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Physiology & Pathology > Medical Physiology Block 7 Week 3 > Flashcards

Medical Physiology Block 7 Week 3 Flashcards

1
Q

What happens to children with excessive GH secretion? deficiency in GH secretion?

A

Individuals with excessive GH secretion during childhood develop gigantism (lengthening of long bones)

those with a deficiency of GH develop pituitary dwarfism

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2
Q

Does deficiency of GH beginning in adult life result in a major clinical illness?

A

No

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3
Q

What happens to adults who have excessive GH secretion (after puberty?)

A

acromegaly: Characterized by the growth of bone (increased diameter; growth plate has already fused; increased bone density) and many other somatic tissues, including skin, muscle, heart, liver, and the gastrointestinal tract

Progressive thickening of bones and soft tissues of the head, hands, and feet

Cause morbidity as a result of joint deformity, hypertension, pulmonary insufficiency, and heart failure

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4
Q

Describe synthesis of growth hormone.

A

Synthesized as a larger preprohormone

Cleaved to a prohormone while being transported between RER and Golgi

Cleavage of the pro-sequence and disulfide bond formation occur during transit through the Golgi bodies

Stored in secretory granules in the cytosol of the somatotrophs until it is secreted

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5
Q

What hormones have homology to growth hormone?

A

human placental lactogens, placental-variant GH, and prolactin

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6
Q

Describe daily profile of GH secretion.

A

Over 70% of total daily GH secretion occurs during the induction of slow-wave sleep

Exercise, stress, high-protein meals, and fasting cause a rise in the mean GH level in humans (increased frequency, not amplitude)

The integrated amount of GH secreted each day is higher during pubertal growth than in younger children or in adults

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7
Q

Describe GHRH modulation of somatotrophs.

A

GHRH binds to a G protein–coupled receptor (GPCR) on the somatotrophs and activates Gα s , which, in turn, stimulates adenylyl cyclase

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8
Q

What hormone increases growth hormone secretion? decreases?

A

ghrelin (acylated; growth hormone secretagogue receptor), estradiol, and testosterone; triggerd by high dietary protein intake

somatostatin (Galpha i)

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9
Q

What is the effect of GH?

A

GH triggers the secretion of IGF-1 from GH target tissues throughout the body.

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10
Q

Describe negative feedback of GH and GHRH.

A

IGF-1 inhibits GH secretion, increases secretion of somatostain, and suppresses GHRH release from the arcuate nucleus in the hypothalmaus

growth hormone inhibits its own secretions via short loop feedback

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11
Q

How is growth hormone transported in plasma?

A

Significant fraction is complexed to GH-binding protein (formed by proteolytic cleavage of the extracellular domain of GH receptors in GH target tissues; high affinity); most circulates freely

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12
Q

Describe growth hormone receptor.

A

monomeric, single membrane spanning segment; extensively glycosylated, tyrosine kinase-associated receptor (dimerizes; JAK2/STAT3); modulates apoptosis (trophic signal?)

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13
Q

What are acute effects of growth hormone?

A

Stimulation of lipolysis in adipose tissue, inhibition of glucose uptake by muscle, and stimulation of gluconeogenesis by hepatocytes; stimulates chondrocyte proliferation (stimulating formation of cartilaginous ECM) and promotes longitudinal bone growth

long term effect is production of IGF-1

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14
Q

How is IGF-1 transported in the blood? Where does most of it come from?

A

bound to binding proteins; produced by the liver (IGF-1 is secreted into the extracellular space, where they act locally in a paracrine fashion; binding to proteins inhibits the entry of IGFs into the vascular system)

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15
Q

Describe the IGF-1 receptor.

A

tyrosine kinase (heterotetramer that is structuarally related to the insulin receptor)

two completely extracellular alpha chains (linked to one another by disulfide bonds) and two transmembrane beta chains

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16
Q

Can insulin bind to IGF-1 receptor? Can IGF-1 bind to insulin receptor?

A

Yes to both; lower affinity (hybrid receptors exist in the body)

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17
Q

Describe IGF-2 signaling.

A

Although IGF-2 also binds to the IGF-1 receptor (most important function), it preferentially binds to IGF-2 receptor, a single-chain polypeptide distinct from IGF-1 receptor)

if expressed on the plasma membrane, it is suggested that the receptor recruits JAK2/STAT3 or 5 (nuclear signaling)

may bind to mannose-6-phosphate (if located in the ER): Physiological role appears to be in processing mannosylated proteins by targeting them for lysosomal degradation

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18
Q

When do IGF-1 levels and growth rate diverge? Why?

A

During adulthood, longitudinal growth essentially ceases, yet secretion of GH and of IGF-1 continues to be highly regulated (hormones decline with age)

Early childhood is characterized by very rapid growth but quite low IGF-1 levels (IGF-2 concentration is greater during fetal life and peaks just before birth; peaks to adult levels at age 1)

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19
Q

Is insulin signaling required for IGF-1 production?

A

Yes; Increased insulin appears to be required, at least in some tissues, for GH to stimulate IGF-1 effectively

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20
Q

What other hormones promote growth?

A

Hyperinsulinemia results in increased fetal growth

An excess of adrenal glucocorticoids inhibits growth

Androgen or estrogen excess occurring before the pubertal growth spurt accelerates bone growth (narrows longitudinal growth window)

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21
Q

What is a stimulus for decrease in growth rate?

A

Growth levels off in accordance with the development of secondary sexual characteristics

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22
Q

What is longitudinal growth?

A

Longitudinal growth involve lengthening of the somatic tissues (including bone, muscle, tendons, and skin) through a combination of tissue hyperplasia and hypertrophy

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23
Q

Describe longitudinal growth of bone.

A

For bone, longitudinal growth occurs by hyperplasia of chondrocytes at the growth plates of the long bones, followed by endochondral ossification; the calcified cartilage is remodeled as it moves toward the metaphyses of the bone, where it is eventually replaced by true lamellar and trabecular bone

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24
Q

When does bone growth stop?

A

epiphyseal closure occurs toward the completion of puberty (calcification of the cartilaginous surrounding matrix also occurs)

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25
Q

Which hormones modulate body mass? linear growth? What determines body type?

A

insulin, glucocorticoids, adiponectin, and leptin

growth hormone (IGF-1), IGF-2, insulin, thyroid hormone, glucocorticoids, androgens (or estrogens)

interplay between hormones, genetics, race, ethnicity, and diet

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26
Q

Is their only one form of growth hormone?

A

No; 3 main forms (multimers of these monomers exist)

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27
Q

What determines off-target affinity of hormone?

A

Its homology to the endogenous ligand

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28
Q

Does growth hormone bind the prolactin receptor?

A

Yes

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29
Q

REVIEW: How does PKA modulate calcium channels?

A

phosphorylation activates L-type calcium channels

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30
Q

Describe the profile of growth hormone and growth hormone receptor during gestation.

A

high levels of growth hormone; low presence of GH receptors (desensitized or immature?)

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31
Q

What is Laron’s syndrome?

A

resistance to GH hormone due to the absence of GH receptors

Children have smaller mean size than average (1 standard deviation lower)

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32
Q

Describe the profile of growth rate over time. IGF-1? GH?

A

in postnatal state, growth rate is high and rate decreases until puberty, when there is an increase in growth rate (measured as height); steadily declines after puberty

In postnatal state, IGF-1 is low and increases to its peak during puberty before steadily declining as a consequence of aging.

growth hormone begins high and declines with age

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33
Q

What increases synthesis of IGFBP-1? decreases?

A

catecholamines, PPAR agonists, reactive oxidative species, glucagon and cortisol

insulin

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34
Q

What domain of IGFBP-1 is important for cellular signaling? What does it bind to? What is the effect?

A

RGD (Arg-Gly-Asp)

integrins

acts as a coactivator of insulin or IGF-1 receptor signaling by activating FAK, ILK suppressing PTEN, which normally inhibits PI3K, a downstream target of insulin signaling

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35
Q

What are the different states of IGFBP-1?

A

If unphosphorylated, it can bind integrins, can multimerize, associate with alpha 2 macroglobulin (releases IGF-1)

when phosphorylated, it binds IGF-1 (increasing its half life but silencing its activity)

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36
Q

What are pathologies associated with the IGF-1 receptor?

A

cancer: anti-apoptotic properties

aging may cause desensitization of the IGF-1 receptor for its ligand (immunoreactive and non-immunoreactive)

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37
Q

Describe IGF-1R signaling.

A

overlaps with insulin signaling (IRS-PI3K-AKT-mTOR; IRS-SHP2; IRS-GRB2/SOS-RAS-RAF-MEK-MAPK)

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38
Q

What is the result of IGFBP-1 overexpression? IGFBP-3?

A

stunt in fetal growth

selective organomegaly (spleen, liver, heart)

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39
Q

What causes decreased growth?

A

glucocorticoids, lack of T3, insulin receptor defects result in Leprechaunism

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40
Q

What causes increased growth?

A

sex steroids, insulin signaling (macrosomy), and thyroid hormone

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41
Q

What can stimulate GHRH exogenously?

A

clonidine and L-DOPA

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42
Q

What is the effect of growth hormone replacement? What are negative outcomes?

A

Increase in lean body mass and decrease in body fat

Splenomegaly and dysregulation of signaling (may be fatal)

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43
Q

What is the consequence of absence of growth hormone before puberty?

A

Dwarfism: decreased muscle strength, thinning bones, increased body fat (abdomen, hip, thighs), decreased collagen production, decreased energy (moodiness and depression)

insulin resistance, atherosclerosis, decreased NO synthesis and endothelial dysfunction

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44
Q

What is the composition of bone?

A

Bone consists largely of an extracellular matrix composed of proteins and hydroxyapatite crystals (calcium phosphate; complexed to magnesium), in addition to a small population of cells

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45
Q

What are cell types that are present in bone?

A

Osteoblasts promote bone formation (secrete ECM, osteoid, and quiescent cells line the tissue)

osteoclasts promote bone resorption

osteocytes (are osteoblasts that have become surrounded by matrix) sense mechanical stress on bone and secrete growth factors that stimulates osteoblasts; also play a role in transfer of mineral from the interior to the growth surfaces

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46
Q

Describe the two types of bone.

A

cortical (compact; 80% of total mass): dense

trabecular bone is found in the interior (composed of thin spicules) and is characterized by much higher fractional rate of turnover

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47
Q

What is the fundamental unit of bone?

A

osteon: haversian canal surrounded by ring-like lamellae)

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48
Q

How do osteocytes and osteoblasts communicate?

A

Osteocytes are interconnected with one another and with the osteoblasts on the surface of the bone by canaliculi (permits the transfer of calcium from the interior to the surface; gap junctions)

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49
Q

Describe collagen molecule.

A

triple helix of two alpha 1 monomers and one alpha 2 monomer; cross-linkages

provides site nucleation of hydroxyapatite crystals (mineralization)

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50
Q

Describe components required for mineralization of bone.

A

osteocalcin (induced by active form of vitamin D and secreted by osteoblasts) binds calcium (gamma carboxylated glutamic acid) and hydroxyapatite crystals

osteonectin, also produced by osteoblasts, binds hydroxapatite and collagen fibers

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51
Q

Describe bone remodeling.

A

PTH and vitamin D stimulate osteoblastic cells to secrete factors such as M-CSF (differentiation of stem cells to osteoclast precursors and mononuclear osteoclasts)

PTH indirectly stimulates bone resorption by osteoclasts. Osteoclasts do not have PTH receptors. Instead, the PTH binds to receptors on osteoblasts and stimulates the release of factors, such as IL-6 and RANK ligand (member of TNF family), and the expression of membrane-bound RANK ligand. These factors promote bone resorption by osteoclasts.

Osteoblasts export calcium and phosphate from intracellular vesicles that have accumulated these minerals (bone formation appears to occur exclusively at site of previous resorption by osteoclasts)

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52
Q

Describe bone resorption

A

Osteoclasts resorb bone in discrete areas in contact with the ruffled border of the cell (binding of integrins to vitronectin on bone matrix; secretion of acid)

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53
Q

How do osteoblasts antagonize osteoclasts?

A

By binding RANK ligand, osteoprotegerin (produced by stroma and osteoblasts) protects the bone from osteoclastic activity.

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54
Q

What promotes increase of RANK ligand and decrease of osteoprotegrin?

A

glucocorticoids

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55
Q

What proteins are expressed on osteoclasts?

A

integrins, V-type proton pump, carbonic anhydrase (provides protons; linked to chloride/bicarbonate exchanger)

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56
Q

Where are the parathyroid glands located? How many?

A

posterior surface of thyroid gland; 4

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57
Q

What is the major regulator of PTH? What is the mechanism?

A

ionized plasma calcium: inhibits synthesis and release

calcium-sensing receptor (G alpha protein q and i; also present in the kidney; may have affinity for magnesium)

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58
Q

What increases PTH release? decreases? How?

A

phosphate; vitamin D

upstream regulatory regions in gene

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59
Q

Does proPTH exist in storage granules? Is the hormone cleaved in the granule?

A

no; into two fragment (N-terminal contains all biological activity)

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60
Q

Is PTH bound to a protein the circulation?

A

No

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61
Q

Describe PTH receptor signaling. What are the target tissues?

A

The PTH receptor couples through G proteins to either adenylyl cyclase or phospholipase C

Kidney (proximal and distal convoluted tubules) and bone (osteoblast) have the greatest abundance of PTH1R receptor

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62
Q

What is the net effect of PTH?

A

The net effects of PTH on the kidney and bone are to increase plasma [Ca 2+ ] and to lower plasma [PO 4 3− ]

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63
Q

What is the role of PTH on the kidney?

A

A key action of PTH is to promote the reabsorption of Ca 2 + in the thick ascending limb and distal convoluted tubule of the kidney

PTH reduces the absorption of phosphate in the proximal nephron (internalization of Na/Pi symporter; may decrease reabsorption of sodium, bicarbonate, and water)

PTH stimulates 1-hydroxylation of 25-hydroxyvitamin D in the mitochondria of the proximal tubule

Increases magnesium absorption in the ascending limp of the loop of Henle

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64
Q

What is the primary signal for vitamin D synthesis in the kidney?

A

decreased phosphate concentration in the blood (as a result of PTH)

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65
Q

What are the actions of vitamin D?

A

enhancement of renal calcium reabsorption, enhancement of calcium absorption by the small intestine (absorption of calcium phosphate (calcium binding protein gene transcription and modulation of phosphate transport through Na/Pi symporter)

modulation of the movement of calcium and phosphate in and out of the bone (indirect effect predominates: Provides [Ca++] and [PO4-] (through its effect on kidney and intestine) making them available for bone mineralization)

Vitamin D promotes calcium absorption primarily by genomic effects that involve induction of the synthesis of epithelial calcium channels, pumps, and calcium-binding proteins

promotes phosphate reabsorption in the kidney to counteract PTH (minimal)

decreases 1-a-hydroxylase (negative feed-back), and increases 24-hydroxylase activity

66
Q

What is the result of persistent increases of PTH on bone?

A

Stimulates bone to reabsorb calcium and phosphate from the hydroxyapatite crystals of bone mineral (to transport into the blood)

67
Q

What is the effect of intermittent increases in plasma PTH on bone?

A

PTH promotes bone synthesis directly by activating calcium channels in osteocytes

PTH stimulates bone synthesis indirectly in that osteoclastic bone resorption leads to the release of growth factors such as insulin-like growth factor 1, 2, and TGF-beta

68
Q

Is 25-hydroxylation of vitamin D in the liver regulated?

A

No

69
Q

What happens when someone ingests a meal containing calcium?

A

The rise in plasma [Ca 2+ ] inhibits PTH secretion. The decline in PTH causes a decrease in the resorption of Ca 2+ and phosphorus from bone, thus limiting the postprandial increase in plasma Ca 2+ and PO 4 3− levels. In addition, the decrease in PTH diminishes Ca 2+ reabsorption in the kidney and thus facilitates a calciuric response. If dietary Ca 2+ intake remains high, the lower PTH will result in decreased 1-hydroxylation of 25-hydroxyvitamin D, which will eventually diminish the fractional absorption of Ca 2+ from the GI tract.

70
Q

What happens when dietary intake of calcium is insufficient?

A

the body will attempt to restore Ca 2+ toward normal by increasing plasma [PTH]. This response will help to mobilize Ca 2+ from bone, to promote renal Ca 2+ retention, and over time, to increase the level of 1,25-dihydroxyvitamin D, which will enhance gut absorption of Ca 2+.

71
Q

What happens if someone ingests excess phosphorus by drinking a soft drink?

A

the rise in plasma [PO 4 3− ] will lower plasma [Ca 2+ ] because the increased plasma Ca/PO ion product will promote the deposition of mineral in bone. The resultant decrease in plasma [Ca 2+ ] will, in turn, increase PTH secretion. This rise in PTH will provoke phosphaturia that will act to restore plasma [PO 4 3− ] toward normal while Ca 2+ and PO 4 3− are mobilized from bone by the action of PTH. Over longer periods, the action of PTH to modulate the 1-hydroxylation of 25-hydroxyvitamin D plays an increasingly important role in defending the plasma [Ca 2+ ] by increasing intestinal Ca 2+ absorption.

72
Q

What is the trigger for calcitonin release? Where is it produced from?

A

triggered by raising the extracellular plasma calcium concentration to levels higher than normal.

C cells of the thyroid (neural crest cells)

73
Q

Describe calcitonin receptor signaling.

A

like PTH it may activate either PLC or adenylyl cylcase

transiently inhibits osteoclasts and may result in mild, decreased reabsorption of sodium, phosphate, and calcium by the kidney

Calcitonin inhibits osteoclasts by preventing transport of lysosomes and their fusion to the plasma membrane (G alpha protein s; PKA-mediated)

May have long term effect of maintaining bone turnover (modulation? Increasing efficacy of bone deposition and diminishing resorption?)

74
Q

Why is the effect of calcitonin on bone transitory?

A

rapid downregulation of the receptor

75
Q

What is the effect of sex steroids and glucocorticoids on bone remodeling?

A

Sex steroid hormones promote bone deposition, whereas glucocorticoids promote resorption

76
Q

Describe PTH-related peptide.

A

PTHrP appears to be made in different normal (lactating breast) and malignant tissues (squamous cell tumors, carcinomas, and lymphomas)

mimics PTH

77
Q

REVIEW: What is the function of calcium? Is plasma concentration heavily regulated?

A

hormone secretion, muscle contraction, nerve conduction, exocytosis, activation/inactivation (signaling)

YES

78
Q

REVIEW: What is the function of phosphate? Is plasma concentration heavily regulated?

A

part of ATP molecules, activation/inactivation of enzymes

NO

79
Q

REVIEW: What is the function of magnesium?

A

ATP requires magnesium for activity; acts as an enzyme cofactor, and regulates neuromuscular excitability

80
Q

What are the hormones involved in mineral metabolism? What are the target tissues?

A

PTH, vitamin D, and calcitonin

intestine, bone, kidney

81
Q

How is calcium transported in blood?

A

45% is ionized (free, unbound); 45% bound to albumin; 10% complexed to small anions (phosphate, citrate, carbonate, and oxalate)

82
Q

How is phosphate transported in blood?

A

50% ionized; 10% bound to albumin; 40% complexed to cations (i.e. calcium)

83
Q

How is magnesium transported in the blood?

A

2/3 free; 1/3 bound

84
Q

What is considered the “growth plate” in bone? Where is bone marrow relative to bone?

A

epiphyseal line

medullary cavity

85
Q

What is the osteoid?

A

extracellular matrix of bone: hydroxapatite, type 1 collagen (tensile strength and nidus for mineralization or nucleation), osteocalcin, osteonectin

86
Q

Which bone type is more vascularized?

What is the general site of bone metastases?

A

both trabecular bone (also called cancellous or spongy)

87
Q

What is osteocytic osteolysis?

A

transfer of calcium from the interior to the growth surface through canaliculi

88
Q

Describe osteoblast paracrine signaling.

A

secretion of M-CSF: differentiation of stem cells into osteoclast lineage

secretion of IL-6 and RANK ligand: activation of mature, multi-nucleated osteoclasts

89
Q

What is the lacuna?

A

site of bone resorption (ruffled border; lysosomal enzymes, proteases, acid secretion)

Binding of integrins to vitronectin on bone matrix is referred to as sealing zone

90
Q

Why does PTH have a short half life?

A

The short half life of PTH allows calcium to be tightly regulated on a moment-to-moment basis

91
Q

What two hormones show reduced secretion following transient increases in intracellular calcium?

A

renin and PTH

92
Q

What is the consequence of calcium sensing receptor activation in parathyroid gland?

A

Calcium sensing receptor activation decreases prepro-PTH gene transcription, and ultimately decreases the rate of PTH synthesis (also decreases secretion)

93
Q

What is the effect of magnesium on PTH release?

A

low magnesium stimulates PTH release (however, Prolonged low magnesium levels inhibit PTH release because magnesium is required for exocytosis)

94
Q

Does magnesium get resorbed from bone along with calcium?

A

Yes

95
Q

What are symptoms of hypocalcemia?

A

muscle stiffness, contractions (or cramps), decreases cardiac contractility, hyperexcitability of nerves (seizures), anxiety, and cardiac arrest

96
Q

What are symptoms of hypercalcemia?

A

polyuria, constipation, fatigue, calcium deposition (calcification), and cardiac arrythmias

97
Q

Can low magnesium cause fatigue?

A

Yes

98
Q

What do cacimimetics treat?

A

treat hyperparathyroidism (and those with secondary hyperparathyroidism caused by end-stage renal disease; if calcium is not reabsorbed by the kidney then there is a vicious cycle of PTH release)

99
Q

How is osteoporosis treated?

A

calcicilytics to block CaSR and administration of exogenous PTH; antiresorptives: bisphosphonates, estrogen replacement, calcitonin, and Denosumab (anti-RANL); anabolics

100
Q

Which osteoporosis treatment is most effective?

A

bisphosphanates (expensive)

101
Q

Is bone resorption and deposition in equilibrium with normal physiology? osteoporosis? intermittent PTH administration? bone cancer?

A

Yes; erosion of the osteoid; increases bone deposition; erosion

102
Q

Describe the main characteristics of puberty in men.

A

During the final month of fetal life, the testes descend into an integumentary pouch called the scrotum (inguinal canals are sealed shortly after birth)

First sign of puberty is enlargement of the testes (growth of seminiferous tubules and enlargement of Leydig cells)

Marked increased in growth rate (total body size; pubertal spurt) occurs late in puberty; increases in growth hormone secretion and testosterone production

103
Q

What parameter is closely regulated in the testes?

A

internal temperature

104
Q

What molecules are the driving force behind secondary sexual development?

A

androgens

105
Q

Are androgens anabolic?

A

Yes; stimulate linear growth, nitrogen retention (protein synthesis) and muscular development

106
Q

Describe LH signaling. FSH?

A

LH binding to receptors on the Leydig cells (adenylyl cyclase and cAMP) stimulates transcription of proteins (sterol-carrier protein 2 and steroidogneic acute regulatory protein) involved in biosynthesis of testosterone (transport of cholesterol throughout the cell)

FSH bindng (adenylyl cylcase and cAMP) to receptors on basolateral membrane of the Sertoli cells, stimulates genes transcription and protein synthesis of ABP, aromatase, growth factors (spermatogenesis), and inhibin

107
Q

Describe negative feedback in male reproductive system.

A

inhibition of pulsatile release of GnRH by the hypothalamic neurons (decreases release of LH) AND inhibin inhibits the release of FSH by the gonadotrophs in the anterior pituitary

108
Q

How does GnRH stimulate release of LH and FSH? Is secretion of GnRH pulsatile?

A

G alpha protein q (PLC-IP3/DAG-PKC/calmodulin)

YES

109
Q

Does LH or FSH have a higher half life?

A

FSH

110
Q

Which hormones are part of the same family as LH and FSH? Describe the structure of LH (or FSH).

A

LH and FSH are members of the same family of hormones as human chorionic gonadotropin (hCG) and TSH

Composed of two polypeptide chains designated alpha and beta (alpha subunits are identical for all four hormones)

hCG can be substituted for LH in the clinical setting

111
Q

Describe the levels of GnRH throughout development.

A

Gonadotropin secretion begins to decline in utero during late fetal life and increases again during the early postnatal period

112
Q

What critical developmental event occurs in the postnatal state outside of the GnRH-LH/FSH axis?

A

A short-lived postnatal surge of LH and testosterone secretion occurs in males

113
Q

How does secretion of LH and FSH change from postnatal state to post puberty?

A

Release of FSH is greater than that of LH during prepubertal period, a pattern that reverse after puberty.

114
Q

Which hormone is preferentially released in men following GnRH stimulation? Why?

A

GnRH preferentially triggers LH release in men

Maturation of the testes results in secretion of inhibin and inhibition of FSH secretion

115
Q

Describe cross-talk between LH and FSH.

A

FSH acting on Sertoli cells produces growth factors that may increase the number of LH receptors on the Leydig cells during development and may result in an increase in steroidogenesis (increase in testosterone production)

116
Q

Describe testosterone synthesis.

A

Mitochondria: P450 SCC (RLS: removes side chains; modulated by LH)

Smooth ER: 17alpha hydroxylase; 17, 20-desomlases produces DHEA); 17beta-hydroxysteroid dehydrogenase (makes a hydroxyl group from a ketone); 3beta-HSD (produces a ketone)

117
Q

What metabolites of cholesterol has higher androgenic potency than testosterone? What converts testosterone to DHT?

A

DHT

5alpha-reductase converts testosterone to DHT

118
Q

Is the androgen receptor a homodimer?

A

Yes

119
Q

How is testosterone metabolized?

A

converted to 17-ketosteroids in the liver and DHT in the prostate;

Excreted in urine as water-soluble conjugates of either sulfuric or glucuronic acid (or feces)

120
Q

Describe spermatogenesis.

A

Primordial germ cells migrate to the gonad, where they become spermatogonia; mitotically divide; enter first meiotic division (each primary spermatocyte divides into two secondary spermatocytes, each with a haploid number of duplicated chromosomes); the secondary spermatocyte enters the second meiotic division producing two spermatids, each of which has a haploid number of unduplicated chromosomes); maturation yields spermatozoa

121
Q

How do Sertoli cells support spermatogenesis

A

Gap junctions between the Sertoli cells and developing spermatozoa may represent a mechanism for transferring material between these two types of cells. Release of the spermatozoa from the Sertoli cell has been called spermiation . Spermatids progressively move toward the lumen of the tubule and eventually lose all contact with the Sertoli cell after spermiation.

122
Q

Describe maturation of spermatozoa.

A

changes in motility, metabolism, and morphology

Spermatozoa derived from the head (caput) of the epididymis are often unable to fertilize ova, whereas larger proportions of the spermatozoa captured from the body (corpus) are fertile; spermatozoa obtained from the tail (cauda) of the epididymis, or from the vas deferens, are almost always capable of fertilization

123
Q

Where is sperm stored?

A

Sperm are stored in the epididymis as well as the proximal end of the vas deferens.

124
Q

Describe composition of seminal fluid.

A

only 10% sperm cells;

composition of ejaculation fluid: First fluid to exit is a mixture of prostatic secretions and spermatozoa with epididymal fluid; subsequent emissions are composed of mainly secretions derived from seminal vesicle.

isotonic (lumen of epididymis is acidic; addition of alkaline secretions from seminal vesicles)

fructose, citric acid, ascorbic acid, vitamin B, prostate gland factor prevents clumping; choline and spermine

ions: calcium, sodium, magnesium, potassium, chloride, phosphate

125
Q

Describe penile innervation.

A

The penis receives both somatic efferent (motor) and afferent (sensory) innervation through the pudendal nerve (S2 through S4)

The principal functions of motor innervation to the male accessory glands include control of smooth muscle contraction, vascular tone, and epithelial secretory activity

126
Q

Describe erection.

A

During erection, relaxation of the smooth muscle of the corpora allows increased inflow of blood to fill the corporal interstices and results in an increase in volume and rigidity

release of acetylcholine onto endothelial cells (release of NO); NO diffuses to vascular smooth muscle

During erection, a decrease in this sympathetic tone allows relaxation of the corpora and thus contributes to tumescence (swelling)

Contraction of the striated ischiocavernosus muscle during the final phase of erection increases pressure inside the corpora cavernosa to values that are even higher than systemic arterial pressure; Contraction of the striated bulbospingiosus muscle increases engorgement of the corpus spongiosum, and thus the glans penis, by pumping blood up from the penile bulb underlying the this muscle.

127
Q

What is emission?

A

Seminal emission refers to movement of the ejaculate into the prostatic or proximal part of the urethra

Emission is the result of peristaltic contractions of the ampullary portion of the vas deferens, the seminal vesicles, and the prostatic smooth muscles

Accompanied by constriction of the internal sphincter of the bladder preventing retrograde ejaculation of sperm into the urinary bladde

128
Q

Are smooth muscles in the penis a synctium?

A

NO

The efferent ducts and proximal regions of the epididymis display spontaneous contractions that can be increased through adrenergic agents acting on alpha adrenergic agents

In contrast, the distal end of the epididymis and the vas deferens are normally quiescent until neural stimulation is received during the ejaculatory process (in response to sympathetic fibers in the hypogastric nerve and release of norepinephrine)

129
Q

What triggers ejaculation? Describe the spinal reflex.

A

entry of semen from the prostatic urethra into the bulbous urethra (an emission)

The afferent (i.e., sensory) impulses reach the sacral spinal cord (S2 through S4) and trigger efferent activity in the somatic motor neurons that travel through the pudendal nerve.

130
Q

What is the function of androgen-binding protein?

A

regulates concentration of free androgens in the circulation

131
Q

What is the function of GnRH-associated peptide?

A

may inhibit prolactin

132
Q

Does continuous GnRH inhibit LH and FSH secretion?

A

yes

133
Q

What is the result of growth hormones produced by Sertoli cells?

A

increased number of spermatocytes and spermatids; increased motility of spermatozoa

134
Q

What is the predominant androgen of the adrenal gland?

A

DHEA

135
Q

How is testosterone transported in serum?

A

2% free; 98% bound to either testosterone binding globulin, albumin, and corticosteroid binding globulin

136
Q

How do plasma testosterone levels change with age?

A

Serum testosterone increases in utero following fertilization; after birth, there is a brief spike and then rapid decline to almost no testosterone in serum for about 10 years; rapid increase during puberty and remains high during adult life (senescence and some decline at older age)

137
Q

How are androgen receptors regulated?

A

bound to heat-shock proteins

138
Q

Does testosterone stimulate erythropoeisis?

A

Yes

139
Q

What are important components of sperm?

A

fructose is the energy source and zinc is important for generation of disulfide linkages

140
Q

How does nitric oxide stimulate vasodilation?

A

cyclic GMP decreases intracellular calcium (requires guanylyl cyclase); decreased phosphorylation of myosin light chain; activation of myosin light chain phosphatase; relaxation of vascular smooth muscle

141
Q

What is the consequence of androgen deficiency (pre-puberal) in men?

A

poor secondary sexual development, voice remains high pitched, muscle mass does not develop, lack of strength and endurance, scarce hair development; epiphyseal plate continues to grow

142
Q

What is the consequence of androgen deficiency (post-puberal) in men?

A

decreased libido, impotence, decreased growth of hair, and wrinkled features in the face

143
Q

Describe the uterus.

A

muscular organ

three regions: fundus, corpus, and cervix

The external surface of the uterus is covered by serosa whereas the endometrium (interior of uterus) consists of complex glandular tissue and stroma

144
Q

Describe puberty in women.

A

Puberty is the transition from a noncyclic, relatively quiescent reproductive endocrine system to a state of cyclic reproduction function that allows procreation

Sexual characteristics appear, adolescent growth spurt occurs

Beginning of menstrual cycles (menarche), breast development (thelarche), and an increase in adrenal androgen secretion (adrenarche)

145
Q

Describe trends in gondotropin secretions in females.

A

Surge in the levels of the pituitary gonadotropins, luteinizing hormone and follicle-stimulating hormone occurs during intra-uterine life; a second peak takes place in the immediate postnatal period (levels decrease until just before puberty)

146
Q

When are GnRH pulse common in the pubertal female?

A

REM sleep

147
Q

Describe the ovarian cycle.

A

FSH stimulate a follicle to complete its development (folliculogenesis); granulosa cells of the follicles increase production of estradiol, which stimulates the endometrium to undergo rapid and continuous growth and maturation (proliferative phase)

Rapid rise in ovarian estradiol secretion eventually triggers a surge in LH, which causes ovulation

After releasing its ovum, the follicle transforms into a corpus luteum; the luteal cells produce progesterone and estrogen, which stimulate further endometrial growth and development (secretory phase); for an unknown reason the corpus luteum rapidly diminishes its production of estrogens and progestins, thereby resulting in a catastrophic degeneration of the endometrium that leads to menstrual bleeding (menstrual phase)

148
Q

Describe changes in sensitivity of gonadotropins for GnRH during the ovarian cycle.

A

Early in the follicular phase of the cylce, when the gonadotrophs are not very GnRH sensitive, each burst of GnRH elicits only a small rise in LH; Later in the follicular phase, when the gonadotrophs in the anterior pituitary become more sensitive to the GnRH in the portal blood, each burst of GnRH triggers a much larger release of LH (estradiol)

149
Q

How long is the ovulation?

A

about 48 hours

150
Q

Describe estrogen synthesis in females.

A

The superficial theca cells and theca-lutein cells can take up cholesterol and produce the adrenal androgens (do not have aromatase)

Deeper granulosa cells and granulosa-lutein cells have the aromatase (and 17beta-HSD)

151
Q

Describe follicular growth.

A

Primordial follicles become primary follicles

The secondary follicle contains a primary oocyte surrounded by several layers of cuboidal granulosa cells

Tertiary follicles are characterized the a fluid-filled space called the antrum (fluid secreted into the center of the follicle by granulosa cells), gap junctions, desmosomes (requires FSH)

Graafian follicle is characterized by an enlarged antrum that almost encircles the oocytes

152
Q

Describe characteristics for the dominant follicle.

A

Conversely, estrogen increases the effectiveness of FSH in the more mature follicles by increasing the number of FSH receptors.

Dominant follicle has greater rate of granulosa cell proliferation, more FSH-dependent FSH activity and more estrogen production than the less dominant follicles

153
Q

What terminates the LH surge?

A

LH surge appears to terminate in part as a result of rising levels of progesterone, through negative feedback, and in part as a loss of the positive feedback that is derived from estradiol (depletion of gonadotropin stores may contribute)

meiosis I: LH and progesterone enhance the activity of proteolytic enzymes (collagenase) within the follicle and thus lead to digestion of connective tissue in the follicular wall (ovulation)

154
Q

Describe progesterone levels during the ovarian cycle.

A

increase near the end of ovulation and gradually increase before decreasing before menses (of remain elevated from placental hCG)

155
Q

Describe female sex response.

A

Whereas the excitement phase is under the influence of the parasympathetic division of the ANS, as is the erection phase in men, orgasm seems to be related to the sympathetic division, as is the emission phase in men

The cervix dilates during orgasm, thereby facilitating sperm transport into the upper part of the reproductive tract; the release of oxytocin at the time of orgasm stimulate uterine contractility, which also facilitates gamete transport

156
Q

Describe trends in female puberty.

A

age of onset decreasing (dependent on increased nutrition, distance away from the equator, and lower altitudes)

athletes and morbid obese have delay puberty

157
Q

T/F: inhibins and activins only act on pituitary?

A

T

158
Q

Characterize LH surge.

A

peaks 12 hours after its initiation; last for 48 hours

159
Q

T/F: Body temperature is slightly decreased in luteal phase of ovarian cycle?

A

F

160
Q

Describe layer of the endometrium

A

zona basalia, zona spongiosa: glands, and zona compacta: glands and stroma

Physiology & Pathology (40 decks)

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