Final Exam Flashcards
(352 cards)
1
Q
What are the four types of steroid receptors and their main functions?
A
Glucocorticoids - blood glucose/stress
Mineralocorticoids - sodium/potassium
Androgens - male sex (binds testosterone)
Progesterone - support pregnancy/embryogenesis
2
Q
What are the key thyroid receptors and their main functions?
A
Thyroid hormone - development/metabolism/heart rate
Estrogen - female sex
Vitamin D - calcium/phosphorus/development/apoptosis
3
Q
What two families of receptors are nuclear receptors and where are they located?
A
Steroid - cytoplasm
Thyroid - nucleus
4
Q
What nuclear hormone type is known to be transported across the membrane instead of diffusing across the membrane?
A
Thyroid hormone
5
Q
What are the hormones for nuclear receptors?
A
Small lipophilic/hydrophobic hormones that can diffuse across the membrane
6
Q
What are hormone response elements (HRE)?
A
A short DNA sequence within the promoter region of a gene that is capable of binding to specific hormone receptor complexes and regulate transcription.
7
Q
What is bound to a steroid hormone before the hormone binds?
A
heat shock proteins (HSP)
8
Q
What happens when heat shock proteins are released from the steroid receptor?
A
The nuclear localization signal (NLS) is exposed, allowing the hormone to bind.
9
Q
What happens to the hormone-receptor complex in steroid receptor signaling?
A
It is transported into the nucleus and binds to HRE to activate transcription
10
Q
What are the three domains of a nuclear receptor?
A
- Amino terminal domain
- DNA binding domain
- Ligand binding domain
11
Q
What is the importance of Zinc in the DNA binding region?
A
Important for dimerization and binding to different regions of DNA (binds with cysteine)
12
Q
What form of thyroid hormone has genomic actions?
A
T3
13
Q
What form of thyroid hormone signaling uses signal transduction?
A
Nongenomic
14
Q
Timing of genomic vs non-genomic actions of thyroid hormones?
A
Genomic - slow enough for transcription
Non-genomic - rapid (seconds to an hour - unless there is cross-talk)
15
Q
How are non-genomic effects of the thyroid hormone different from genomic effects?
A
Non-genomic effects have nothing to do with the nuclear thyroid hormone receptor and transcription because it is too rapid. Instead, it involves membrane receptors and/or modulation of intracellular pathways.
What is happening at the plasma membrane.
16
Q
What are integrins?
A
Receptors that mediate attachment between a cell and other cells or the extracellular matrix.
17
Q
What are examples of non-genomic rapid intracellular effects?
A
- Ion flux - sodium and calcium
- Mitochondria activity
- Glucose and amino acid uptake
- Actin polymerization - remodeling, neuronal connections, cell movement, intracellular trafficking, muscle contraction, pseudopod formation)
18
Q
How are target genes vs ion channels regulated by thyroid hormone?
A
Target genes - genomically/nuclear effects
Ion channels - nongenomically/nonnuclear effects
19
Q
Where does crosstalk occur?
A
Between thyroid hormone genomic and nongenomic paths - between the receptor and the plasma membrane
20
Q
How can thyroid hormone affect thyroid receptors in the nucleus (through cross-talk)?
A
Through phosphorylation cascades - when thyroid receptors are phosphorylated, they are activated and co-repressor proteins dissociate.
21
Q
Give an example of crosstalk.
A
T4 binds integrins at cell surface and stimulates MAPK pathway to phosphorylate thyroid receptors (nongenomic) that then causes dissociation of co-repressors promoting activation of transcription by TR/T3 (genomic).
22
Q
What is Cretinism?
A
Hypothyroidism in developing children leading to physical and mental disabilities
23
Q
What are possible causes of Cretinism?
A
Anti-TSH receptor antibodies from mother, severe iodine deficiency or defect in baby’s thyroid axis.
24
Q
What is HRE specific for?
A
Whatever steroid binds (ARE, ERE, TRE)
25
What is unique about estrogen receptor classification?
It is in the thyroid receptor family based on homology, but it is a steroid (signals like a steroid hormone)
26
What are thyroid hormones composed of?
Two linked iodinated tyrosine molecules derived from iodine (cleaved prohormone thyroglobulin)
27
What are the two main forms of thyroid hormones?
Thyroxine (T4) - most abundant
Triiodothyronine (T3) - most active
28
What are the effects of hyperthyroidism vs hypothyroidism?
Hyper = weight loss (even though eating a lot)
Hypo = weight gain (Hashimoto's disease)
29
What are the main functions of thyroid hormones?
1. increase oxygen consumption
2. increase basal metabolic rate
3. increase energy expenditure
4. regulate glucose metabolism
5. promote fetal growth
30
What is the importance of iodine in thyroid hormones?
Regulates TH production and is an important structural element in TH (T4 has more more iodine than T3)
31
What do thyroid hormones require to travel in circulation?
Blood binding proteins
32
What is the function of deiodinase?
Enzyme-catalyzed removal of iodine and can be either activating or deactivating depending on what iodine is removed
33
What is the differences between T3 and reversal T3?
T3 - deiodination of outer ring of T4 (in peripheral tissue)
rT3 - deiodination of inner ring of T4 (inactive/no genomic effects)
34
What is the thyroid gland made up of?
Small globular sacs (follicles) that are filled with a fluid called colloid
35
What is the function of follicular cells?
Line the follicles, synthesize thyroglobulin and actively take up iodine
36
What happens at the apical-colloid interface?
Iodine is oxidized so that thyroglobulin can be iodinated
37
Where is iodinated thyroglobulin stored until it is needed?
In the colloid (fluid in the follicles)
38
What happens when TSH stimulates the need for TH?
Colloid contents (iodinated thyroglobulin) are engulfed by the same or neighboring follicle cells where cleavage produces T4 and T3 that gets released into circulation.
39
What cells in the anterior pituitary release thyroid stimulating hormone (TSH)?
Thyrotroph cells
40
What stimulates the production of TSH? What inhibits the production of TSH?
Stimulates = TRH
Inhibits = somatostatin and TH negative feedback
41
What happens to TH production with excess iodine?
Negative feedback - inhibits TH production
42
What are the functions of blood-binding proteins?
Make hormones soluble in plasma
Provides a reservoir of hormone that exchanges with free form fraction
Prolonger half-life
43
What are the two forms hormones take in the plasma?
Free form = biologically active
Bound form = blood binding protein (or other molecule)
44
What are albumins?
A family of water-soluble globular proteins (like globulins) that bind to steroids, fatty acids and thyroid hormones
45
How is TH transported into target cells vs the nucleus of the target cells?
TC - by specific carrier/transporter proteins
N - diffusion
46
What must TH bind to in the cytoplasm in order to move around?
Cytoplasmic binding proteins
47
What is significant about the affinity of thyroid receptors?
They have higher affinity for T3 (90%) than T4 (10%), so most of T4 is converted to T3 before binding
48
What converts T4 into the biologically active form (T3) before binding to thyroid receptors?
deiodinase enzymes
49
Why is the interaction of thyroid receptors (TRs) with retinoid X receptors (RXRs) important gene expression?
Forms a heterodimer that interacts with the response element. The interaction between TR and RXR leads to a conformational change leading to the activation or suppression of target genes
50
What are the effects of cold temperatures on thyroid hormone production?
Promotes release of TH and TSH to increase heat production and thermogenesis
51
Why are thyroid response elements (TREs) considered less specific?
Can lead to activation or suppression, not just one specific action/role
52
What is the difference between the corepressor complex and the coactivator complex?
Corepressor - uses histone deacetylases (HDACs) to close chromatin and repressing gene transcription
Coactivator - uses histone acetyltransferases (HATs) to open chromatin for transcription
53
What are the different substances that have non-genomic effects mediated by changes in levels of T3/T4 in the plasma membrane?
Calmodulin
Integrin
PIPs
cAMP
Protein kinase
54
Why are the levels of PIPs important in nongenomic effects of thyroid hormones?
Signal changes in Ca regulation and changes in plasma membrane regulation
Responsive to thyroid hormone levels on the outside of the membrane
55
What are some examples of second messengers in TH cross-talk?
Cyclin dependent kinase (CDK)
Mitogen activated protein kinase (MAPK)
Tyrosine kinase
56
How does a human fetus acquire TH?
Can synthesize TH early on
Substantial transfer of TH across the placenta - contains deiodinases that convert T4 to T3
57
What is Goiter?
Overstimulation of the thyroid gland cause enlargements
58
How can Goiter arise from both hyperthyroidism and hypothyroidism?
Hyper = overstimulation of TRH or TSH
Hypo = thyroid deficiency/lack feedback, so TSH production increases, increasing the size of the thyroid gland
59
What are possible causes of Goiter?
Lack of iodine in diet
Drug blocking
Autoimmune disease
60
What is Hashimoto's Thyroiditis (or chronic lymphocytic thyroiditis)?
An autoimmune disease where the thyroid gland is attacked by a variety of cell and antibody mediated immune process - common cause of hypothyroidism
61
How does lymphocyte (WBC) action lead to Hashimoto's Thyroiditis?
Lymphocytes sensitized to thyroidal antigens totally destroy normal thyroidal architecture, decreasing T3 production, increasing TSH (goiter) until gland fails
62
What is the most common first symptom of Hashimoto's Thyroiditis?
Weight gain despite normal eating habits
63
What defines Graves Disease?
Common form of thyrotoxicosis characterized by hyperthyroidism, goiter and bulging eyeballs.
64
What are some common characteristics of Graves Disease (other than the main triad)?
Change in metabolism
Increased heart rate and blood pressure
Increased ventilation
More anxious state (depression)
Weight loss and sweating
Low levels of carbon dioxide in the blood
65
What is the difference between autoimmune hypothyroidism and autoimmune hyperthyroidism?
Hypo = TSH receptor binds antibodies that block
Hyper = TSH receptor binds antibodies that stimulate
66
What is another name of vasopressin?
Antidiuretic Hormone (ADH)
67
What hormones does that posterior pituitary release?
Oxytocin and vasopressin (or ADH)
68
What is released from the adrenal medulla?
Epinephrine and norepinephrine
69
What are the three layers of the adrenal cortex and what hormone does each layer secrete?
1. Zona glomerulosa - mineralocorticoids (aldosterone)
2. Zona fasciculata - glucocorticoids (cortisol)
3. Zona reticularis - androgens (DHEA)
70
What is the basis of all hormones produced in the adrenal cortex?
Cholesterol - steroid hormones
71
What does DHEA stand for?
Dehydroepiandrosterone
72
What is the major mineralocorticoid and what is its function?
Aldosterone - increases K secretion and sodium and water retention by the kidneys - increasing blood pressure
73
What is the main regulator of aldosterone?
Renin-angiotensin-aldosterone system
74
What is the Renin-Angiotensin-Aldosterone system activated by?
Low blood pressure and high K levels
75
What is the major glucocorticoid and what is its function?
Cortisol - helps the body deal with stress
76
What tissues does cortisol act on?
Liver
Muscles/Smooth muscles
Adipose tissue
Pancreas
77
What is the main function of mineralocorticoids/glucocorticoids/androgens?
Mineralocorticoids - regulation of mineral (K and Na)
Glucocorticoids - regulation of glucose metabolism
Androgens - male hormones
78
Why is the breakdown of muscle proteins into amino acids important?
Can be used to synthesize glucose, fats and generate energy
79
What is the function of cortisol in the liver?
Promotes catabolism of glycogen to glucose
80
What is the function of cortisol in the muscles?
Inhibits glucose uptake and consumption and promotes protein degradation to amino acids
81
What is the function of cortisol in adipose tissue?
Promotes lipid breakdown for additional energy
Lipolysis: triglycerides --> fatty acids and glycerol
82
What is the function of cortisol in the pancreas?
Decreases insulin and increases glucagon secretion = increase blood glucose
83
How does cortisol maintain higher blood pressure?
Increase the sensitivity of vascular smooth muscles to vasoconstrictors and inhibiting the release of vasodilators
84
What is the mechanism of glucocorticoid drugs?
Increase cortisol to reduce inflammation and suppress the immune system
85
What controls the release of cortisol?
Hypothalamic-pituitary-adrenal (HPA) axis
86
How does the Hypothalamic-pituitary-adrenal (HPA) axis promotes the release of cortisol?
1. Hypothalamus releases CRH in response to stressor
2. Anterior pituitary release ACTH
3. Adrenal gland releases cortisol
87
How does the cortisol negative feedback loop work?
Production of cortisol from adrenal gland feedback to the hypothalamus (CRH) and anterior pituitary (ACTH)
88
When are cortisol levels high vs low?
High = morning
Low = night
89
What is DHEA produced in response to?
ACTH from the anterior pituitary
90
What is DHEA converted into?
testosterone or estrogen
91
What is unique about ADRENAL androgens in males?
Only make up a small proportion of androgens in males, most produced by testes.
92
What is unique about ADRENAL androgens in females?
Major source of androgens in females (especially after menopause)
93
What system is the adrenal medulla apart of?
The sympathetic nervous system - "fight or flight" response to short-term stress
94
What is the adrenal medulla composed of?
Modified postganglionic neurons - chromaffin cells
95
What is the function of sympathetic preganglionic fibers?
Stimulate chromaffin cells to produce epinephrine and norepinephrine
96
What are the functions of epinephrine and norepinephrine in the sympathetic system?
Increase cardiac output, accelerate respiratory rate and release stored energy
97
Where does epinephrine and norepinephrine cause vasoconstriction/vasodilation in the sympathetic system?
Cause vasoconstriction in most organs but vasodilation in the heart and skeletal muscles
98
What are some characteristics of the zona fasciculata?
Rich in mitochondria, lipid droplets and SER
99
Which adrenal cortex layer has no 17alpha-hydroxylase activity?
Glomerulosa
100
Which adrenal cortex layer has no P450aldo activity?
Fasciculata
101
What receptor does cortisol bind to?
Glucocorticoid receptors - nuclear receptor
102
What other receptors can glucocorticoids bind to?
Mineralocorticoid receptors
103
What is the function of corticosteroid-binding globulin (CBG)?
A blood binding protein needed to transport cortisol in circulation
104
Where does mobilization of amino acids occur for glucocorticoids?
Muscle, Lymphoid tissue and connective tissue
105
Where is excess glucose stored (that isn't used for energy)?
Liver and adipose tissue in the form of glycogen and fats
106
What happens to glycogen stored in the liver during a fasted state?
Converted back into glucose to keep supplying the body with energy
107
What happens once the glycogen store in the liver is used up in a fasted state?
The body taps into energy stores in adipose tissues
108
How does the fasted state result in fat burning?
Fat from adipose tissue is broken down into free fatty acids and converted into metabolic fuel
109
What is cholesterol a precursor for?
Bile, steroid hormones and vitamin D
110
How is cholesterol transported in blood plasma?
In lipoproteins
111
How are lipoproteins classified?
Based on their density (VLDL, LDL, HDL) - particles that contain more lipids are larger but have lower density (proteins increase density)
112
What is the function of the proteins that sit on the surface of the lipoproteins?
Serve as "address tags" determining the destination and function of the lipoprotein
113
What is the function of low-density lipoproteins (LDLs)?
Carry cholesterol from the liver to other tissues - has the highest cholesterol content and is the major cholesterol carrier in the blood
114
What is the function of high-density lipoproteins (HDLs)?
Return excess cholesterol to the liver (reverse cholesterol transport)
115
What happens with high levels of LDL in the blood?
Associated with cholesterol plaque build-up and cardiovascular diseases (known as "bad" cholesterol)
116
Why is HDL known as "good" cholesterol?
It removes excess cholesterol from tissues and the blood stream
117
Where does cholesterol go after being absorbed by the intestines?
Carried through the blood stream to the liver
118
What are cholesterol pools and where are they stored?
Combination of endogenous and dietary cholesterols and triglycerides stored in very low density lipoproteins (VLDL)
119
What happens when muscles and adipose tissue extract triglycerides from the VLDLs?
VLDLs get tuned into LDL
120
What happens with the excess cholesterol that is returned back to the liver vis HDL?
Turned into bile that goes to the intestines where it breaks down fat
121
What is Apolipoprotein B100?
A form of LDL - helps move cholesterol around in the body
122
What happens with high levels of Apolipoprotein B100?
Higher risk of cardiovascular disease (because it is a LDL)
123
Through what process are lipoproteins taken up by cells?
Endocytosis after binding to lipoprotein receptors (receptor mediated endocytosis)
124
Why is cytochrome P450 important in cholesterol degradation?
It is the rate limiting step of steroid synthesis by enzymatically removing the cholesterol side chain to make pregnenolone
125
What are the steps of steroid biosynthesis?
1. Cholesterol
2. Pregnenolone
3. Progesterone
Cortisol, corticosterone (aldosterone) and testosterone (estradiol)
126
Where is 17alpha hydroxylase produced?
Thecal cells
127
Where is 17alpha hydroxylase expressed in the adrenal cortex and why is this important?
Layer 2/3 (fasciculata and reticularis) - cortisol and androgens are only expressed in these layers
128
Where is P450aldo expressed in the adrenal cortex and why is this important?
Layer 1 (glomerulosa) - aldosterone only expressed in layer 1
129
What does StAR stand for and what does it do?
Steroidogenic acute regulatory protein - transports cholesterol to the inner mitochondria membrane
130
What converts cholesteryl esters into cholesterol?
Cholesteryl ester hydroxylase (CEH)
131
What are the three main ways cortisol is regulated?
Circadian rhythm, stress and feedback (ACTH and cortisol)
132
What are the three regulatory feedback mechanisms for cortisol?
1. Short - ACTH from pituitary to CRH in hypothalamus
2. Long (fast) - ACTH from pituitary to adrenal gland to make cortisol, cortisol to ACTH in pituitary
3. Long (slow) - ACTH from pituitary to adrenal gland to make cortisol, cortisol to CRH in hypothalamus
133
What are parvocellular cells?
Cells in the lateral geniculate nucleus that release CRH in a circadian dependent pulsatile fashion
134
What is erythropoietin (EPO)?
Made naturally out of oxygen in the kidneys (at higher amplitudes)
135
What is the precursor for melatonin?
Serotonin (5HT) - tryptophan
136
What is the importance of peripheral oscillators in circadian rhythm?
Feedback loops that are entrained by neural pathways, hormones and feeding rhythms
137
What are examples of external cues that entrain the circadian rhythm?
Feeding schedules, light, activity and heat/temperature (thyroid hormone)
138
What system is responsible for the circadian rhythm response to light cues?
Retinohypothalamic tract (retina to SCN)
139
What is the circadian response to photic input?
Induction of various genes and chromatin remodeling within the SCN neurons
140
What is needed for photoreceptors to produce serotonin?
Blue light
141
What are some stress stimulators of ACTH release?
Physical exercise/work
Emotion
Pain
Trauma
Hypoxia - not enough O
Hypoglycemia - low blood sugar
Extreme temperature changes
Surgery
Depression
Infection
142
What is released with CRH during stress?
Vasopressin
143
What is Cushing Syndrome?
Constant high levels of circulating cortisol due to overproduction by the adrenal gland
144
How does cortisol help the body deal with stress?
Mobilizing energy resources, increasing blood glucose and makes it more available in the brain
145
How can high levels of corticosteroids be beneficial?
Suppress inflammation and antibody production by B-cells
146
What are some reasons for the high cortisol levels with Cushing Syndrome?
1. Tumor on adrenal gland
2. High ACTH due to tumor in pituitary gland
Or administration of glucocorticoids for therapeutic purposes
147
What are the key symptoms of Cushing Syndrome?
1. Obesity
2. More fat development on face and torso (water retention)
3. High blood pressure
4. Muscle/bone weakness
148
What is an indicator of Cushing Syndrome?
High cortisol levels at night
149
What is another name for Cushing Syndrome?
Hyperadrenocorticism
150
What are the benefits of a longer exhalation?
Increased CO2 – retention of carbon dioxide in lungs
Vasorelaxation – lower blood pressure (decrease heart rate)
Increased H2O – retaining more water (nasal breathing)
Heat – warmer with longer exhalation
Increased nitric oxide (NO)
151
What is Cushing's disease?
Specific type of Cushing syndrome due to excessive ACTH from a pituitary tumor
152
What is Addison's disease?
Insufficient production of cortisol (often accompanied by an aldosterone deficient)
153
What is another name for Addison's disease?
Hypoadrenocorticism
154
What are the main causes of Addison's disease?
Infectious disease or autoimmune destruction of the adrenal cortex
155
What is hypogycemia?
Low levels of glucose in blood
156
Why is there an increase in ACTH production is Addison's disease?
Underproduction of cortisol decreases negative feedback on the pituitary
157
What happens if too much aldosterone is produced?
Lose osmotic balance in the kidney lumen
158
What is the main function of aldosterone in the lumen of the kidney tubules?
Na+ pumped across cells into extracellular fluid (conserved) while K+ and H+ pumped into lumen (to be lost in urine)
159
What is the major target of mineralocorticoids?
Kidney distal tubules (Na/K exchange)
160
How does reabsorption of water occur in response to mineralocorticoids?
Passively - osmotic effect directly related to increased resorption of sodium
161
What are the two main regulators of aldosterone secretion?
1. Concentration of K in the extracellular fluid
2. Angiotensin II (decrease bp = decrease aldosterone, increase bp = increase aldosterone)
162
What is released if blood flow is too high?
Atrial natriuretic peptide (ANP)
163
How does ANP regulate blood pressure and salt-water balance?
By promoting renal sodium and water excretion
164
How is renin produced?
Juxtaglomerular cells in the kidney produce prorenin that is converted into renin in response to a drop in blood pressure
165
What are the main functions of Angiotensin II?
1. Systemic vasoconstriction (arterioles)
2. Sodium/water retention (kidneys) by...
- aldosterone release from adrenal
- ADH release from pituitary
3. Stimulate thirst (hypothalamus)
166
What is the main function of the Renin-Angiotensin-Aldosterone system (RAAS)?
Increased blood volume and blood pressure
167
What is the function of the macula densa cells in the kidneys?
Sense the amount of sodium, potassium and chloride in the ascending tubules of the kidneys and inform the juxtaglomerular cells if renin is needed
168
What are the effects of excess aldosterone on renin secretion?
Inhibits renin secretion
169
What happens with too much aldosterone vs not enough aldosterone?
Too much aldosterone:
- High blood pressure – water retention
- Lose too much potassium – cardiac problem
- Too much ACTH
Not enough aldosterone (not enough adrenal function):
- Low blood pressure
- Glucocorticoid deficiency – go hand in hand
- Retain too much potassium – had for heart
170
What competes with cortisol for mineralocorticoid receptors?
Aldosterone (but cortisol concentrations are 100x greater)
171
What blocks cortisol from binding to mineralocorticoid receptors? How does it do this?
Cortisone
172
Where are steroids synthesized?
Smooth ER and mitochondria
173
What is chronic licorice intoxication?
Water and sodium retention coupled with low plasma K causing hypertension and low renin activity
174
What converts cortisol to cortisone (inactive form)?
11-beta hydroxysteroid dehydrogenase (HSD)
175
What does licorice inhibit?
11-beta hydroxysteroid dehydrogenase (HSD) - not inactivation of cortisol (to cortisone)
176
Where is CRH found?
In the hypothalamic paraventricular nucleus (PVN)
177
Where is the circadian rhythm of cortisol secretion derived from?
Connections between the PVN and SCN
178
What projections from the SCN regulate sleep-wake cycles?
Projections to the dorsomedial and posterior hypothalamic areas
179
What is the function of the seminiferous tubules in the testes?
Produce spermatozoa and contain Sertoli cells
180
What are Leydig/interstitial cells?
Major endocrine cells of the testes that produce sex steroid hormones (testosterone mostly, DHT and estradiol) and activins
181
What is the function of Sertoli cells?
Produce inhibins and factors (ex. androgen-binding proteins)
Nurse cells for spermatozoa
Limit the amount of cytotoxins that can reach the spermatozoa
182
What does DHT stand for?
Dihydrotestosterone
183
In the mitochondria, what cleavage enzyme coverts cholesterol to pregnenolone?
Cytochrome P450 side chain (P450SCC)
184
Where does pregnenolone translocate to for conversion to testosterone?
Smooth ER
185
What two routes can pregnenolone take to be converted to testosterone?
1. Progesterone
2. Dehydroepiandrosterone (DHEA)
186
What is the difference between testosterone and dihydrotestosterone?
Testosterone is the predominant androgen and dihydrotestosterone is the more potent androgen
187
How is testosterone converted to the more potent androgen DHT?
5alpha reductase
188
Testosterone and DHT bind to the same androgen receptor, which one has higher affinity?
DHT
189
What is estradiol?
The predominant from of estrogen
190
What are the two different estrogen receptors?
ER-alpha and ER-beta
191
What happens after estrogen binds to its receptor?
HSP dissociates
Homodimer or heterodimer formed with another estrogen-receptor complex
192
What does GnRH release?
LH and FSH
193
What is the function of LH in testosterone?
Stimulates Leydig cells to produce and secrete testosterone
194
What is the function of FSH in testosterone?
Stimulates testicular growth and acts on Sertoli cells to enhance production of androgen-binding protein (ABP)
195
What is the function of inhibins?
Inhibit FSH release
196
What is the function of activins?
Augment GnRH-mediated release of FSH
197
Where are inhibins produced in males vs females?
Males - Sertoli cells
Females - Granulosa cells and corpus luteum
198
Where are activins produced in males vs females?
Males - Leydig cells
Females - Granulosa cells and corpus luteum
199
What three cells are ovarian follicles comprised of?
1. Oocytes
2. Granulosa cells
3. Theca cells
200
What is the function of granulosa cells?
Only have FSH receptors and produce estradiol
201
What is the function of theca cells?
Only have LH receptors and produce androgens (androstenedione) that are precursors for granulosa cells to convert to estradiol
202
What is the function of the corpus luteum?
Produces progesterone in response to LH
203
What is follicular atresia?
The depletion of the pool of oocytes during childhood/adulthood
204
What happens with proliferation of granulosa cells?
Begin expressing FSH, estrogen and androgen receptors
205
What happens with maturation of follicles?
Production of more estradiol leading to an increase in the LH and FSH receptor density
206
What cells express 17alpha-hydroxylase and lack aromatase?
Theca cells
207
What cells lack 17alpha-hydroxylase but have aromatase?
Granulosa cells
208
What ovarian follicle cells are more exposed to the circulatory system? Why is this important?
Theca cells - to take up cholesterol from circulation and synthesize androgen precursors
209
What is the function of aromatase?
Convert androgens into estrogens
210
What happens when estrogen levels continually rise?
Uterine lining (endometrium) thickens and LH surge promotes ovulation
211
Why is the LH surge required?
For maturation of the oocyte
212
How does LH promote the formation of the corpus luteum?
Promotes the granulosa cells and theca cells that remain in the ovulated follicle to differentiate into granulosa lutein cells and theca lutein cells
213
What does LH stimulate the corpus luteum to produce?
Progesterone
214
What is estradiol production stimulated by?
FSH
215
What is considered a dominant follicle?
Follicle with the most granulosa cells (most FSH receptors)
216
When do granulosa cells start to express LH receptors for the production of progesterone?
In the luteal phase with formation of the corpus luteum
217
What are the main functions of FSH in ovulation?
Stimulates maturation of the ovarian follicles (prevents follicular atresia)
Promotes estradiol production by granulosa cells and the corpus luteum
218
What are the main functions of LH in ovulation?
Triggers ovulation and the development of the corpus luteum
Stimulates production of androgens by theca cells
Stimulate progesterone production by corpus luteum
219
What happens with rising levels of estradiol?
Negative feedback on LH and FSH
220
What do female hormonal contraceptives tend to be made of?
Two synthetic sex hormones - ethinyl estradiol and progestin
221
How doe female hormonal contraceptives prevent ovulation?
Mimicking the negative feedback effects of estradiol and progesterone - lowering FSH and LH and suppressing ovarian production of estradiol and progesterone
222
What does the endometrium consist of?
Glands, stromal fibroblasts and extracellular matrix
223
What are the effects of estrogen vs progesterone on the endometrium?
Estrogen - promotes growth
Progesterone - inhibits growth
224
What is endometriosis?
Chronic inflammatory disease involving growth of endometrial tissue outside of the uterine cavity
225
What are the three possible ways endometriomas are formed?
1. Retrograde menstruation theory - backward flow of endometrial tissue through the fallopian tubes
2. Coelomic metaplasia theory - extrauterine cells abnormally differentiate into endometrial cells
3. Lymphatic and circulatory spread - endometrial cells enter the blood stream and implant on distance tissues
226
What are the effects of DNA methylation?
Gene repression
227
What is the function of GATA-binding factor 6 in endometriotic cells?
Converting progesterone to androstenedione
228
What is the function of Steroidogenic Factor-1 (SF-1) in endometriotic cells?
In combination with GATA6 - plays a role in the conversion of cholesterol to estradiol in endometriotic cells
229
What is the function of ESR2s in endometriotic cells?
Encodes the estrogen receptor beta (ErBeta)
230
What is the cumulative effects of GATA6, SF1 and ESR2 in endometriotic cells?
Hypomethylation - increasing gene expression leading to elevated estrogen signaling and reduced progesterone signaling
231
What does the increased estradiol signaling by GATA6, SF1 and ESR2 stimulate?
COX-2 and ESR2
232
What happens with the stimulated production of COX-2 and ESR2?
High local concentration of estradiol and prostaglandins, which allows cell survival and promotes pain and inflammation
233
What does the decreased progesterone signaling by GATA6, SF1 and ESR2 stimulate?
Prevent formation of weaker estrone
234
What are clinical management options for endometriosis?
1. Progestins (decrease LH and FSH)
2. GnRH agonists (down regulates GnRH receptors - decrease LH and FSH)
3. GnRH antagonists (decrease LH and FSH)
4. Oral contraceptives (stop GnRH production)
235
What are some biological mechanisms that allow endometriotic cells to survive outside the uterus?
1. Reduced apoptosis
2. Defective differentiation
3. Inflammation
4. Angiogenesis
5. Genomic alterations
6. Epigenomic alterations
236
How is FSH regulated?
Primarily regulated at level of gene expression
237
How is LH regulated?
Some gene expression, but LH surge mostly regulated at level of secretion
238
What causes the differential production and release of FSH vs LH?
1. GnRH pulse frequency
2. Levels/signaling of ovarian hormones - activins, inhibins, estradiol, progesterone, testosterone (GPCRs)
239
What frequency of pulsatile release from the GnRH favors FSH vs LH?
Low-frequency = FSH secretion
High-frequency = LH secretion
240
Is LH or FSH stored in vesicles?
LH - pre-synthesized and stored in storage granules for LH surge
241
What is the function of kisspeptins in pulsatile release of GnRH?
Regulate GnRH secretion and the hypothalamic-pituitary gonadal (HPG) axis
242
What stimulates the LH surge?
When estradiol levels reach a certain (high) threshold
243
How does positive feedback of the hypothalamic-pituitary-ovary axis lead to the LH surge?
High estradiol triggers a massive release of GnRH, increasing GnRH pulse frequency.
Pituitary sensitivity to GnRH increases inducing expression of GnRH receptors
Stimulate LH secretion
244
What hormones have negative feedback effects on estradiol release?
Ovarian hormones = estradiol, progesterone, testosterone and inhibins
245
What happens in puberty?
Increased FSH and LH production, therefore increased gonadal sex steroid production
246
What is the earliest even of puberty in males and females?
Onset of pulsatile release of GnRH during REM sleep
247
What is thought to be the puberty "on switch" and why?
Kisspeptin signaling - important role in GnRH pulses/secretion
248
How does estradiol/testosterone stimulate growth spurts?
Estradiol - Stimulates IGF-1 and GH
Testosterone - Enhance GH effects to increase IGF-1
249
What are some signs of declining female fertility with age?
Aging oocytes and loss of ovarian follicles (impaired folliculogenesis)
250
What happens to LH/FSH levels during menopause?
Very high levels of LH/FSH
251
What causes the high levels of LH/FSH during menopause?
1. Decrease inhibins, increase activins
2. Increase GnRH pulse frequency
3. Decreased negative feedback due to low progesterone
252
What happens to estradiol levels in menopause?
Fluctuate greatly in perimenopause and fall drastically in menopause
253
What happens to circulating androgens in menopause?
Decrease (but less that estradiol)
254
Where are post-menopausal estrogens derived?
Peripheral tissues converting/aromatizing androgens (ex. adrenal glands producing androstenedione)
255
What is the predominant estrogen in postmenopausal women?
Estrone (1/3 potency of estradiol)
256
What are some key features of estrogen?
Adipose tissue metabolism
Cardio protection
Neuroprotection
Maintenance of bone density
Growth and proliferation of breast tissues
Enhancement of insulin sensitivity and glucose tolerance
257
What receptors does E/NE bind to?
alpha/beta adrenergic receptors
258
What is the rate limiting step in catecholamine synthesis?
Tyrosine hydroxylase
259
What induces the production of phenyl ethanolamine N-methyltransferase (PNMT)?
Cortisol
260
What adrenergic receptors activate Gi vs Gq vs Gs?
Alpha 1 = Gq (PLC)
Alpha 2 = Gi (AC)
Beta = Gs (AC)
261
What binds to Gq GPCRs?
Angiotensin II
262
What is the synthesis pathway for catecholamines?
Tyrosine
(Tyrosine Hydroxylase)
DOPA
(DOPA decarboxylase)
Dopamine
(Dopamine-beta hydroxylase)
Norepinephrine
(PNMT)
Epinephrine
263
What are the three interfaces for calcium exchange?
1. Intestines
2. Bones
3. Kidney (renal tubules)
264
What are the main regulators of calcium?
Vitamin D and PTH (some calcitonin)
265
What is used to keep extracellular Ca 10,000 fold greater than intercellular Ca?
ATP-dependent Ca pumps and Na/Ca exchangers
266
What type of calcium had regulatory effects?
Ca unbound
267
What signals the release of Ca from the ER and mitochondria into the cell?
Inositol triphosphate (IP3) signaling
268
What are the effects of PTH and VD when there is low serum calcium?
PTH increases Ca release from bone and decreases Ca loss in urine
VD increases absorption of Ca in intestines and increase reabsorption of Ca in kidneys
269
What is the difference between calcitriol and calcitonin?
Calcitriol increases blood calcium levels and calcitonin decreases blood calcium levels
270
What do osteoblasts vs osteoclasts have receptors for?
Osteoclasts = calcitonin
Osteoblasts = PTH and VD
271
What is the function of osteoclasts?
Bone reabsorption - cell moves to bone surface and secretes acid and enzymes to break down bone
272
What are osteoclasts stimulated/inhibited by?
Stimulated = osteoblasts
Inhibited = calcitonin
273
What is the function of osteoblasts?
Bone forming - secrete bone matrix
274
What do lymphoid progenitor cells mature into?
Lymphocytes (T/B cells) - immunity
Myeloid progenitor cells
275
How does HCl produced by osteoclasts help with bone remodeling?
Breakdown of hydroxyapatite into calcium and phosphate for release into the blood stream
276
What is the function of macrophages in bone remodeling?
"Mop" up after osteoclast breakdown and apoptosis
277
Where is calcitonin made?
Parafollicular cells in thyroid gland (C-cells)
278
What is the function of VD in bone formation?
Maintaining normal blood levels of calcium and phosphate
279
What is one of the precursors for VD?
7-dehydrocholesterol
280
How is Vitamin D production upregulated?
Decreased phosphate, calcium and VD
Increased PTH
281
What form of VD is used to determine VD levels?
25OHD3 in the liver
281
Where is VD precursor stored until needed?
Liver and fat
282
What is the inactive form of VD and when is it synthesized?
24,25(OH)2D3 - synthesized when VD levels are already good
283
What deactivated VD in the liver and kidneys?
Hydroxylases
284
What happens to VDR when bound to 1,24(OH)2D (calcitriol)?
Forms a heterodimer with retinoic X receptor on VD response element (VDRE)
285
What does binding of VDR and RXR to VDRE stimulate?
Transcription and production of proteins - maintaining normal blood levels of calcium and phosphate
286
What promotes the uptake of Ca ions in the intestines?
VD by upregulating mRNA
287
What happens to PTH with an increase in Ca ion influx?
Inhibition of PTH synthesis and release from granules
288
What is the role of calcitonin in bone remodeling?
Inhibits osteoclasts and stimulates osteoblasts
289
How are the effects of calcitonin different from the effects of PTH?
Calcitonin - Ca influx increases secretion
PTH - Ca influx decreases secretion
290
What receptor does PTH vs calcitonin use?
PTH = GPCR(Gq)
Calcitonin = GPCR (Gs)
291
What kind of receptors is the MT1 melatonin receptor?
GPCR (Gi)
292
What are the effects of melatonin of estrogen?
Reduces estrogen signaling -suppresses ER-alpha mRNA expression and reduces cAMP levels
293
What are the down-regulatory effects of melatonin?
Down-regulates growth factor pathways that support cell proliferation and survival
294
What is the role of VD in breast cancer?
Higher levels of VD are associated with a decrease risk of breast cancer
Inhibits ERalpha, aromatase and COX-2
295
What was VD found to activate the transcription of?
Tryptophan hydroxylase at VDRE
296
Why is it important that calcitonin acts faster than PTH?
Prevent hypercalcemia by inhibiting osteoclast breakdown of bone into Ca and phosphate
296
What are some causes of hypercalcemia?
Hyperparathyroidism (ex. tumor)
Increased Ca absorption (gut/bone)
Decreased Ca excretion (kidney)
Overproduction of VD
297
What are some causes of hypocalcemia?
Hypoparathyroidism
Decreasing Ca absorption
298
How can corticosteroid medications lead to hypocalcemia?
Reduce inflammation/immune system with side effect of decrease Ca absorption
299
What causes Rickets?
Lack of VD causing decreased Ca and phosphate
300
What are the results of Rickets?
Secondary hyperparathyroidism (PTH too high) and increased bone resorption
301
What is osteomalacia?
Mineralization of newly formed bone matrix is defective
302
What causes osteomalacia?
Lack of VD, low Ca or low phosphate leading dysfunction of osteoblasts
303
What is the function of cytokine FGF23?
From bone - inhibits VD production and blocks phosphate reabsorption in kidneys
304
What is FGF23 linked with?
Increased rickets and osteomalacia
Human chronic kidney disease
305
What is FGF23 secreted in response to?
Secreted by osteocytes (osteoblasts) in response to oral phosphate or increased 1,25(OH)2D3
306
What is Lytic Paget's Disease (Osteitis Deformans)?
Rapid bone loss due to a high rate of bone degradation/reabsorption
Increased by FGF23
307
How can Lytic Paget's Disease (Osteitis Deformans) be treated?
Calcitonin
308
How does kidney deterioration lead to secondary hyperparathyroidism?
Decreases VD formation and increased phosphate retention leading to decreased serum Ca and increased PTH
309
What is osteoporosis?
Disorder of the bones in which the bones become brittle, weak and easily broken - decrease in mineralization and strength of bones over time
310
How does Cushing's disease lead to an increased chance of osteoporosis?
High levels of cortisol
311
What is associated with osteoporosis?
Low estrogen and high glucocorticoids
Long-term VD insufficiency
312
What is the main circulatory form of VD?
25(OH)D - calcitriol
313
What happens with decreased functionality of steroidogenic factor-1 (SF-1)?
Low levels of androgens leading to 46XY females
314
What happens with translocation of sex-determining region Y (SRY) protein (SRY still functional)?
Part of the Y chromosome has been translocated to part of the X chromosome = 46XX males
315
What happens with mutation of sex-determining region Y (SRY) protein (SRY not functional)?
46XY females
316
What is the function of sex-determining region Y (SRY) protein?
Initiates teste development
317
What levels of androgens are needed to develop as a male/female?
Male = High levels
Female = Low levels
318
What is the bipotential period?
When either Mullerian ducts or Wolffian ducts can form
319
What causes the gonadal differentiation of Mullerian ducts and Wolffian ducts?
Mullerian = exposure to estrogens
Wolffian = exposure to androgens (testosterone)
320
What is the fetus highly sensitive to during the bipotential phase?
Androgens
321
What is the function of Anti-Mullerian hormone (AMH)?
Produce Steroli cells and Leydig cells that control stabilization of Wolffian ducts
322
What is Amenorrhea?
Lack of menstrual cycle after age 16
323
What are some causes of amenorrhea?
1. GnRH deficiency (Kallmann's Syndrome) - GnRH neurons not developing properly
2. Functional hypothalamic amenorrhea - reduced GnRH pulse frequency
3. Hyperprolactinemia - DA not inhibiting prolactin release
324
What inhibits GnRH release?
Prolactin - inhibited by dopamine
325
What is Klinefelter's Syndrome (male 47, XXY)?
Extra X chromosome that changes the amount of estradiol in circulation - no clear secondary sex characteristics
326
What is Turner's syndrome (female 45,X)
Loss of an X chromosome leading to gonadal dysgenesis - no secondary sex characteristics
327
What is androgen insensitivity syndrome?
Testes present but absent Wolffian ducts - female appearing external genitalia
328
What is Intersex 46, DSD?
Have testes but genital ducts/external genitalia not fully masculinized
329
How does androgen biosynthetic dysfunction in 46, XY individuals occur?
1. LHR mutation
2. 17alpha hydroxylase deficiency
3. 5alpha reductase deficiency
330
How does excess androgen in 46, XX individuals occur?
1. 21alpha hydroxylase deficiency
2. Aromatase deficiency
3. Increased androgen exposure
331
What is the function of 21alpha hydroxylase?
Production of cortisol and aldosterone
332
What happens with use of testosterone injections?
Lower FSH levels, decreasing normal production of androgens
333
What affects both aging and obesity?
Caloric intake
334
What are the risks of testosterone therapy?
Heart attack, stroke, blood clots and heart-rhythm irregularities
335
What are the effects of ageing on pancreatic functioning?
Decrease glucose metabolism by increasing insulin resistance and decreasing insulin secretion
336
What are the effects of ageing on thyroid functioning?
Decrease TSH and decrease T3 (due to decreased T4 metabolism)
337
What are the effects of ageing on pituitary functioning?
Decrease in GH
338
What are the effects of ageing on liver functioning?
Decrease IGF-1
339
What are the effects of ageing on gonadal/adrenal functioning?
Decrease E2, T and DHEA
340
What are some examples of autoimmune diseases?
Addison's
Graves
Hashimoto's
Type 1 Diabetes
341
How do T/B cells have such a diverse recognition capacity?
They can rearrange their DNA during development to change the ability of antibodies and receptors to recognize different types of polypeptides
342
What is the function of T/B cells?
Immune function
T = T cell receptors
B = antibodies
343
What is a central pathogenic step in the development of autoimmune disease?
Breakdown of self-tolerance
344
How are dangerous T and B cells with self reactive receptors eliminated?
Negative selection (apoptosis)
345
What are possible disruptors of self-tolerance?
Defects in apoptosis-related death receptor molecules
Defects in internal apoptosis mechanisms
Defects in suppression of T cells
Defects in B cell tolerance to self
Hypocortisolism
346
What are the effects of cortisol on the immune system?
Suppresses the immune system (T/B cells)
347
What are environmental factors that effect autoimmunity?
Infectious agents
Diet
Toxins
348
What is the connection between Type 1 diabetes and Rubella?
Antibodies against rubella proteins have a similar molecular structure to the antibodies against proteins in the beta-cells of the pancreas
349
What happens with circadian levels of cortisol?
Lower immune function (T-cells)
350
What does Addison's disease develop antibodies against?
21-alpha hydroxylase
