lareg volumes of H2O.
- Blood becomes hypo-osmolar.
- Plasma Na+ drops (hyponatremia).
What are the 2 mechanism by which hyponaturemia occurs?
- Dilution of plasma.
- Increased excretion of sodium by the kidneys.
Growth hormone induces growth via ____________ _________ ________, produced by ______________.
- Insulin-like growth factor-1 (IGF-1).
- Hepatocytes.
What stimulates the release of growth hormone from acidophils?
GHRH - Growth hormone-releasing hormone.
What two thing may inhibit the release of growth hormone?
- Somatostatin.
- High blood glucose.
True or false: IGF-1 stimulates growth of long bones by stimulating hyperplasia of chondrocytes at the epiphyseal plate.
TRUE.
What is the most common cause of hypersecretion of growth hormone?
An adenoma of the anterior hypophysis AKA anterior pituitary.
What are the two most common consequences of hypersecretion of growth hormone?
- Gigantism in children.
- Acromegaly in adults.
True or false: A mutation in the acidophil-interacting protein is a predisposing factor to hypersecretion of growth hormone.
FALSE: A mutation in the aryl hydrocarbon-interacting protein is a predisposing factor to hypersecretion of growth hormone.
________ ________ has an acute anti-insulin metabolic effect and chronic growth-promoting effects.
Growth hormone.
What is the mechanism of the acute anti-insulin effects of growth hormone?
Binding of growth factor to a tyrosine kinase receptor on the target tissue - causing downstream effects.
Antagonizes the hepatic and peripheral effects of insulin on glucose metabolism, as a defense against hypoglycemia.
What is the major source of IGF-1 in the circulation?
The liver.
What happens to IGF-1 as it travels through the blood?
IGF-1 travels bound to IGF-binding protein.
What happens in the bone from growth hormone?
Growth hormone, parathyroid hormone, and estrogen all stimulate further release fo IGF-1.
A drop in serum levels of IGF-1 or glucose stimulates:
Release of growth hormone, via GHRH.
Function of IGF-1:
Stimulates the growth of long bones by stimulating the hypertrophy of chondrocytes at the epiphyseal plates.
In endochondral ossification, the growth in length of the long bones depends on what?
Interstitial growth of the epiphyseal growth plates.
What are the epiphyseal growth plates made of?
Hyaline cartilage.
In endochondral ossification, the _________ ____________ _________ forms as a result of vascularization of the bone collar, and _____________ of the diaphyseal chondrocytes.
- Primary ossification center.
- Hypertrophy.
Explain the mechanism by which the epiphyseal growth plates form:
- Blood vessels enter the newly formed medullary cavity of the bone.
- Vessels grow toward either epiphyseal ends of the bone.
- Subsequent formation of the epiphyseal growth plates.
True or false: In adults, the bones reach maximum length and width, so the epiphyseal growth plates become ossified - forming the epiphyseal line.
TRUE!
__________ zone of the bone: Primitive hyaline cartilage responsible for growth in length of the long bones.
Reserve zone.
___________ zone of the bone: Proliferating chondrocytes line up as vertical and parallel columns of cells.
Proliferating zone.
____________ zone of the bone: Apoptosis of chondrocytes and calcification of the matrix occurs here.
Hypertrophic zone.
_____________ zone of the bone: Blood vessels penetrate the calcified septa, carrying osteoprogenitor cells with them.
Vascular invasion zone.
Layers of the periosteum:
- Fibrous layer - Outer layer, with fibroblasts and dense irregular C.T.
- Osterogenic layer - inner layer, contains progenitor cells that develop into osteoblasts.
What are the four major zones of endochondral ossification?
- Reserve zone.
- Proliferative zone.
- Hypertrophic zone.
- Vascular invasion zone.
What is the primary stimulator of chondrocyte activity and bone growth?
IGF-1
Other than IGF-1, what can stimulate chondrocytes and bone growth?
- Insulin.
- Thyroid hormones.
_____ _________ influence a steep amount of bone growth in adolescence.
Sex Steroids - by stimulating secretion of GH and IGF-1.
Sex steroids stimulate:
Growth promotion via secretion of GH and IGF-1.
While sex hormones can stimulate bone growth, they can also stop bone growth by:
inducing ossification of the epiphyseal plates - epiphyseal closure.
Indian Hedgehog Homolog (IHH) protein regulates:
Growth of epiphyseal plate hyaline cartilage.
Indian Hedgehog Homolog (IHH) proteins are secreted by:
Proliferating chondrocytes.
True or false: IHH inhibits the secretion of parathyroid-related peptide (PTH-rP) by the chondrogenic layer of the perchondrium - effectively regulating epiphyseal plate growth.
FALSE - IHH stimulates the secretion of parathyroid-related protein (PTH-rP) by the chondrogenic layer of the perichondrium - effectively regulating epiphyseal plate growth.
What is the function of Parathyroid-related peptide (PTH-rP)?
parathyroid-related peptide stimulates chondrocyte proliferation and delay hypertrophy - maintaining the amount of proliferating chondrocytes.
How do we balance between proliferating anf hypertrophy of chondrocytes?
Feedback loop between IHH and PTH-rP.
What condition in mice will a lack of IHH protein expression result in?
Dwarfism and a lack of endochondral ossification.
Bone growth for ______ of a bone requires an osteoclastic ______, followed by a chondrocyte ______.
- Length.
- Chase.
- Run
Explain the steps of growing the length of a bone:
- The ossification front invades and destroys chondrocytes - as it passes thru the area.
- Calcification of the cartilage matrix occurs, surrounding hypertrophic chondrocytes.
- Proliferating chondrocytes in front from the ossification front increase length of the cartilage.
Where do osteoclasts come from, and what is their function?
- Osteoclasts are derived from monocytes.
- Osteoclasts enlarge the bone marrow.
Cbfa1/Runx2 stimulates what?
The transition of mature chondrocytes to hypertrophic chondrocytes.
What inhibits the transition of mature chondrocytes into hypertrophic chondrocytes?
Sox9.
Where do osteoprogenitor cells come from, and what is their function?
- Derived from the perivascular mesenchyme.
- Go to the primary ossification center to generate osteoblasts.
Function of an osteoblast:
To deposit osteoid along the calcified cartilage of the bone, this osteoid will become calcified. They travel with the ossification front.
_________ chase and invade the zone of bone that was previously occupied by __________.
- Osteoclasts.
- Chondrocytes.
True or false: As the bone grows in length, new layers form on the outer portions of the diaphysis via appositional growth.
TRUE!
Ossified bone, that has undergone initial formation via endochondral or intramembranous ossification, can only grow by:
Appositional growth.
Cycles of appositional deposition and resorption will result in:
Increase in bone width, diameter, and thickness.
What will happen to the marrow cavity during appositional cycles of bone deposition and resorption?
The marrow cavity enlarges by removal of bone at the endosteal surface.
Periosteum:
A membrane that covers the outer surface of all bones, except at the joint of long bones.
Endosteum:
A membrane that lines the inner surface of all bones.
New Haversian system bone is added _________ the __________ by its osteogenic layer.
- Beneath.
- Periosteum.
How will ossification present when IGF-1 is absent?
There will be a massive reduction in the width of the hypertrophic zone, causing a decrease in longitudinal bone growth.
_________ ________ AKA ________-_______ ________ Is an autosomal recessive disorder that is caused by an insensitivity to growth hormone (GH).
- Laron syndrome.
- Laron-type dwarfism.
True or false: Laron-type dwarfism is associated with mutations in the gene for the IGF receptor.
FALSE: Laron-type dwarfism is associated with a mutation in the gene for the GH receptor.
Which condition will present with very low levels of IGF-1 and its carrier protein - IGF-binding protein 3?
Laron syndrome.
Clinical manifestations of Laron Syndrome?
- Short stature.
- Resistance to diabetes and cancer.
_______ _______ - there will be a shortened epiphyseal growth plate.
Laron syndrome.
What is the most common disease of the growth plate, and a major cause for dwarfism?
Achondroplasia.
_______________ is an autosomal dominant disorder, where homozygous cases are fatal.
Achondroplasia.
What pathological factor causes achondroplasia.
A mutation in the fibroblast growth factor receptor 3 gene, causing impaired proliferation of cartilage at the growth plate and preventing endochondral ossification.
In which condition, does the likelihood of the etiological mutation increase with paternal (dad) age?
Achondroplasia.
Clinical manifestations of achondroplasia include normal sized of enlarged ________ _______, shortened ______ and _____, skeletal abnormalties, and normal levels of ________ and ______.
- vertebral column.
- Arms and legs.
- Growth hormone (GH) and IGF-1.
True or false: Achondroplasia is a disease that is caused by defect in paracrine cell signalling.
TRUE.
In achondroplasia, there is a _________ in the proliferation of chondrocytes in the growth plate.
Reduction.
In achondroplasia, which receptor is in a constant state of activation, limiting growth?
FGFR3
In a healthy individual, the FGFR3 receptor will:
inhibit cartilage proliferation, in appropriate amounts.
True or false: In achondroplasia, both longitudinal and appositional growth are disrupted.
FALSE - Only longitudinal growth is. Appositional growth will be normal, and bones will have a normal thickness with a shortened length.
What is the normal pattern of growth hormone (GH) secretion?
GH is released into the blood in pulses throughout the 24 hour sleep-wake cycle, with peak secretion happening during the 1st two hours of sleep.
When there is a growth hormone (GH) secreting adenoma on the pituitary gland, what happens to GH release?
GH release will not have a pulsatile pattern, and will secrete high levels of GH at all hours.
What is the major consequence of a GH secreting adenoma on the pituitary gland, in children.
Gigantism.
What is the major consequence of a GH secreting adenoma in the anterior pituitary gland in adults?
Acromegaly.
In a glucose GH test, patients with somatotropic adenomas will show:
GH levels that are not suppressed by glucose consumption, and may even rise. In this case IGF-1 can be measured instead of GH.
In a healthy individual, the glucose GH test will show:
An hour after the patient has eaten glucose, there will be a suppression of GH levels to 2 ug/L or less.
What type of tumor is often associated with excess secretion of GH?
Functional somatotroph adenomas.
Pre-pubertal GH tumors to the pituitary gland, may impair:
gonadotrophs and epiphyseal plates will continue to grow abnormally.
True or false: Nonfunctional pituitary adenomas do not cause any distortion to anatomy.
FALSE - Nonfunctional pituitary adenomas distort overlying brain tissue.
Excess GH in adults causes ___________.
Acromegaly.
Excess GH in children causes ___________.
Gigantism.
Gigantism will affect which tissues?
- Cause linear and periosteal growth of long bones.
- Cartilage, membranous bones, and soft tissues.
What disease is due to post-pubertal GH excess?
Acromegaly.
Acromegaly will affect which tissues?
Long bones do not grow in length, but cartilage and membranous bones grow abnormally, causing soft tissues to become enlarged.
What will the labs of someone with acromegaly present?
- Increased GH.
- Increased IGF-1.
- Increased insulin.
- Increased calcium and phosphorus ions.
- Increased glucose.
- Abnormal (increased or decrease) ACTH.
Which hormone regulates the plasma concentration of free calcium ions?
Parathyroid hormone (PTH)
Functions of calcium:
- Enzyme activation/inactivation.
- Intracellular second messenger.
- Exocytosis.
- Nerve conduction.
- Muscle contraction.
- Structural integrity of the bone.
True or false: Since parathyroid hormone regulates the concentration of free calcium ions, it will also regulate enzyme activation/inactivation and structural integrity of the bone.
TRUE!
99% of total body calcium is found in the _________.
Bones
Explain how parathyroid hormone increases calcium ion influx into the plasma:
- Directly - by stimulating bone and kidneys to increase influx into plasma.
- Indirectly - Increases absorption from the gut.
How does parathyroid hormone decrease the concentration of phosphate in the plasma?
By inhibiting the renal tubular reabsorption of phosphate, increasing its excretion in urine.
Location of the parathyroid glands:
Posterior surface of the thyroid, between the thyroid capsule and cervical C.T.
May also be found in the mediastinum or neck.
The ______ _______ _______ differentiates into the inferior parathyroid gland and thymus.
3rd branchial pouch.
The _______ _________ ________ differentiates in to the superior parathyroid glands and the ultimobranchial body.
4th Branchial pouches.
What are the two cell types of the parathyroid gland, and what is their function?
- Chief cells - secrete parathyroid hormone.
- Oxyphil cells - a transitional form of chief cells.
What is DiGeorge Syndrome, and what is it caused by?
- An absence of the parathyroid glands or thymus - associated with hypocalcemia and birth defects.
- Is caused by the deletion of a piece of chromosome 22.
Which disease is caused by a “catch-22”
DiGeorhe Syndrome (velo-cardio-facial syndrome) - causes by deletion of a portion of chromosome 22.
In which condition, are infections common in children due to problems with T-cell mediated response, because of a loss of the thymus?
DiGeorge Syndrome (velo-cardio-facial-syndrome)
What is a major consequence of thymus loss or hypoplasia?
A loss of T-cell maturation, impairing T-cell mediated immune responses.
__________ cells: Contain an abundance of mitochondria, which make the cell acidophillic staining in H&E. Additionally, does not have rough ER or golgi apparatus.
Oxyphil cells.
True or false: Chief cells are responsible for PTH secretion, while oxyphil cells have no relevant secretions.
TRUE!
_____________________ is activated by a reduction in serum calcium, and causes subsequent increase in PTH secretion to increase serum calcium.
Ca2+-sensing receptor (CaSR)
Pre-pro-parathyroid hormone is a precursor to the parathyroid hormone, that is synthesized in the:
Rough endoplasmic reticulum of chief cells.
When extracellular concentrations of calcium ions is _______, PTH synthesis will be ________.
- low.
- Increased.
What will be inhibited by an increase in the concentration of extracellular calcium ions?
parathyroid hormone synthesis and release.
When calcium binds to CASR, it will cause inhibition of ________________ and stimulate ____________________ action.
- Adenyl cyclase.
- phospholipase C (PLC)
When calcium binds to CASR, what will be the end responses?
- Suppression of PTH gene expression.
- Acceleration of intracellular degradation of PTH.
- Inhibition of PTH release.
What are the two methods to suppress PTH gene expression and synthesis?
- Calcium binding to CaSR.
- 1,25 - dihydroxy vitamin D by causing up-regulation of CaSR gene expression and directly inhibiting PTH gene.
How does activation of phospholipase c (PLC) cause inhibition of release of granules containing parathyroid hormone?
- Activation of PLC causes the production of secondary messengers (IP3, DAG, PIP2)
- IP3 increases levels of cytosolic calcium - from intracellular storage.
- DAG stimulates protein kinase C (PKC) activity.
- inhibited release of granules containing parathyroid hormone.
A high concentration of _________ __________ will inhibit the fusion of vesicles containing PTH.
cytosolic calcium
What kind of mutation will result in the prevention of chief cells to sense an increase in serum calcium?
Inactivating mutations of one allele of CaSR.
True or false: If chief cells are unable to sense an increase in serum calcium levels, there will be a lack of parathyroid hormone.
FALSE - there will be an excess of PTH.
Familial benign hypercalcemia - cause, effects, and treatment:
- Cause: Inactivating mutation of alleles of the CaSR gene.
- Effects: Skeletal changes + unremitting hyperparathyroidism.
- Treatment: Need to do a parathyroidectomy in newborns with this condition.
What will occur if chief cells assume that serum calcium levels are high, when it is not? What is it caused by?
- A decrease in parathyroid hormone production.
- Can cause hypocalcemia, with seizures.
- Treatment: Supplemental PTH.
- Cause: An activating mutation in the CaSR gene.
True or false: Autoimmune diseases that effect the calcium-sensing receptor (CaSR) can either inactivate CaSR or activate CaSR
TRUE.
Increased PTH will cause:
Increased serum calcium.
Decreased serum calcium vs increased serum calcium:
- Decreased serum calcium: No activation of CASR, leading to PTH release, which causing increase in serum calcium.
- Increased serum calcium: Calcium binds CaSR, which inhibits PTH release, causing a decrease in serum calcium.
Action of PTH in the bones:
Promotes demineralization and calcium release by acting on stromal osteoblasts in the bone marrow - causing a net resorption.
Action of PTH in the kidneys:
- Stimulates reabsorption of calcium in the proximal tubules of the renal cortex in the distal nephron.
- Stimulates synthesis 1,25-dihydroxy-vitamin D3 (activated calcitriol).
Activated 1,25-dihydroxy-vitamin D3 (calcitriol) will cause what to happen?
Facilitates increased Ca2+ absorption in the intestinal mucosa.
PTH causes calcium re-absorption in which organs?
- Bone marrow.
- Kidneys.
- Intestines.
Plasma vitamin D will be converted to 25-OH D via ______________ in the kidney, and then further converted to 1,25 OH2D via ______________ in the kidneys.
- 25-hydroxylase.
- 1-hydroxylase.
Plasma 1,25-OH2D is the form of calcium that is:
Reabsorbed as calcium and phosphate from the GI tract into the blood.
Another name for calcitriol?
1,25-dihydroxycholecalciferol.
True or false: Calcitriol causes reabsorption of calcium in the kidneys, intestines, and bones. While 1,25-Dihydroxycholecalciferol causes utilization of calcium.
FALSE: They are the exact same thing.
What will have a negative feedback on the liver, preventing over-action of vitamin D3 when it is too high in concentration?
25-Hydroxycholecalciferol.
Via PTH both __________ and __________ will be resorpbed from the bones.
Calcitriol and cortisol.
Via PTH which form of calcium will be reabsorbed by the kidneys?
Calcitonin.
Via PTH which form of calcium will be reabsorbed from the small intestines?
Calcitonin.
What is calcium homeostasis?
Calcium balance in the body - total intake and output.
What are the 4 stages of bone remodeling? What is the general goal?
- Activation.
- Resorption.
- Reversal.
- Formation.
Replacement of old bone with newly formed bone, by a resorption + production sequence.
In bone remodeling osteoclasts do ____________, while osteoblasts _______________.
- Resorption.
- Reversal.
True or false: Bone remodeling is a continuous process throughout life, occuring at random location.
True!
What is function of Bone remodeling?
To create an optimum bone strength by repairing microscopic damage and maintain calcium homeostasis.
________-__________: Microscopic damage to bone tissue.
Micro-cracking.
Activation stage of Bone remodeling:
Osteoclast precursors are recruited, and differentiate into osteoclasts. Active osteoclasts will start bone remodeling toward the outer lamella.
What are the residuals from remodeling of the osteon called?
Interstitial lamellae.
Resorption phase of Bone remodeling:
More recruitment of osteoclasts occurs, and resorption expands past the original osteon.
Reversal stage of Bone remodeling:
Osteoblasts Revere the resorption by secreting osteoid. There will be a “cement line” indicates a boundary of new lamella and old lamella. Reversal continues toward the center of the osteon.
Formation phase of bone remodeling:
Osteoblasts continue laying down new bone, and become trapped within the mineralized bone matrix. This causes osteoblasts to become osteocytes.
In which condition is more bone resorbed than produced, due to dysfunction of bone remodeling?
Osteoporosis.
What allows for communication between osteoblasts and osteoclasts?
Hormones, cytokines, growth factors, and signal-transducing molecules.
Systemic factors and local cytokines can controlled the coupled process of bone remodeling, these are deposited in the:
bone matrix.
Osteoprogenitor cells will proliferative and mature into _________________, via ______, ______, _______.
- Active osteoblasts.
- Runx2, Wnt, and bone morphogenic protein (BMP).
Surface osteoblasts are mediators of:
Osteoclastogenesis.
Step 1 of osteoclastogenesis:
A monocyte derived from bone marrow reaches an area of bone formation, and a receptor for M-CSF is expressed on it.
Step 2 of osteoclastogenesis:
Monocytes becomes a macrophage. M-CSF bind to its receptor on the macrophage, and induces expression of RANK for its ligand RANKL on the surface of osteoblasts.
Step 3 of osteoclastogenesis:
The osteoblast-expressed transmembrane protein ligan RANKL, binds to the osteoclast RANK receptor. The cell commits to to osteoclastogenesis. The monocyte becomes a multinucleated osteoclast precursor.
Step 4 of osteoclastogenesis:
A resting (non-functional) osteoclast uncouples from the osteoblast.
Step 5 of osteoclastogenesis:
The maturation of osteoclasts is complete when the sealing zone and ruffled border appear. Bone resorption can occur.
For maturation from a resting osteoclast to a function osteoclast to occur, what must we use?
ayb3 (alpha-gamma-beta-3) integrin. Which causes formation of the sealing zone.
What mechanism allows an osteoblast to regulate the population of functional osteoclasts?
Osteoblasts will present a RANKL decoy protein called osteoprotegerin, which blocks RANKL from binding to RANK - stopping osteoclastogenesis.
RANKL receptor is on the ____________, while the RANK ligand is on the ______________.
- Osteoblast
- Osteoclast.
True or false: PTH - parathyroid hormone stimulates osteoclastogensis.
TRUE: PTH stimulates M-CSF and RANKL expression, in turn stimulating osteoclastogenesis.
Which condition will impair the balance between osteoprotegerin and RANK, which allows for osteoclastogenesis to occur?
Hypercortisolism.
Vitamin D and PTH can both stimulate:
Osteoblasts to do secretions that benefit osteoclastogenesis.
In the osteoclast, what prevents excessive rise in intracellular pH?
A chloride shift.
Explain the anatomy of a mature osteoclast:
- Actin filaments accumulate to form a sealing zone, where the plasma membrane is close to the bone.
- Has a ruffled border.
- Sealing zone is made up of actin filaments, ayb3 Integrin, and osteopontin.
By which mechanism do osteoclasts break down mineralized bone?
- Carbonic anhydrase II will create H+ ions from CO2 and H2O.
- H+ is released into the howship’s lacuna by an H+-ATPase pump to create an acidic environment. (lower than 4.5) - This degrades mineralized tissue.
- Cathepsin K is release into Howship’s lacuna to degrade exposed organic material. - This degrades collagen and noncollagenous proteins.
Subosteoclastic compartment is another name for:
Howship’s lacuna.
What will occur due to abnormal function of osteoclasts?
- Absent bone remodeling.
- Can result in Osteopetrosis - where the bone is abnormally brittle and the marrow canal is not developed.
Which cell is considered “a one-cell epithelium”?
Osteoclasts.
What is the cause of osteopetrosis?
A mutation in the M-CSF gene, because without M-CSF there cannot be normal osteoclast differentiation.
What will occur due to a deficiency in carbonic anhydrase II?
Marble bone disease - a variant of osteopetrosis.
Symptoms of marble bone disease?
- Exophthalmos.
- Deafness.
- Facial paralysis.
- Speech impediment.
- Small size of medullary canal of the bones.
Cancer metastasis to bone is extremely frequent in which types of advanced cancer? Which type of cancer is it less common in?
- Breast and prostate cancer.
- Lung cancer.
Describe an osteolytic bone metastases:
Activation of excessive osteoclast number and activity.
Describe osteoblastic bone metastases:
A result of osteoblast and osteoclast activation or excessive bone deposition.
List the factors that account for frequent bone metastasis:
- Tumor cells have humoral factors that stimulate osteoclast formation.
- Tumor cells arrive in bone marrow often, cause it is an area with high blood flow.
- Tumor cells stimulate neovascularization and promote more tumor growth, causing more release of humoral growth factos, which are locally liberated by osteolysis.
What are the consequences of tumor cells causing neovascularization?
Further tumor growth, where bone is a site for growth factors they get liberated there, causing bone metastasis.
In osteolytic bone disease, metastatic tumor cells release factors that stimulate ______________ _____________ and _________________
- Osteoclastic.
- Recruitment.
- Differentiation.
What is the step-by-step mechanism of osteolytic bone disease?
- Metastatic tumor cells release factors that stimulate osteoclastic recruitment and differentiation.
- Osteoclasts break down bone unnecessarily.
- Bone resorption causing the release of growth factors that stimulate tumor growth.
- As the tumor grows, it produces substances that increase osteoclast-mediated bone resorption.
What is the step-by-step mechanism of osteoblastic bone disease?
- Metastatic tumor cells release growth factors that promote the activity of osteoblasts and osteoclasts.
- Excessive new bone formation occurs around the tumor cell deposits.
- Osteoclastic activity releases growth factors that stimulate tumor cell growth.
- Osteoblastic activity releases unidentified osteoblastic growth factors that also stimulate tumor cell growth.
Osteosclerosis:
When excessive new bone formation occurs around tumor-cell deposits - a consequence of osteoblastic bone disease.
Parathyroid hormone-related peptide (PTHrP) is encoded is encoded by what type of gene?
A gene that is completely distinct from the PTH gene.
What peptide can cause hypercalcemia in certain malignancies?
PTHrP. - Parathyroid hormone related peptide.
PTHrP is made in a variety of ________ and __________ tissues, while PTH is only made in the __________ _______.
- Normal and malignant.
- Parathyroid gland.
True or false: PTH and PTHrP are encoded by different genes and found in different tissues, but have the same function on the kidney and bones.
TRUE.
__________ ____________ is a clonal proliferation of neoplastic plasma cells, or their precursors that are committed to plasmacytic differentiation.
Multiple myeloma.
Multiple myeloma plasma cells will produce pro-osteoclastogenic (induces osteoclastogenesis) cytokines. These include:
- IL-3
- Macrophage inflammatory protein-1 alpha and beta.
- Tumor necrosis factor alpha.
How does multiple myeloma affect the bones?
it forms multiple foci of plasma cell proliferation in the bone.
In multiple myeloma, only _____________ bone lesions develop.
osteolytic.
In most cancers, bone metastasis can have both ___________ and ___________ forms.
Osteolytic and osteoblastic.
How do multiple myeloma plasma cells inhibit new bone formation?
Multiple myeloma cells produce Dickkopf-1 (DKK1) which inhibits beta-catenin-dependant Wnt signalling, ultimately inhibiting osteoblast activity.
How do multiple myeloma plasma cells activate osteoclasts?
Multiple myeloma plasma cells produce RANKL, which binds to RANK, ultimately activating osteoclast activity.
______________: When bone resorption exceeds bone deposition, and bone bone matrix and minerals are lost.
Osteoporosis.
Which hormone can normally inhibit excess production and action of osteoclasts, while also enhancing osteoblast activity? Preventing excess resorption of bone.
Estrogen.
A lack of estrogen will cause:
- Increased osteoclastic activity.
- Decreased osteoblastic activity.
- Increased resorption of bone.
- Decreased formation of new bone.
What puts older women at a higher risk of developing osteoporosis?
Estrogen deficiency post-menopausal.
How does hypercortisolism lead to osteoporosis?
An increase in glucocorticoids increases the production of RANKL, and decreases production of osteoprotegerin, ultimately increasing osteoclastogenesis and causing more bone resorption.
What is the most common metabolic abnormality of bone?
Osteoporosis.
In osteoporosis, there will be a loss of bone matrix and minerals, anatomically this will present as:
- Decreased bone mass and density.
- Decreased thickness of the cortical and trabecular bone.
Why is osteoporosis more common in women than in men?
- men have a greater starting bone mass, taking longer to develop osteoporosis.
- Postmenopausal decrease of estrogen in women.
What falls under primary osteoporosis?
- Common type.
- Idiopathic type in children + young people.
- Post-menopausal (mmost common)
- Senile type.
What causes fall under secondary osteoporosis?
- Underlying disease - like hypercortisolism or renal disease.
- Drugs - heparin.
- Hypogonadism - caused by hypopituitarism.
- Malnutrition - anorexia.
- Space travel - lack of stress on the bones in no gravity.
What are preventative measures for osteoporosis?
- Ca+ and Vitamin D supplements.
- No smoking - it inhibits osteoblast activity.
- Weight baring activity.
Treatments for osteoporosis:
- Biphosphates - to inhibit bone resorption.
- Antibodies against RANKL - Inhibits osteoclastogenesis.
- Calcitonin or estrogen supplementation - inhibits osteoclast activity.
In __________ __________ __________, normal handling of calcium and phosphate is disrupted, causing osteoporosis and calcifications.
Chronic renal disease.
What is the primary cause of secondary hyperparathyroidism?
End-stage renal disease.
In __________ there will be a lack of reabsorption of calcium, causing ___________. This leads to overproduction of ______, ultimately causing differentiation and multiplication of ___________. This is the process by which renal disease leads to osteoporosis.
- Nephropathy.
- Hypocalcemia.
- Parathyroid hormone PTH.
- Osteoclasts.
In failing kidneys, they cannot excrete __________ properly, or convert enough __________ to its active form.
- Phosphate.
- Vitamin D.
In which condition does insoluble calcium phosphate form and cause hypocalcemia, leading to excess PTH release, and eventually leading to formation of osteoporosis?
End-stage renal disease.
True or false: Chronic renal disease —> secondary hyperparathyroidism —-> Osteoporosis.
TRUE.
Inadequate dietary vitamin D3 or excessive phosphorus in the diet can cause:
long-term over stimulation oof the parathyroid glands - AKA nutritional secondary hyperparathyroidism.
Bone ossification includes ______, _________, and ___________ of bone.
Growth, modeling, and remodeling.
Which two bone diseases have a defect in the mineralization of the bone matrix?
- Rickets.
- Osteomalacia.
What separates rickets and osteomalacia?
- Rickets is seen in children.
- Osteomalacia is seen in adults.
In which type of rickets is it due to a mutation in the receptor for calcitriol.
Hereditary vitamin-D resistant rickets.
A parathyroid adenoma can cause hyperparathyroidism, this can clinically present as:
- Broken bones - osteitis fibrosa cystica.
- Kidney stones - Nephrolithiasis and nephrocalcinosis.
- Depression and seizures.
- Gallstones, acute pancreatitis, and peptic ulcers.
What is one of the primary consequences of hypoparathyroidism?
Hypocalcemia that causes sodium channels to open in cell membranes, leading to spontaneous firing of action potentials causing spasms - this is called hypocalcemic tetany.
What is the cause for hypocalcemic tetany?
Hypoparathyroidism.
What is a developmental cause for hypoparathyroidism?
DiGeorge Syndrome - where parathyroid glands and thymus are completely absent.
What are the genetic causes for hypoparathyroidism?
Activating mutations of CaSR, so chief cells assume serum calcium is elevated when it is not, ultimately decreasing PTH.
What is the autoimmune causes for hypoparathyroidism?
Targeting antibodies toward CaSR which constantly activates it, decreasing PTH.
Accidental removal of the parathyroid glands during a thyroidectomy can cause:
Iatrogenic hypoparathyroidism.
What cells produce calcitonin? Where are they found?
Neural crest-derived parafollicular C-cells, found in the medulla of thyroid gland.
An increase in _____________ will cause increased release of calcitonin from C-cells.
Serum calcium.
True or false: The main function of calcitonin is to inhibit the effects of parathyroid hormone.
FALSE - The main function of calcitonin is to antagonize the effects of parathyroid hormone.
Calcitonin will decrease ______ ________, and increase _________ _______ ________.
- Bone resorption.
- Renal calcium excretion.
What genes and tissues is calcitonin expressed b?
By a gene located on chromosome 11p, and is also expressed in the tissues as calcitonin gene-related peptide (CGRP).
Calcitonin gene-related peptide (CGRP) is associated with:
Neurotransmitter and vasodilator functions, involved in testicular descent.
Hyper-calcitoninemia is caused by:
- Nutritional disorders - High Ca+ causing mineral imbalance.
- Osteopetrosis - In the vertebrae and tibia of bull.
- Thyroid neoplasia - In humans is medullary thyroid carcinoma, in bulls it is ultimobranchial tumors.
What are the steps of T3 T4 production and release?
- Thyroid stimulating hormone binds to the TSH receptor on the thyroid cell.
- An ATP-driven sodium-iodide symport brings those ions into the cell.
- This activates thyroid peroxidase (TPO), which oxidizes iodide and attaches it to the rings of tyrosine in thyroglobulin. Making MIT or DIT. In the thyroid follicle.
- MIT or DIT rings are added to another DIT, forming T3 and T4 within thyroglobulin.
- T3 and T4 within thyroglobulin are endocytosed back into the follicular cells.
- Lysosomal enzymes release T3 and T4 from thyroglobulin.
- T3 and T4 are secreted into the blood.
True or false: Much more T3 is released into the blood than T4.
FALSE: much more T4 is released into the blood than T3.
Once lysosomal enzymes break up the thyroglobulin to release T3 and T4, what happens with remainders of thyroglobulins?
The amino acids get recycled for more thyroglobulin synthesis.
The iodide-sodium cotransporter on the follicular cells is _____ ________.
ATP driven.
Which thyroid hormone is less potent, has a longer half-life, and takes 11 days to have peak effect?
T4
Which thyroid hormone is very potent, with a short half-life, and a rapid effect - taking 3 days to show peak.
T3
At the tissues, what does T4 get transformed into? Using what enzyme?
- Active T3.
- 5’-monodieodinase.
What are the overall effects of thyroid hormone?
Increase metabolic rate and O2 consumption.
How does thyroid hormone increase O2 consumption and metabolic rate?
- Increasing # of mitochondria.
- Increasing # of Respiratory enzymes.
- Increasing the number of sodium potassium ATPase pumps.
- Increase number of other enzymes.
Why is dietary selenium needed for T3 production?
Selenium-containing deiodinases are involved in T4 metabolism.
The process of breaking down T4 into T3 is called:
Deiodination - cause it uses deiosinases.
What effect does thyroid hormone have on the lungs, the heart, and the kidney?
LUNG: Increased ventilation and increased CO2.
HEART: Increased cardiac output.
KIDNEY: Increased urea, and increased renal function.
Hyperthyroidism will cause ______________, while hypothyroidism will cause ________________.
- Oligomenorrhea - infrequent periods.
- Menorrhagia - heavy periods.
Hashimotos disease, surgery, lithium drugs, radioactive iodine treatment, and dietary iodine deficiency can all cause:
Hypothyroidism.
____________ __________ = Autoimmune lymphocytic thyroiditis.
Hashimotos disease.
In fetal development, hypothyroidism can result in __________, which is caused by _________ ______________.
- Cretinism.
- Maternal hypothyroidism.
At what point in fetal development does T4 production by the fetus become significant?
18-20 weeks.
In preterm births, from a mother with hypothyroidism, the baby can have:
Neurodevelopmental disorders
Hypothyroidism can result in ____________ in adults, which is just a deficiency of _____________.
- Myxedema.
- Thyroid hormone.
In which condition do we see a goiter develop due to an increase in TSH?
Hypothyroidism.
Hypothyroidism can present at the heart with:
Bradycardia - a slow pulse.
What would be seen in a lab for primary hypothyroidism?
Decreased T4 and increased TSH.
Hypothyroidism is far more common in ________.
women.
What is cretinism?
Hypothyroidism during fetal development that results in stunted growth and mental retardation.
In which hypothyroidism associated condition will you see course skin and a puffy face due to fluid retention?
Myxedema
What is goiter?
A lack of negative feedback on the anterior pituitary (due to hypothyroidism) causes uninhibited TSH secretion - presenting as an enlarged thyroid gland.
True or false: Goiter can occur in both hyperthyroidism and hypothyroidism.
TRUE!
_____________ ___________: Hypothyroidism caused by thyrotoxicosis caused by disruption of thyroid follicles.
Hashimoto thyroiditis.
In Hashimoto thyroiditis (hashitoxicosis) T3 and T4 levels will be _________, TSH will be __________, and radioactive iodine uptake is __________.
- Increased.
- Diminished.
- Decreased.
What initiates thyrocyte destruction in hashitoxicosis?
T-cell sensitization to thyroid antigens - thyroid peroxidase and thyroglobulin.
What are the 3 proposed mechanisms for how thyrocytes are destroyed in hashitoxicosis?
- CD8+ cytotoxic T-cell destruction.
- By activated macrophages, causing thyrocyte injury.
- Antibody-dependent cell-mediated cytotoxicity.
In 75% of cases, hyperthyroidism is caused by _______ _________.
Graves disease.
________ ________: An autoimmune disease where autoantibodies called thyroid-stimulating immunoglobulins (TSIs) are attacking the TSH receptors. This will present as goiter, exophthalmos, tachycardia, warm skin, and fine finger tremors.
Graves disease.
What two factors may cause hyperthyroidism?
- Graves disease.
- Nodular goiter or hyper-functioning adenoma of the thyroid or pituitary gland.
Clinical manifestations of hyperthyroidism include:
- Exophthalmos - bulging of the eyes.
- Tachycardia - rapid pulse.
- Goiter - enlargement of the thyroid gland.
- Decreased TSH.
- Increased T3 and T4.
- Increased TSIs.
True or false: thyroid-stimulating immunoglobulins in Graves disease are produced by thyrocytes and are derived from T-cells that target the thyroglobulin.
FALSE: Autoantibodies are produced by plasma cells, and derived from T-cells targeting TSH receptors.
How do thyroid-stimulating immunoglobulins stimulate the thyroid.
TSIs bond to the TSH receptor, and mimic the effect of TSH, stimulating cAMP production - causing thyroid follicular cells to become columnar, and produce excessive thyroid hormone into the blood.
What is the action of inflammatory cells in graves disease?
To produce cytokines in the stroma of the thyroid gland, that stimulate further thyroid cytokine production, which reinforces the thyroid autoimmune process.
What is Graves’ orbitopathy, and how does it manifest?
Edema and fibrosis of the extraocular muscles and an increase in orbital adipose and connective tissue. Caused by cytokines released from T-cells stimulating adipogenesis from preadipocyte fibroblasts, and anti-TSHr lgs binding to TSH receptor on fibroblasts in the retorbulbar tissue.
Fibrosis of extraocular muscles in graves disease can cause:
Exophthalmos - bulging of the eyes.
How does tachycardia in hyperthyroidism occur?
- T3 goes to nucleus of a cardiocyte, binding to its nuclear receptors, and then binding to thyroid hormone response element in target genes.
- Stimulation of phospholamban, a protein involved in the release and uptake of calcium into the sarcoplasmic reticulum.
- Increased diastolic function occurs in patients.
_________ _________: a life threatening complication of hyperthyroidism/thyrotoxicosis. Infection or physical manipulation of the thyroid gland can make this happen - causing fever, agitation, confusion, and irregular heartbeats leading to heart failure.
Thyroid storm.
How can we prevent thyroid storm?
Suppressing thyroid function with anti-thyroid drugs (thionamides).
Treatment for thyroid storm:
- Beta blockers to inhibit B-adrenorecpetors that are increased by increased thyroid hormone.
- Drugs such as propylthiouracil (PTU) to block production of thyroid hormone.
- Sodium iodide - to block released of already synthesized thyroid hormone. Iodide also causes a decrease in thyroid hormone synthesis.
What methods can we use to clinically assess thyroid disease states?
- Fine needle aspiration - for cytology, to determine if a thyroid nodule is benign. (most are)
- Hormonal evaluation - tells us about a primary, secondary, or tertiary condition.
- Radioactive iodide uptake - a measure of thyroid function, where a hyperactive thyroid would take up increased amounts of it.
A lose dose detection of radioactive iodide uptake can tell us about:
- If a thyroid nodule is working and benign, or if the nodule is non-functioning and malignant.
- If hyperthyroidism is due to thyroiditis (minimal uptake) or graves disease (increased uptake).
A high dosage of radioactive iodide uptake may be used for:
Treating hyperthyroidism - but it may kill the thyroid.
___________ carncinoma originates from thyroglobulin-producing follicular cells in the thyroid gland.
Papillary carcinoma.
___________ carcinoma originates from the parafollicular C-cells.
Medullary thyroid carcinoma.
Glucocorticoids are produced by which system?
Hypothalmo-pituitary-adrenal cortex axis.
Physical stress is managed by the __________ __________ system, while emotional stress is managed by the _________ system.
- Physical stress = reticular activating system.
- Mental stress = limbic system.
What does the hypothalmus do for the hypothalmo-pituitary-adrenal cortex axis?
Make corticotropin releasing hormone (CRH)
What does the anterior pituitary do in the HPACA?
Corticotropin release, stimulated by corticotropin releasing hormone (CRH). The main one is ACTH.
What does the zona fasciculata in the adrenal cortex do in the HPACA?
Produce cortisol - 15-30 mg/day. 75% of it bound to cortisol-binding globulin, 15% bound to albumin.
What hormone has a negative feedback on the hypothalamus and anterior pituitary?
Cortisol.
Mineralcorticoids are produced by which system?
Renin-angiotensin-aldosterone system.
The hypothalmo-pituitary-axis regulates _____________, while the RAAS regulates _____________.
- Glucocorticoids.
- Mineralcorticoids.
Steps of RAAS:
- Angiotensinogen in converted to angiotensin 1, via renin released from juxtaglomerular cells in the kidney.
- Angiotensin 1 is converted to angiotensin 2, using angiotensin converting enzyme (ACE) from the lungs.
- Angiotensin acts on the kidneys, hypothalamus, and vascular smooth mucle, to increase blood pressure.
- Angiotensin 2 also acts on the adrenals to increase aldosterone secretion, which increases kidney reabsorption of sodium.
_____ _____________ requires perfect timing of fetal cortisol and androgen secretion.
Sexual differentiation.
Aldosterone stimulates ___________ ____________ and ___________ _________ in the distal convoluted tubule of the kidney.
- Sodium reabsorption.
- Potassium excretion.
The synthesis of aldosterone happens in the _____ ________ of the adrenal cortex, while the synthesis of cortisol occurs in the _____ _________.
- Zona glomerulosa.
- Zona fasiculata.
True or false: Aldosterone synthesis is only stimulated by angiotensin II, causing an increase in extracellular Na+.
FALSE - it can be stimulated by angiotensin II and minorly by ACTH - causing an increase in extracellular Potassium ions.
What is the action of aldosterone?
To act on renal tubules, increasing sodium reabsorption and water retention - water follows salt.
True or false: Increased levels of cortisol or glucocorticoid drugs often take on mineralcortocoids activity, as ACTH can cause production of aldoterone.
TRUE.
On the apical membrane of a renal tubular cell, sodium moves ______ the cell, while on the basolateral membrane, sodium moves into the ___________.
- Into.
- Peritubular capillary.
Cortisol can have an inhibitory effect on arachidonic acid derivatives, as it can stop the conversion of _______________ to ____________ OR the conversion of _______________ to ________________.
- Membrane phospholipids to arachidonic acid.
- Arachidonic acid to prostaglandins.
Effects of cortisol:
- Anti-inflammatory effects.
- Catabolic actions on most tissues.
- Increases blood pressure.
- Weakens bones by stimulating osteoclasts.
Which organ does cortisol have an anabolic effect on and why?
The liver - as it will promote glucogenesis and gluconeogenesis - why it is called a glucocorticoid.
How does cortisol increase blood pressure?
It stimulates activity of the sympathetic nervous system, by increasing the expression of adrenergic receptors in the tissues.
High levels of cortisol will also have mineralocorticoid action on the kidneys - acting similarly to aldosterone. Stimulating renal reabsorption of sodium.
Cortisol will reduce intestinal absorption of ________, which leads to an increase in ________, causing ultimate bone break down. Cortisol also damages bone by stimulating ____________.
- Calcium.
- Parathyroid hormone (PTH)
- Osteoclasts.
In the adipose tissue, cortisol has the following metabolic effects:
- Inhibits glucose uptake.
- Stimulates lipolysis.
In the skeletal muscle, cortisol has the following metabolic effects:
- Inhibits glucose uptake.
- Stimulates glycogenesis.
- Stimulates protein breakdown (catabolism for gluconeogenesis)
In the liver, cortisol has the following metabolic effects:
- Stimulates glucogenesis.
- Stimulates gluconeogenesis.
- Potentiates actions of epinephrine and glucagon.
Genomic actions of glucocorticoids are:
- Mediated by cytosolic glucocorticoid receptors (GR).
- Change gene expression.
- Do transactivation - through the interaction of GC-GR with a positive GC response element (nGRE).
- DO transrepression - through the interaction of GC-GR with a negative GC response element.
- SLOW CHANGES IN GENE EXPRESSION THAT ALTER CELLULAR FUNCTION.
Non-genomic actions of glucocorticoids are:
- Rapid changes in cellular function, that do not involve changes in gene expression.
- Mediated by cytosolic GR, plasma membrane GR, or non-specific effects caused by direct GC interactions.
- Results in: Transmembrane currents, phosphorylation events, calcium level changes.
What is the rate-limiting step in steroid synthesis?
StAR - steroidogenic acute regulatory protein mediating transport of cholesterol from outer to inner mitochondrial membranes, where P450scc enzyme is.
All steroids are derived from _________.
Cholesterol.
Aldosterone is a steroid made by the conversion of ________________ using __________ __________, which is stimulated by angiotensin II. This occurs in the ________________.
- Corticosterone.
- 18-hydroxylase/aldosterone synthase.
- Zona glomerulosa of the adrenal cortex.
Explain the process of cortisol synthesis:
- Cholesterol is converted to 17-hydroxypregnenolone.
- Using 3beta-HSD, t is further converted to 17-Hydroxyprogesterone
- That is then converted into 11-deoxycortisol, using 21a-hydroxylase.
- Finally, 11-deoxycortisol is converted into cortisol using the enzyme 11b-hydroxylase.
- This final conversion happens in the zona fasciculata of the adrenal cortex.
How are estrogen steroidal hormones made? (estrone and estradiol)
In the zona reticularis, dehydroepiandrosterone is converted to androstenedione. Androstenedione can either be directly converted to estrone, using aromatase enzyme that is mediated by FSH. or it can be first converted to testosterone, and then converted to estradiol via the action of aromatase alone.
Using 5a-reductase, testosterone can be converted into ____________.
Dihydro-testosterone.
When in development is the HPA axis fully functional?
When genitalia differentiate.
Enzymatic mutation in the adrenal steroidogenic pathway cause:
Secondary effects on sex steroid production, and can drastically affect sex differentiation.
Enzyme mutation in the ______ ___________ will cause andrenogenital syndrome.
Zona reticularis.
Enzyme mutation or tumor in the zona fasciculate will cause:
Hypercortisolism - cushing syndrome.
Enzyme mutation or tumor in the zona glomerulosa can cause:
Hyperaldosteronism.
Enzyme mutations in the medulla of the adrenal glands will cause:
Pheochromocytoma.
What occurs due to a deficiency of 21a-hydroxylase?
CONGENITAL ADRENAL HYPERPLASIA.
There will be elevated ACTH, causing a shift toward production of sex hormones and masculinization.
This is the most common form of CAH
What occurs due to a deficiency of 11-hydroxylase?
CONGENITAL ADRENAL HYPERPLASIA.
Decreased cortisol, aldosterone, and corticosterone.
Increased deoxycorticosterone, causing fluid retention and hypertension - as well as masculinization.
In both 21/11 hydroxylase deficiency, there is impaired synthesis of __________ and _________. But there is an increase in __________
- Cortisol and aldosterone. (glucocorticoids and mineralcorticoids)
- Sex steroids.
How does the hyperplasia occur in congenital adrenal hyperplasia?
A deficit of hydroxylases causes no production of cortisol to occur, so the loss of negative feedback, causes increased ACTH secretion, which is responsible for the hyperplasia.
What is the most common form of congenital adrenal hyperplasia?
21-hydroxylase deficient.
Congenital adrenal hyperplasia causes salt loss due to lack of aldosterone, this leads to vomiting, weight loss, adrenal crisis, and failure to thrive. This secondary condition is called:
- Salt wasting.
- Hyponatremic encephalopathy - specifically when sodium levels get so low that water swells in the brain.
Explain virilizers of congenital adrenal hyperplasia:
Adrenogenital syndrome - cirilization continues after birth, causing rapid bone growth.
In females this presents as:
1. Pseudohermaphrodites.
2. Progressive masculinization.
3. Hirusitism.
4. Epiphyseal closure.
5. Period issues.
In males this presents as:
1. Normal appearance at birth.
2. Somatic and sexual precocity.
In 21-hydroxylase deficiency labs will show:
- Hyponaturemia - low sodium
- Hyperkalemia -
- Hypoglycemia -
- Elevated 17a-OHp
Classic 21-hydroxylase deficiency typically causes ___________ to raise.
17a-OH P blood levels.
True or false: Salt wasting congenital adrenal hyperplasia patients have higher 17a-OH P levels than non-salt wasting.
TRUE
_______________ deficiency induces hyperaldosteronism. This condition notably causes _____________.
17a-hydroxylase.
hypertension.
17a-hydroxylase deficiency causes:
elevation of production of mineralcorticoids, causing excess sodium retention and fluid retention leading to hypertension. With phentypically female, but an inability to mature sexually.
Primary adrenocortical insufficiency is caused by:
Hyposecretion of adrenal cortex, due to autoimmune disease, genetic factors, infections, or injury.
What is a condition that is a primary adrenocortical insufficiency due to injury?
Addison disease.
What are the causes of secondary adrenocortical insufficiency?
- Inadequate secretion of ACTH.
- Iatrogenic - prolonged exogenous corticosteroid therapy.
What causes tertiary adrenocortical insufficiency?
Lack of CRH secretion from the hypothalamus. Also injury or disease.
Manifestations of addisons disease:
- Hyperpigmentation.
- Depression.
- Lethargy.
- Weight loss.
- Period loss.
6 Muscle atrophy.
Labs for addisons disease will present as:
- Decreased corticosteroids.
- Increased ACTH.
- Increased potassium.
- Decreased Sodium.
- Decreased chloride.
- Decreased bicarbonate.
- Decreased glucose.
In addisons disease, __________ __________ and _____________ are missing.
Glucocorticoids, mineralcorticoids, and adrenal androgens.
What causes hyperpigmentation in addison disease:
When ACTH is cleaved, the melanocyte-stimulating hormone is also released, and binds to the melanocortin 1 receptor on melanocytes, causing hyperpigmentation.
Primary hypercortisolism:
Is caused by hyperfunction of adrenal cortex.
Secondary hypercortisolism:
Is caused by hyperfunction of ACTH secreting cells.
Is cushing disease.
Tertiary hypercortisolism:
Is caused by CRH hypersecretion.
_________ __________: A term used to describe clinical features of hypercorticism, regardless of cause. Often presenting as adiposity, diabetes, infertility, psychological problems, osteoporosis and muscle wasting, skin changes, and elevated blood pressure.
Cushing syndrome.
In tertiary hypercortisolism caused by an ACTH-secreting pituitary adenomas are ___________ __________ to suppression of CRH.
Partially responsive.
In ___________ ___________ in the lung and kidneys, that secrete active ACTH will not respond to _________ ___________ ___________.
- Paraneoplastic (ectopic) tumors
- Normal feedback mechanism.
The hypothalmo-pituitary axis is responsive to high _________.
Cortisol.
In hypercortisolism, any secreted ACTH will only be coming from:
Ectopic tumors (paraneoplastic tumors)
In chronic corticoid therapy, _______ secretions can be very low, causing _________ _________.
- ACTH.
- Adrenal atrophy.
What is a common iatrogenic cause for Cushing syndrome?
Chronic treatment with high doses of glucocorticoids.
When diagnosing Cushing syndrome, we must confirm increased cortisol levels by:
- An increased urinary free cortisol.
- Failure of serum cortisol to be supressed in response to low dexamethosone.
Urinary free cortisol tells us about:
total blood cortisol and free blood cortisol combined.
What is the first step in seeing that a patient does not have obseity, and has cushings disease?
Free cortisol in the urine.
What is the purpose of the low-dose dexamethasone supression test in cushings disease?
Dexamethasone suppresses the normal morning rise of cortisol in the blood, so a patient with Cushings disease would not show suppression of cortisol.
What is the purpose of a high-dose dexamethasone suppression test in Cushing disease?
Dexamethosone in high doses suppresses increased levels of ACTH by 50%. In patients with Cushing disease due to a pituitary adenoma do not show suppressed ACTH produced by the malignant non-pituitary tumors.
Which condition causes hypertension, pituitary adenoma, hirtsutism, insulin spill over, and adrenal hyperplasia or tumors?
Cushing diseas.
Why is aldosterone not elevated in Cushing disease?
Cause the RAAS system requires mineralcorticoids (angiotensin II), but in Cushing syndrome we only see hyperactivty HPA axis, not RAAS.
True or false: Most adrenocortical carcinomas will produce a hormonal syndrome.
FALSE: Most will NOT.
Hyperaldosteronism is an adrenocortical disorder of the ________ ________________.
Zona glomerulosa.
Hyperaldosteronism can induce hypertension in ______ ________, when a pituitary adenoma causes hyposecretion from the ___________.
- Conn syndrome.
- Kidney.
Hyperaldosteronism can induce hyper tension in _________ __________ ________________, by have a blockage of blood supply to the kidney.
Secondary hyper-reninemic hyperaldosteronism.
Regardless of the cause, hyperaldosteronism that induces hypertension will _______ and _______ rentention and ________ excretion.
- Sodium and water.
- Potassium excretion.
Secondary hyperaldosteronism will be caused by increased ________ secretion from the kidney, which causes in increased production of ______________, which eventually leads to hypersecretion of ______________.
- Renin.
- Angiotensin II.
- Aldosterone.
Primary hyperaldosteronism is caused by:
a pituitary tumor.
Aldosterone acts which structure, and promotes what?
Acts on the distal renal tubuule and promotes sodium exchange for the potassium lost in the urine.
True or false: Both primary and secondary hyperaldosteronism will be result in decreased renin production.
FALSE: Only primary will show decreased renin production, while secondary shows increased renin production.
_____________________: a disease of the adrenal medulla, where active tumors secrete epinephrine and norepinephrine - causing hypertension and sympathetic effects.
Pheochromocytoma.
25% of pheochromocytomas will be:
familial.
What gene mutations will cause familial pheochromocytoma?
VHL, RET, NF1, SDHB, and SDHD.
What type of tumor is seen in pheochromocytoma?
A tumor of multiple endocrine neoplasia syndrome, type IIA and type IIB.
What signs would indicate that a patient has pheochromocytoma?
Hypertension is diagnosed in a young person, or if paroxyms of hypertension are precipitated by exercise, anesthesia, or palpation of the abdomen.
How is pheochromocytoma treated?
Surgical removal of the tumor, with great prognosis because most tumors are benign.
_____________ _____________: The most common cause of primary adrenal insufficiency in developed countries.
Autoimmune adrenalitis.
What is autoimmune polyendocrine syndrome type 1 (APS 1)?
Shows chronic mucocutaneous candidiasis and abnormalities of the skin, teeth enamel, and nails. In association with a combination of organ-specific autoimmune disorders.
Caused by mutations in the autoimmune regulator gene (AIRE) on chromosome 21q22.
Mutation of what gene is associated with APS 1?
Autoimmune regulator (AIRE) gene on chromosome 21q22
What is autoimmune polyendocrine syndrome type 2 (APS 2)?
A condition that starts in early adulthood and presents as a combination of adrenal insufficiency and autoimmune thyroiditis or type 1 diabetes.
What is unique about APS 2, in comparison to APS 1?
APS 2 does not have mucocutaneous candidasis, ectodermal dysplasia, and autoimmune hypoparathyroidism.
Not linked to one gene.
What is the most common form of polyglandular failure syndrome?
Autoimmune polyendocrine syndrome type 2.
APS 1 is also known as:
Whitaker syndrome.
APS 2 is also known as:
Schmidt syndrome.
___________ _________ __________: is a group of genetically inherited diseases that result in proliferative lesions (hyperplasia or tumor) of multiple endocrine organs.
Multiple endocrine neoplasia (MEN)
What are the distinct features of multiple endocrine neoplasia (MEN)
- Tumors occur at young age.
- Tumors arise in multiple endocrine organs.
- Tumors are typically multifocal.
- Tumors are usually preceded by an asymtpomatic stage of endocrine hyperplasia.
- Tumors are more aggressive and recur in a higher proportion.
________: Caused by a germline mutation of MEN1 tumor suppressor gene, which normally enhances signaling through TGF-beta to decrease cell proliferation and enhance p53 function.
Multiple endocrine neoplasia 1 (MEN1)
What structures are involved in MEN 1?
parathyroid gland, pancreas, pituitary gland.
_________: is caused by germ line mutations of RET protooncogene, encoding tyrosine kinase receptor.
Multiple endocrine neoplasia 2.
What structures are involved in MEN IIA?
Thyroid, parathyroid, adrenal medulla.
What structures are involved in MEN IIB?
Thyroid, adrenal medulla, and GI ganglia.
MEN II patients are treated with ______________ ___________, because there is high chance of them developing ____________ ___________ ___________ a deadly cancer of C-cells
- Prophylactic thyroidectomy.
- Medullary thyroid cancer.
What is the most common site of gastrinomas in MEN-1:
Duodenum.
True or false: Patients with MEN I are at high risk of carcinoid tumors, thyroid and adrenocortical adenomas, and lipomas.
TRUE.
MEN II loss-of-function mutations of RET results in:
Intestinal aganglionosis AKA Hirschsprung disease.
Sustaining cells are somatic cells that maintain sexual function in adults. In women (XX) these are called _____________ cells, in men (XY) these are called ____________ cells.
- Granulosa cells.
- Sertoli cells.
Endocrine cells in sexual function are ___________ cells. In women (XX) these are called _________ cells, in men (XY) these are called __________ cells.
- Somatic.
- Theca cells.
- Leydig cells.
Germ cells are haploid gametes, in women these are called __________, and in men these are called _____________.
- Oogonia (XX) or Ova (x)
- Spermatogonia (XY) or sperm (X or Y)
All steroids are generated from ____________.
Cholesterol.
How do we make Dihydrotestosterone?
Testosterone is converted using 5alpha-reductase in the peripheral tissues.
True or false: both estrone and estradiol are made by converting androstenedione using FSH and aromatase.
FALSE:
Estrone: Made from converting androstenedione to estrone using FSH and aromatase.
Estradiol: Androstenedione in converted to testosterone using Oxidoreductase. Testosterone is then converted to estradiol using aromatase - NO FSH Needed.
The type of steroids a cell makes is dependant on:
Types and concentration of enzymes a cell has, and its specific steroidal triggers.
True or false: Meiosis occurs in germ cells and sustaining cells, but does not occur in sexual endocrine cells.
FALSE: Meiosis only occurs in germ cells - sustaining cells and endocrine cells are somatic always.
When does meiosis end in sperm?
Is completed before sperm are released via ejaculation.
When does meiosis end in the egg?
After fertilization - it needs sperm borne soluble factors to activate the oocyte.
The gonads and internal reproductive tract develop from what 3 sources:
- The mesothelium - lining the posterior abdominal wall.
- The mesenchyme - which underlies the mesothelium.
- The primordial germ cells.
Another name for coelomic epithelium:
Mesothelium.
Another name for mesenchyme:
Intermediate mesoderm.
The ______________: grows to form the primordium of the future gonads, and the genital or gonadal ridge. From this epithelium primary sex cords will be able to penetrate the mesenchyme.
Mesothelium.
A bulge of sex tissue medial to the mesonephros:
Genital or gonadal ridge.
From the mesothelium development we will get:
An indifferent gonad that consists of a medulla and cortex.
In XX embryo, what will develop from the gonadal medulla and cortex?
The ovaries.
In the XY embryo, what will develop from the gonadal medulla and cortex?
The medulla will form the testis, and the cortex will regress.
The ___________ ___________ gives rise to the nephrogenic cord, which eventually turns into the ____________ (cranial segments), _____________ (intermediate segments), and _____________ (caudal segments).
- Intermediate mesoderm.
- Pronephros.
- Mesonephros.
- Metanephros.
True or false: The mesonephroi gives rise to the internal reproductive tracts and urinary system - either the wolffian duct, or mullerian ducts.
TRUE>
The Wolffian (______________) ducts develop in the ______ week of development.
- Mesonephric.
- 4th.
The Mullerian (_________________) ducts develop in the _____ week of development.
- Paramesonephric.
- 6th.
What gives rise to gametes?
Primordial germ cells.
Formation of differentiated somatic cells from a gamete step-wise:
- Differentiated somatic cells occur very early.
- They migrate from the ectoderm (3rd week) via the extraembryonic endoderm 5th week)
- They go into the genital/gonadal ridge - which is the future gonads.
If the __________________ is present, the primordium of the testis evolves in week 7 of development.
Y chromosome.
If no Y chromosome is present, what will happen to the primordium of the ovary?
In week 8 of development, the ovaries will evolve from its primordium.
__________ __________: Longitudinal outgrowths along the surface of the mesonephroi within the coelomic cavity.
Genital ridges.
_______ colonizes the genital ridges after leaving the hind gut via the dorsal messentery. At this point, genital ridges are _______ and can interact with _________ __________ ______ to differentiate into testes or ovary.
- Primordial germ cells (PGC)
- Bipotential.
- Coelomic epithelia cells.
True or false: Inducing transdifferentiation of the gonads will require the deletion of many genes.
FALSE: transdifferentiation of the gonads only requires deletion of a single gene.
The development of the gonad of the opposite sex is __________ _________ through out life.
Actively repressed.
If the Dmrt1 gene is deleted in mice, what will occur?
Feminization.
What two genes help fetal development of male sexual anatomy?
Sry acts on SOX9, which occurs at developing Sertoli cells.
What genes will help during fetal development for female sexual differentiation?
Wnt4 and Rspo1 will act on B-catenin, which will occur at developing granulosa cells.
What gene will help maintain male gonad development, during post-natal development?
Dmrt1 acting on Sertoli cells.
What gene will help maintain female gonad development, in post-natal development?
Fox/2 acting on granulosa cells.
If the R-spondin1 (RSPO1) gene is mutated, what may occur?
Female-to-male (XX) sex reversal - male sex development with XX chromosomes. Due to RSPO1’s relationship to Wnt4 to B-catenin signalling, stopping female sex differentiation.
The blind end of the caudal hind-gut forms the ________. During gestation, a septum grows downward, causing this structure to form the ________ posteriorly and the __________ _______ anteriorly.
- Cloaca.
- Rectum.
- Urogenital sinus.
The cloaca divides into the:
Rectum and urogenital sinus.
Before sexual differentiation occurs, what will form around the cloacal membrane?
A genital tubercle, and two genital swelling (which turn into the scrotum or labia)
What gives rise to the nephrogenic cord? And what will the nephrogenic cord give rise to?
- The intermediate mesoderm.
- The mesonephros, pronephros, and metanephros.
In mammals, the pronephros and mesonephros are temporary ___________ __________, and the metanephros becomes the __________ ________.
- Excretory organs.
- Permanent kidney.
Up to the 7th week of development, the internal genital organs contain both sexs via two canal systems called:
- Mesonephric (wolffian) duct.
- Paramesonephric (mullerian) duct.
Which type of the two duct systems and external genitalia will develop based on the:
Presence or absence of functional fetal testes.
What forms the uterovaginal canal?
The fusion of the Mullerian ducts. The uterovaginal canal gives rise to the uterus, cervix, and upper two thirds of the vagina.
What forms the male phenotype - testis and penile genitalia?
Differentiation of the Wolffian (mesonephric) duct, and regression of the Mullerian duct.
The ___________ ________ develops in tissue of the posterior wall of the urogenital sinus, and surrounds the prostatic urethra at the base of the urinary bladder.
Prostate gland.
The _________ tubercle develops around the 4th week, and will differentiate into the _________ or __________ by week 9.
- Genital tubercle.
- Clitoris.
- Penis.
In males, what is required for development of the penis, scrotum, and prostate:
- Dihydrotestosterone.
- A functional androgen receptor.
What is required for female development of the uterus, clitoris, and vagina?
An absence of testosterone.
Wnt4 gene plays a role aswell.
What is hypospadias of the penis?
Irregular urethral opening of the penis - Either opening on glandular, penile, or penoscrotal tissue.
What is epispadias of the penis:
Urethral opening of the penis is on top of the penis - this occurs at perineal tissue.
The process that occurs during normal or hypospadia development of the penis occurs via:
Epithelial fusion events.
What are the 3 phases of testicular descent?
- Abdominal translocation.
- Transinguinal migration.
- Inguinoscrotal migration.
What occurs in the 1st step of testicular descent - abdominal translocation:
The gubernaculum gradually expands and invades into the abdominal musculature, until the testis is positioned near the inguinal ring.
The abdominal translocation portion of testicular descent is dependant upon:
Insl3 to stimulate the growth of the gubernaculum.
What occurs in the 2nd step of testicular descent - Transinguinal migration:
The gubernacular bulb enlarges, which dilates the inguinal canal - allowing for the testis and epididymis to pass through.
True or false: The transinguinal migration portion of testicular descent can become defective due to Insl3 or testosterone changes.
FALSE - not true lol.
What occurs during the 3rd step of testicular descent - Inguinoscrotal migration:
The gubernacular bulb continues to grow toward the bottom of the scrotum, until the vaginal tunic attaches scrotal wall.
What is necessary to masculinize structures during the inguinoscrotal migration step of testicular descent:
Testosterone.
Testosterone has a negative action on the __________ __________, allowing it to regress. It also has a positive effect to masculinize the ________________ __________.
- Cephalic ligament.
- genitofemoral nerve.
Which protein will provide directional guidance to the gubernaculum?
Calcitonin gene-related peptide.
__________ _________: Failure of noral posterior anchoring of the gubernaculum, epididymus, and testis. This is also called the “bell clapper deformity”.
Testicular torsion.
Testicular torsion will cause:
- The spermatic cord to twist.
- Venous drainage to become obstructed.
- Necrosis and infarction.
Impaired testicular descent processes result in:
Cryptorchidism - which is undescended/ectopic testes.
Cryptorchidism (undescended testis) will impair:
- Spermatogenesis.
- Leydig cells to produce testosterone and respond to hormonal stimuli.
What are the causes of isolated cryptorchidism:
- Congenital defects.
- Acquired.
Syndromic cryptorchidism is caused by:
Hypothalamic or pituitary abnormalities - such as Kallmann syndrome, isolated hypogonadotropic hypogonadism, and Prader Willi syndrome.
OR
Disorders of testicular testosterone secretion - like kinefelter’s syndrome, testicular dysgenesis syndrome, noonan syndrome, and congenital adrenal hyperplasia.
OR
Congenital disorders that result in poor development of abdominal musculature - gastroschisis, omephalocele, bladder exstrophy, and prune belly syndrome.
OR
Disorders of testosterone action - androgen insensitivity syndrome.
Cryptorchidism is associated with a higher risk of ________ ________ and ___________.
- Testicular cancer.
- Infertility.
Intrauterine environment is often impactful on the pathogenesis of ___________ ___________.
Isolated cryptorchidism.
True or false: The etiology of cryptorchidism is not understood at all.
True!
What gene actively maintains the female gender in the ovaries?
Foxl2.
What gene actively maintains the male gender in the testis?
Dmrt1.
Sertoli cells secrete _____________ __________, which causes regression of the Mullerian duct - Causing the ________ reproductive development.
- Anti-Mullerian Hormone (AMH>
- Male.
Leydig cells secrete __________________, and _______________ that helps with transabdominal testis descent.
Insulin-like peptide (INSL3) and testosterone.
The conversion of Testosterone to dihydrotestosterone, using 5a-reductase, will assist in:
Prostate and external genitalia development.
The conversion of testosterone to estradiol will utilize:
Aromatase.
What does estradiol do in the fetal brain of males?
Musculinizes brain tissue.
How is a male baby protected from circulating estrogen from the mom. having brain exposure?
By the usage of the alpha-fetoprotein, which binds strongly to the estrogen, preventing it from working in the brain.
For a male to develop normally we need:
- Anti-mullerian hormone (AMH)
- Conversion of testosterone to dihydrotestosterone.
- Insulin-like peptide (INSL3)
- The functional receptors for the above.
SRY gene will express int he urogenital ridge, and cause:
Testis development.
If there is no SRY, there will be:
No testis.
For a female to develop normally, we need:
- Variety of growth factors.
- Rspo1 acting through the Wnt4 and beta-catenin pathway.
In the developing female, paramesonephric ducts _____________, while mesonephric ducts _________.
- Develop (mullerian duct).
- Regress (Wollfian duct)
Testosterone will masculinize the brain, despite:
Chromosomal sex.
Sexually dimorphic nucleus (SDN):
Is the preoptic portion of the brain, that is larger in males than females.
In women, we can increase the size of the SDN by injecting them with testosterone.
How does fetal testosterone effect anogenital distance?
- Testosterone causes the proliferation of sertolis cells - increasing size of testis.
- Masculinization of the reproductive tract occurs, in the a certain window of time.
- Elongation and growth of the penis occurs.
- Penile growth causes expansion of anogenital distance.
- The masculinization programming window determines penis length and anogenital distance.
Phthalates (from plastic, etc etc) is negatively correlated with ______________.
Testosterone.
High concentrations of diethylhexyl phthalate in the first trimester, are inversely associated with:
Anogenital distance - High phthalates = small anogenital distance.
Anogenital distance is a good biomarker for:
Prenatal androgen status.
_________________: Most common sexual differentiation disorder. Extra X chromosome. This is due to seminiferous tubular dysgenesis.
Klinefelter’s syndrome.
___ _________: XX chromosomes, but male presentation.
Sex reversal.
In female sex reversal, there are normal testis and genitalia, but 10% have _____________
Hypospadia.
___________ _________: Lack of two sex chromosomes, just X. Presents as oocyte degeneration leaving streak gonads at birth.
Turner’s syndrome.
Describe pure gonadal dysgenesis:
Similiar to turner’s syndrome but with a lack of somatic effects. Just needs estrogen and progesterone therapy.
In _____ _________________, both ovarian and testicular tissue in the form of a ovotestes will go through internal differentiation.
True hermaphroditism.
Overview of Klinefelters’s syndrome:
- 47 chromosomes - XXY.
- Some genes escape X inactivation. Does show barr bodies.
- Rate: 1 in 500 - most frequent cause of hypogonadism.
- May show cryptorchidism + azoospermia.
- Micropenis occurs.
- Small firm testis - with loss of sertoli cells, showing increased FSH and estrogen, but decreased testosterone and LH.
- Nodules form on leydig cells.
- Gynecomastia.
Information on Turner’s syndrome:
- 45 chromosomes, X0, with no barr bodies.
- Most babies spontaneously abort.
- Shows streak ovaries - no oogenesis, with risk of dysgerminoma.
- Decreased estrogen, increased FSH and LH.
- Most common cause of amenorrhea.
- Presents as short stature, webbed neck, and wide spacing of nipples.
Which condition shows short stature, streak ovaries, and a lack of germinal cells, but does not have somatic abnormalities?
Gonadal dysgenesis.
_________________________: A state where the gonads are of one sex, but there are contradictions in morphological criteria of sex.
Pseudohermaphroditism.
True or false: In a woman with pseudohermaphroditism, the person is genetically female, but has testis instead of ovaries. But still presents with normal secondary sex charecteristics.
FALSE: The person will be genetically female and have ovaries, but will have male secondary sex characteristics. Vice versa for males.
What is the most common cause of pseudohermaphroditism in women? What about rare causes?
- Common: Congenital adrenal hyperplasia.
- Rare: Maternal ingestion of androgens, or virilizing tumors in the mother.
What are some causes of pseudohermaphroditism in men?
- Leydig cell aplasia.
- Disorders of testosterone and dihydrotestosterone biosynthesis.
- Androgen receptor defects.
- Impaired anti-mullerian hormone (AMH) production or action.
How does 3b-HSD deficiency cause male pseudohermaphroditism?
- Without 3b-HSD we cannot do glucocorticoid, mineralocorticoid, androgen, or estrogen synthesis.
- A lack of testosterone allows for genetically male to develop female secondary sex characteristics.
- There will also be no cortisol or aldosterone synthesis - causing other health issues.
- Adrenal hyperplasia occurs.
How does a mutation in 17b-HSD cause male pseudohermaphroditism?
- Blocks effective testosterone production, and elevates estrogen levels.
- Increases FSH and LH.
- Most common cause of male pseudohermaphroditism.
Defective 5a-reductase will cause what changes to gender?
Genetically male person will present female (male pseudohermaphroditism) as there will be no conversion of testosterone to dihydrotestosterone - which helps with male secondary sex development.
Male pseudohermaphroditism can be caused by a deficiency of:
- 5a-reductase.
- 17b-HSD
- 3b-HSD.
- AMH receptor.
- Androgen receptor.
What gene mutation is an indicator of male pseudohermaphroditism due to 5a-reductase deficiency?
Mutations in both copies of the SRD5A2 gene.
In male pseudohermaphroditism due to 5a-reductase deficiency, what occurs during puberty?
Previously female presenting external genitalia will change to present as male - penis grows, erection + ejaculation can occur, voice deepens, etc, etc.
In grown men with male pseudohermaphroditism due to 5a-reductase deficiency, what is unique about them?
- Poor facial hair growth.
- No hairline recession.
- No acne.
- Prostate remains small.
Androgen insensitivity can cause _____ __________________, AKA __________ ___________ __________. An X-linked recessive condition, where there is defective androgen receptors, causes males to develop female secondary sex characteristics.
- Male pseudohermaphroditism.
- Testicular feminization syndrome.
What are the 3 categories of androgen insensitivity AKA testicular feminization syndrome?
- Complete - CAIS - fully female phenotype.
- Partial - PAIS - partially masculinized.
- Mild - Male phenotype.
True or false: In androgen insensitivity, there is normal testosterone synthesis, but no development of the wolffian duct (no androgen receptor).
TRUE!
In androgen insensitivity, ______ levels during development are normal, so the Mullerian duct will _________.
- Anti-mullerian hormone (AMH)
- Regresses.
Which condition is related to a mutation of glycine to glutamate at codon 708?
Androgen insensitivity - male pseudohermaphroditism.
A deficiency of the anti-mullerian hormone receptor can cause:
Male pseudohermaphroditism - as a result of failure to regress the mullerian duct in men.
In androgen insensitivity causing male pseudohermaphroditism, what happens to accumulated testosterone?
It uses aromatase to convert it to estradiol, which causes female sex characteristics.
What is the primary cause for female pseudohermaphroditism?
Congenital adrenal hyperplasia - due to 21-hydroxylase - androgenital syndrome.
In which condition is there improper formation of the female reproductive organs - with a blind-ended vagina and no uterus?
Mayer-rokitansky-kuster-Hauser (MRKH syndrome) - too AMH for a woman.
True or false: Ovarian granulosa cells can make AMH, but it is detrimental to fertility.
FALSE: AMH produced by ovarian granulosa cells plays a role in folliculogenesis.
If the receptor for AMH is mutated causing an excess of AMH, what would occur in women?
Mullerian agenesis.
What is freemartinism?
This occurs when two twins - 1 female and 1 male - exchange substances by blood. If the female twin receives AMH from the male twin, it can result in Mullerian agenesis. This is because the male twins reproductive system will develop sooner than the females.
____________ ________: A rare form of inherited hypogonadotropic hypogonadism. This condition occurs due to improper migration of GnRH-secreting neurons from the olfactory bulbs to the hypothalamus. Occurring due to mutation in the ______ _________.
- Kalmann syndrome
- KAL protein.
In Kallmann syndrome, what will seen clinically?
- Hypoosmia or anosmia - change in smell.
- GnRH deficiency.
- Hypogonadism.
- Eunuchoidism - Never progress through puberty.
In Kallmann Syndrome, _________ ________ will be normal, but growth will not be stunted after __________. Although, there will be no pubertal growth spurt.
- GH secretion.
- Puberty.
True or false: Less than half of all human pregnancies will result in the birth of a completely healthy infant.
TRUE!
Birth defects of the external genitalia will be a risk at what weeks of fetal development?
7-10 weeks - when male and female sex differentiation and maturation occurs. Can occur up until 38 week though.
What are the two methods to disrupt an endocrine receptor?
- Mimicking - endocrine disrupting chemical (EDC) binds to a hormone receptor, mimicking it - causing abnormal hormone response
- Blocking - An EDC will bind to a receptor either directly to the hormone binding site, or indirectly, and block the binding of its hormone - stopping hormone activity entirely.
At which levels can we cause endocrine disruption?
- Hormone synthesis - blocking the production of hormones, by altering enzymes.
- Transport - Can block transport locally in the blood, or force storage by the tissues of a hormone.
- Activation/metabolism - Activate tissues to degrade and metabolize a hormone.
- Receptor bind - blocking or mimicking the hormone for its receptor.
Phthalates are an example of what level of endocrine disruption?
Hormone synthesis - by decreasing the production of 3B-HSD needed for steroidogenesis.
Sulphotransferases - PAHs and PCBs are an example of what level of endocrine disruption?
Activation and metabolism - by sulphonation.
Finasteride, proscar, and propecia at on 5a-reductase to metabolize it - at what level is this endocrine disruption?
Activation/metabolic.
p,p’-DDE blocks the action of the __________ receptor, while o,p’-DDE blocks the action of the ____________ receptor to cause endocrine disruption.
- Androgen.
- Estrogen
Pesticides cause a lack of binding of receptors at which level of endocrine disruption?
Transport.
What effects may occur due to testicular dysgenesis?
- Decreased Leydig cell function, causing
- Low testosterone and INSL3 production, causing -
- Cryptorchidism, hypospadias, and short ano-gonadal distance.
- Improper Sertoli cell function, causing -
- Impaired germ cell differentiation, causing -
- Testicular cancer, germ cell neoplasia, and impaired spermatogenesis.
In which condition do we see cryptorchidism, hypospadias, short ano-genital distance, bad spermatogenesis, and testicular cancer?
Testicular Dysgenesis Syndrome.
In cryptorchidism, there is a substantially increased risk for -
Testicular cancer.
Human Papilloma Virus is associated with which cancers?
Frequent cause for cervical cancer and penile cancer - as well as oropharyngeal cancer.
HPV types 6 and 11 are found in __________ ________.
Benign lesions.
HPV types 16 and 18 are found in ___________ ________.
Malignant lesions.
True or false: HPV that is correlated to cancer is highly preventable, using vaccines.
TRUE!
Exposure to ___________ will promote prostate carcinogenesis by promoting self-renewal.
Biphenol A
How does estrogen mimicking chemicals lead to prostate cancer?
These will stimulate prostate stem cells to multiply - becoming more prone to abnormal growth.
Biphenol A causes ____________ __________, which ultimately causes prostate __________.
- endocrine disruption.
- Dysgenesis.
Types of ovarian cysts:
- Follicular cysts.
- Luteal cysts.
- Theca-lutein cysts.
What condition occurs when ovaries become studded with cysts - having increased LH, testosterone, estrogen and androstenedione.
Polycystic ovary syndrome.
Obesity and hyperinsulinemia are consequences of which female reproductive disorder?
Polycystic ovary syndrome.
Primary amenorrhea:
Absence of a period before hitting puberty - a woman who has never experienced normal periods.
Secondary amenorrhea:
Absence of a period for 3+ years, in a woman who had experienced normal periods in the past.
Common causes for amenorrhea?
- Lack of GHRH, GnRH, or TSH.
2, Hypopituitarism. - Primary hypothyroidism - with increased Prolactin + decreased GnRH.
- Prolactinoma.
Hyperprolactinemia causes ___________________ _____________.
Hypogonadotropic hypogonadism.
What are two common causes fro hyperprolactinemia?
- Drug inducing - dopamine receptor antagonists.
- Prolactinoma - prolactin secreting adenoma.
Excess prolactin formation will decrease:
Reproductive function and sex drive - by suppressing gonadotropin secretion.
How does a 17s-hydroxylase deficiency cause amenorrhea, lack of sex characteristics, and hypertension?
Because 17a-hydroxylase deficiency prevents the production of androgens and estrogens.
Which reproductive toxicants will turn germ cell nests into multi-oocyte follicles, reducing fertility?
Plasticizers and synthetic estrogens.
Which female reproductive toxicants will cause a depletion of primordial follicles, leading to infertility and senescence?
PAHs, solvents, and water disinfection byproducts.
In the menstrual phase of the uterine cycle, what is occuring?
Shedding of the endometrium, and formation of a follicle.
What is occurring in the proliferative phase of the uterine cycle?
Growth of the endometrium, and an ovum.
Exposure to chemicals that target pre-antral to ovulatory follicles can:
Impair steroid production, causing a block in ovulation and hormonal homeostasis - leading to infertility.
Metrorrhagia:
Bleeding in between menstrual periods.
Hypomenorrhea:
Deficient amount of menstrual blood flow.
Oligomenorrhea:
Infrequent menstruation.
Polymenorrhea:
Increased frequency of periods.
Menorrhagia:
Very intense increase in periods periods. This is associated with endometrial polyps, adenomyosis, or leiomyomas.
Primary dysmenorrhea:
Due to excess prostaglandin production (arachidonic acid derivatives). Causes extreme pain. This can be managed using NSAIDS or COX inhibitors.
Secondary dysmenorrhea:
Extreme period cramping and pain associated with leiomyomas, pelvic adhesions, or endometriosis.
Atrazine is an endocrine disrupting chemical that causes:
Failure of an LH surge in women - causing a failure to ovulate.
Dioxins are endocrine disrupting chemicals, that cause:
- Hemorrhagic follicles - causing failure of ovulation.
- Endometriosis.
NSAIDs and TCDD are endocrine disrupting chemicals, that cause:
Failure of progesterone synthesis - causing failure to ovulate.
Clinical manifestations of endometriosis:
- Secondary dysmenorrhea - extreme pain and cramping.
- Increased risk for ectopic pregnancy.
- Endometrium that shows glands and stroma with scattered histiocytes.
In ____________ _______ and ________, we will diagnosis them using biopsy, and will present with hyperplastic glands. If these glands have atypia, it indicate adenocarcinoma.
Endometrial hyperplasia and adenoma.
How does formation of polyps occur in perimenopausal women?
Lowered hormone signaling causing incomplete endometrial sloughing , build-up of the endometrium is a polyp.
In the presence of excess ___________, the menstrual cycle is disrupted. Endometrial cells will continue to proliferate, causing _____________ _____________ glands.
- Estrogen.
- Adenomatous hyperplastic glands.
What is the most common malignant tumor of the female reproductive tract?
Endometrial cancer.
In endometrial cancer estrogen induced hyperplasia and neoplasia may be associated to mutations of which gene?
Inactivation of tumor suppressor gene PTEN.
_________ endometrial cancer: The carcinoma is confined to the endometrium.
Stage 1.
_________ endometrial cancer: Tumors extend through the wall of the uterus, but not outside of the pelvis.
Stage 3.
___________ endometrial cancer: Carcinoma extends into the cervix and invades the myometrium.
STAGE 2.
__________ endometrial cancer: Carcinoma invades the bladder or rectum, and is extending outside of the pelvis.
STAGE 4.
Cervical cancer is a squamous cell carcinoma that is commonly associated with:
HPV.
How do we diagnose cervical cancer?
- PAP smear.
- Colposcopy.
- Cone punch biopsy.
What is the transitional zone of the cervix?
The area where the outer squamous epithelium (exocervic) meets with the inner columnar epithelium (endocervical canal). This is an area with high proliferation rates, making it susceptible to cancers and contraction of HPV.
Women who have had multiple partners or multiple pregnancies are at a higher risk for:
Cervical cancer.
Compare cervical intraepithelial neosplasia to invasive cancer:
CIN:
Lacks epithelial maturation.
Basement membrane is still intact.
Invasive cancer:
Basement membrane is breached.
Stage 0 cervical cancer:
No gross lesions - CIN is limited to the mucosa.
Stage I cervical cancer:
Invasive carcinoma confined to the cervix or body of the uterus.
Stage 2 cervical cancer:
Carcinoma extends beyond the cervix and uterus, but doesn’t expand past the upper vagina.
Stage III cervical cancer:
Tumor reaches pelvic wall.
Stage IV cervical cancer:
The tumor has spread beyond the pelvis or infiltrated neighboring organs - metastasis may occur.
Cancer of the __________: venereal disease is a major predisposing factor, and this will present with leukoplakic changes before carcinoma development.
Vulva.
Cancer of the _________: Clear-cell adenocarcinoma, which can be caused by in-utero exposure to DES. Because this structure is thin walled and has lots of lymphatics, this form of cancer is likely to metastasize
Vagina.
In-utero exposure to which chemical is known to cause vaginal cancer, infertility, breat cancer and high risk of miscarriage in women 15-20 years after birth?
Diethylstillbestrol - DES. A synthetic estrogen that is TOXIC.
Which genes are associated in part with ovarian cancer?
BRCA 1 and BRCA 2
What is the leading cause of death from gynecological origin?
Ovarian cancer.
Ovarian tumors may originate from:
- Surface epithelial origin.
- Germ cell origin.
- Sex cord stromal cell origin.
- Non-specific or metastasis.
