Week 3 Flashcards
(87 cards)
1
Q
21 year old pre-med student presents to the clinic for intermittent palpitations with associated shortness of breath and a tingling sensation in her hands. She confirms anxiety and has lost 6 lbs unintentionally.
- what is going on in this part of her life?
- is she burnt out?
- what other sxs could you see
A
- high stress=high cortisol level
- not yet, but on way
- Some people gain or lose weight -> It tends to deposit centrally; Some people tend to feel sick
2
Q
What hormones come out of the cortex?
A
○ Glucocorticoids (cortisol)
○ Androgens
- Mineralocorticoids (aldosterone)
3
Q
stress response
- process called when body is burdened with stress
- phases
- 1st phase
- what curve looks like and what it means
A
- General adaptation syndrome
- alarm, resistance, exhaustion
- alarm: light initiating phase that kind of knocked her off course where you can see the curve go downward just a little
- body having the stressful event and it hasn’t kicked in anything from the adrenals yet, so the stress kind of knocked the person down a little bit, and then as the curve starts to go upward, that’s where cortisol is jumping on board as well as the catecholamines coming from the adrenal glands
4
Q
HPA axis
- mechanism of ACTH at the adrenal cortex
- pathway at the adrenals
- one effect of ACTH binding adrenals
- how does it result in cortisol
- As you increase levels of cortisol, what does that do to your axis?
A
From the hypothalamus, it releases CRH from the paraventricular nuclei–> CRH binds to corticotropes on the anterior pituitary –> ACTH from POMC is released –> stimulates adrenal cortex to release cortisol
- peptide, receptor is on the membrane (G protein coupled receptor) and called MCR2
- This is a G alpha-s receptor –> adenyl cyclase –> triggers cAMP –> activation of PKA
- ACTH causes the activation of cholesterol-ester-hydrolase which increases cholesterol bioavailability and increases the activity of STAR (transports cholesterol to inner mitochondrial membrane)
- These are the rate limiting steps, and eventually you’ll get the production of pregnenolone –> this then allows the production and release of cortisol –> cortisol has its effects on target organs
- It inhibits it by binding to the anterior pituitary as well as back on the hypothalamus –> this negatively inhibits that axis –> decreases the amount of CRH released, decreases ACTH released
5
Q
When do cortisol levels increase?
- when are they highest
- ACTH
- why is time important?
- what happens if you’re a night worker
A
- They’re highest in the morning and lowest at night
- You should normally have cortisol levels early on in the morning, and it will peak around 8am; then as you go on about the day, cortisol levels decrease
- ACTH is pulsatile, so you have about 7-15 episodes per day and that’s going to stimulate a cortisol release in about 15 minutes of a surge
- If you’re only taking cortisol levels at 2pm, you may not see what’s really going on throughout that axis –> This is why when we look at lab values, we have to look at specific time points
- If you slept during the day and worked at night, your circadian rhythm would change – Your cortisol levels would be flipped
6
Q
Why do we want high cortisol in the morning?
- What’s the point of it?
A
- You want cortisol to be released in the morning to wake up and increase energy, but fasting is also going on during this time so you want cortisol to be released so that you can increase glucose levels in blood to be able to use it as energy
- The point is to increase blood glucose in the body so that you have it energy
7
Q
How is cortisol transported in the blood?
- why is it important?
- when can it bind?
A
- It’s transported with a binding globulin
- Cortisol has a short half-life, so it wants to bind to a protein so that it can help extend its half-life when it’s not being used
- Cortisol is active and can bind to its receptor when it’s not bound, so any cortisol that’s bound cannot bind to its receptor –> keeps its bioavailability a lot longer so that it’s not degraded since it’s not being used up
8
Q
Cellular mechanism of cortisol at its target organ
- where does it bind
- effect on water balance
- other factors that help kidney
A
- Cortisol will be bound to its binding globulin –> when it gets close to the cell then it releases its binding globulin –> cortisol crosses into the membrane –> cortisol binds to its intracellular receptor –> causes heat shock proteins to be released –> receptor dimerizes –> crosses into the nucleus –> binds to its response element –> undergoes transcription and translation –> production of proteins and whatever is needed for that response at those particular cells of the target organ
- can bind to its receptor on cells but can also bind to mineralocorticoid receptors found in the collecting ducts of the kidney
- It would throw water balance off by causing more reabsorption of sodium
- cortisol being bound to a globulin protein helps to allow mineralocorticoid activity to overcome the cortisol activity (aldosterone is going to win out in the kidney), and the other part is that aldosterone dissociates a lot slower than cortisol from its receptor
9
Q
How do you create cortisone from cortisol?
- what is cortisone
- importance of this form
A
- 11 beta hydroxy-steroid-dehydrogenase type II converts cortisol to cortisone
- inactive form of cortisol
- In the kidney, there’s high levels of 11 beta hydroxy-steroid- dehydrogenase type II, so when cortisol gets to that area, it’s converted into cortisone and then it can’t bind to the receptor and affect kidney
10
Q
What does 11 beta hydroxy-steroid-dehydrogenase type I do?
A
- converts from cortisone to cortisol
11
Q
What are the early physiological effects of cortisol? At these target organs what is cortisol doing?
- At the liver
- Skeletal muscle
- Adipose tissue
- Pancreas
- Bone
- Skin
- Reproductive tract
- Immune response
- CV
- Adrenal medulla and sympathetics
A
- Increased gluconeogenesis & glycogenolysis
- Increases in proteolysis & glycogenolysis; cortisol can affect GLUT4 upregulation so you get a decrease glucose uptake and decrease in protein synthesis
- Increase lipolysis & release of FFA and glycerol
- Increase in glucagon, decrease in insulin
- Decreased bone formation, Increased bone resorption, Decrease in osteoblast
- Inhibit fibroblast activation and proliferation and decrease collagen formation
- Decrease function
- Decreases
- Increase adrenergic receptors (Alpha 1 receptors, beta receptors in the heart) –> will increase CO and peripheral vascular resistance
- Increase catecholamines
12
Q
What are stress hormones?
- importance of multiple
A
cortisol, catecholamines, epi, and glucagon, GH
- you have to think about all the other hormones that are being upregulated
13
Q
Exercise
- what kind of response
- what hormones
- glucose use -> how?
A
- stress response
- Dealing w/ cortisol, epi, glucagon, and exercise
- The combo of glucagon, epi, GH, cortisol will allow for glucose to be uptaken and utilized where it need to be
- upregulation of GLUT4 in the exercising muscles due to increased AMP kinase to allow for utilization of the glucose
14
Q
Relaxation techniques
- autogenic training
- centering prayer
- clinical hypnosis
- exercise
- guided imagery
- meditation
- music therapy
- progressive muscle relaxation
- tai chi
- therapeutic breathing
- yoga
- point of this technique
A
- decreased sympathetic tone by visualizing bodily sensations
- contemplative/mindful prayer using mantra
- individualized suggestions paired with guided visualizations
- coordination of physical activity with breathing
- visualizations to cultivate relaxing thoughts ad emotions
- active practice developing “let-it-be” mindset
- uses sounds and harmonies to induce relaxation
- contraction and relaxation of one muscle group at a time
- slow, intentional movements coordinated with breathing
- abdominal breathing, RR <6/min
- coordination of physical postures with breathing
- these techniques were trying to get out of that default mode network of thinking to a higher level of brain wave activity (alpha wave on ECG), which is a more meditative thought pattern
15
Q
Late effects of chronically elevated cortisol?
- liver
- Fat
- blood glucose
- bones
- skin
- flushed face
- decreased reproductive function
- immune system
- CV effects
A
- Increase glycogen synthesis; Proteolysis - breakdown of muscle which can lead to thin extremities, weakness
- Bc of increases in insulin you are no longer breaking down the fat.. You are storing the fat centrally -> central obesity;
- still upregulated, but we are also increasing insulin so now in combination with the obesity we can get insulin resistance
- When you have long term bone resorption –> bone density decreased –> could have osteoporosis
- With chronic cortisol skin becomes very thin, and you’ve lost matrix –> capillary support goes away –> the capillaries can bust which leads to the bruising and striae can occur
- Flushed face - aka plethora related to the alterations in collagen
- Decrease in GnRH –> decrease in FSH/LH and eventually estrogen and that can cause infertility, decreased libido
- At risk for recurrent infections
- Increasing peripheral vascular resistance systemically for a longer period of time –> can now present w/ HTN
16
Q
what is considered chronic cortisol elevation
- is there a transition period?
A
- At least a few weeks (could be a few months or a few years) to really see many of the end effects manifesting themselves
- yes, but prob don’t know when that happens or the length of the period.
17
Q
What the diff etiologies of hypercortisolism?
- ACTH dependent
- ACTH independent
A
- Can either be from a secondary condition (pituitary adenoma), Or can be ectopic (not from the axis at all) such as carcinoma in the lung that is over producing ACTH
- Not dependent upon ACTH, Primary condition prob at the adrenal gland itself, Or could be through exogenous source, Such as glucocorticoids
18
Q
How to determine etiology of patients underlying endocrine disorder
- based off
- why?
- what should you see?
- why that drug?
- what does it mean with no response?
- what does it mean with no response to low dose but having a response with high dose
- what is CRH stimulation used for?
A
- dexamethasone test
- is an exogenous form of cortisol
- Should go under neg feedback to decrease ACTH and then decrease amount of cortisol being released
- Crosses the blood brain barrier, so we can see it make its way to hypothalamus
- that the cortisol is ectopic
- it means that the cells secreting ACTH are not as responsive as normal
- confirms that axis works
19
Q
Dx for labs that show
- no response to low dose dexamethasone, a response to high dose dexamethasone, and increase in ACTH and cortisol with CRH stimulation
- what kind of problem is this?
A
- ACTH dependent pituitary adenoma
- secondary
20
Q
Pit adenoma
- kinds
- tx
A
- micro and macro; majority are micro, macro are usually non-functional and present because of mass effect
- cut it out
21
Q
Difference between cushing syndrome and dx
A
- syndrome: anything that causes sxs from excess gluco-corticoids
- dx: pituitary adenoma
22
Q
ACTH dependent etiologies
A
- pituitary adenoma
- ectopic ACTH
23
Q
ACTH independent etiologies
A
- adrenal adenoma, carcinoma
- iatrogenic
24
Q
Treatment for iatrogenic etiology
- type to give
A
- taper dose of steroid until you get to physiologic level for that person
- hydrocortisone
25
Types of steroids
- long term
- short term
- cross blood brain barrier
- hydrocortisone
- prednisone
- dexamethasone
26
Pt with dysuria, and dipsticknotable for infection. This is second UTI in few months. Patient has weight gain.
- what is causing UTI (direct)
- indirect cause of UTI
- increased cortisol is causing immune repression--leaves patient prone to infection
- increased cortisol -> increase glucosuria -> make patient more susceptible to UTI
27
Resistance phase of general stress adaptation
- caused by
- how do we help?
- higher amount of stress for longer amount of time
| - needs something to tone down
28
Adaptogens for adrenal resistance
- Ashwaganda
- Siberian Ginseng
- Vit B complex
- Vit C
- pre-eminent adaptogen, take daily basis, helpful with thyroid
- initially studied for physical stamina for russian olympians but helpful with mental stamina too
- Co factor for neuro transmission and helps reduce cortisol; use P5P for sleep, titrate until patient starts having dreams again
- Vitamin C: co factor for metabolism of neurotransmitters -> adrenals need most vit C
29
33 yr old female with fatigue, unintentional weight loss, nausea, diffuse arthralgias, light headedness, and problems with memory, depression, and decreased libido. PE shows decreased BP and tanned skin.
- importance of tanned skin
- dx
- etiology
- other name
- high ACTH levels--POMC is precursor for ACTH and stimulates melanocytes --> so elevated POMC= increase in ACTH and increase in stimulation for melanocytes
- addisons dx
- adrenal cortex destruction and in developed countries it is usually autoimmune
- Adrenal insufficiency
30
What is the Cosyntropin test
- function
- what is it
- expected results with normal
- what happens if nothing is seen
- trying to stimulate adrenals
- it is sythetic ACTH
- If the adrenal gland was responsive you would get increase of cholesterol and STAR and then increase cortisol production
- problem is at the level of the adrenal gland (primary)
31
oligospermia
- Oligo=few
| - low sperm count
32
GnRH
- where is it produced?
- size
- process
- timing
- signaling
- binds to?
- what inhibits its release
- what stimulates its release
- What determines whether a GnRH analogue stimulates or suppresses gonadotropins?
- arcuate nuclei
- decapeptide- 8 AA
- gene product is a prepro GnRH, then gets ride of signal peptide and some of the peptides like GAP (GnRH Associated Peptide) present in it. Gets rid of that in the ER to produce the final decapeptide GnRH
- pulsatile; Longer pulses of GnRH favor FSH production, and shorter pulses of GnRH favor LH production
- gonadotrophs; GalphaQ
- Beta endorphins, IL-1, prolactin hormone, GABA and dopamine
- Leptin, norepinephrine, neuropeptide
- Administration strategy: Pulsatile/intermittent dosing---stimulates GnRH release; continuous would suppress GnRH
33
LH and FSH
- produced by?
- are both produced from one cell or 1 from different cell?
- kind of protein
- longer half life?
- when are they produced?
- target organs in male and receptor type?
- end product
- inhibition
- activation
- gonadotrophs
- Some can produce one or the other, and some can do both
- glycoproteins
- FSH
- pulsatile; Longer pulses of GnRH favor FSH production, and shorter pulses of GnRH favor LH production
- LH In male: acts on Leydig cells; FSH in male: acts on Sertoli cells; G alpha s
- production of testosterone
- inhibin B inhibits FSH -> produced by sertoli cells
- activin from the sertoli cels
34
testosterone
- end products?
- Site of synthesis
- stimulation for synthesis
- 1st pathway of conversion
- 2nd pathway of conversion
- estradiol and DHEA
- Testes; specifically the Leydig cells -> in the interstitial spaces around the blood vessels between the seminiferous tubules
- LH (GalphaS)--> CREB initiates transcription of StAR and CYP11A1 --> converts cholesterol to pregnenolone
by cleaving the sidechain and converts C27 to a C21
- Delta 5: 17-alpha-hydroxylase converts pregnenolone to17-alpha hydroxypregnenolone ->
17,20-Lyase converts to dehydroepiandrosterone (DHEA) -> DHEA can also be converted to androstenedione via 3beta HSD or 17-betaOH steroid dehydrogenase converts DHEA to androstenediol which then uses 3 beta HSD converts androstenediol to testosterone
-Delta 4: Conversion of pregnenolone to progesterone through 3 beta hydroxysteroid dehydrogenase--> Progesterone will go down to make testosterone
35
Difference between strucutal forms of GnRH, FSH/LH, and testosterone
○ GnRH is a peptide
○ LH and FSH are glycoproteins
○ Testosterone is a steroid
36
Leptin and male reproductive system
| - action
- activates GnRH
37
What does too much estradiol do in men?
- gynecomastia
38
Sertoli cells
- function
- end result
- other production
- Mature the sperm- both meiosis I & II are gonna be ongoing through Sertoli cells as the provde nutrition for the spermocytes and phagocytose the remnant bodies of the sperm
- spermatazoa by helping spermatid shed excess cytoplasm so it can be slim and trim
39
Androgen binding protein
- binds to testosterone and helps to maintain active levels l of testosterone in seminiferous tubule which is very essential to maintain spermatogenesis.
40
How does testosterone effect sperm count?
- low testosterone-> less active testosterone in seminiferous tubules-> low spermatogenesis-> oligospermia
- Mullerian inhibitory substance and transferrin (plasma unbinding protein that caries iron in it) required in seminal fluid.
41
blood-testes barrier
- function
- importance
- Who maintains the blood testes barrier?
- acts as barrier between blood and testes; protect testes from substances and inhibits some hormones from acting on the testes and has immune protection as well.
- protects luminal compartment of your seminiferous tubules from exposure to blood borne toxins, chemicals or even immune cells. The lumen of the seminiferous tubules has all your advanced sperm cells like spermatids and spermatazoa.
- If immune cells were able to come directly into luminal compartment, it would lead to anti-sperm antibodies which would then eat up the sperms. This could be another cause for infertility.
- Sertoli cells via tight junctions between them. They control entry of various components from the blood, which is close to the basement membrane, on the basal compartment of the seminiferous tubules into the luminal compartment.
42
DHT
- stands for?
- how is it made?
- receptor it binds to?
- function
- dihydrotestosterone
- converted in peripheral target cells by 5- alpha reductase.
- Intracellular (not plasma bound) Androgen receptors
- cytoplasmic receptors are in inactive form, they have DNA binding domain and ligand binding domain and are bound to heat shock protein which keep them in inactive form. As soon as ligand binds it-> heat shock proteins let go-> receptor activated-> travels into nucleus-> dimerizes-> DNA binding motive becomes active-> binds to androgen response elements to target gene-> helps in transcription of target gene.
43
Meds to use when you need decrease of testosterone
- Finasteride is a 5-alpha reductase inhibitor so it stops the conversion of testosterone-> DHT bc DHT is more active form of testosterone that binds androgen receptors.
- Flutamide- competitively inhibits androgen receptor itself-> prevents transcription effects of testosterone
44
physiologic functions of testosterone
```
• Axillary hair growth
• facial hair
• development of secondary sex organs- growth of penis & seminal vesicles
• deepening of voice
• Spermatogenesis
• Libido
- increased muscle mass, etc.
```
45
actions of DHT?
* Embryotic development of prostate
* Testis descension
* Pubic/axillary hair development
* Activity of sebaceous glands
* Male pattern balding
46
Main action of testes vs DHT
s internal male genital tract differentiation is major function of testosterone. Whereas external genitalia and prostatic growth is mainly because of DHT.
47
Spermatogenesis
- steps
- controlled by?
- what do you see?
- depends on?
- Mitosis of spermatogonia -> primary spermatocyte -> meiotic division forming secondary spermatocyte- > 2nd meiotic division forming spermatid -> spermatazoa
- FSH and testosterone -> increase spermatogonia proligeration and increase sertoli androgen binding protein
- At any given time, all steps of spermatogenesis can be identified in the testis.
- FSH acting at Sertoli cells and Intratesticular testosterone level has to be relatively high
48
Relate the key event in spermiogenesis to functional importance of sperm function
- nuclear chromatin condensation
- acrosome development
- repositioning of spermatids; development and growth of flagellum
- formation of mito sheath around flagellum
- haploid chromatin carriers either X or Y chromosome
- Acrosome contains enzymes needed for mucus penetration and fertilization
- microtubular structure provides motility, allowing sperm movement through genital tract
- provides energy for flagellar movement
49
Normal Semen parameters for fertility in adults
* Needs to be in alkaline environment in order to be functional
* Normal volume- 20mL
* Sperm count- 40 million per ejaculate--> 20 million/mL
50
Basis for male conctraception
Progestin inhibits FSH and LH below the levels that are required for spermatogenesis
51
What are some pharmaceuticals that are used to increase spermatogenesis?
○ Pulsatile GnRH analogs like leuprolide
○ Estrogen receptor antagonists that inhibit gonadotropin release
○ FSH
HCG (human chorionic gonadotropin) has been shown to increase spermatogenesis
52
SHBG
- stands for
- function
- synthesis
- effect on testosterone
- effect on time
- same thing as ABP?
- transports all sex hormones in the blood to their target cell
- sex/steroid hormone binding globulin
- in the liver
- Bound form of testosterone is non-functional (inactive) because it has to transport through the plasma membrane to get thru the cell, and when bound, it can't b/c of the protein
- creates a buffer so that testosterone stays longer in circulation and it protects it from degradation (increases half-life of hormone)
- no
53
ABP
- function
- importance
- made by Sertoli cells and binds testosterone and keeps it active in seminiferous tubule and seminal fluid, while SHBG is binding protein in the blood
- In the seminiferous tubule, testosterone does not have any specific receptors but there needs to be an active concentration of it there for the process to occur. So the role of testosterone is obligatory, but indirect in regards to spermatogenesis.
54
Metabolization of testosterone
When testosterone gets metabolized, it will be converted to ketosteroids which can be added to glucuronic acid which will make it more water soluble, or it can be added to sulfate and then eliminated via the urine
55
Free testosterone
- what does that mean?
- how much?
- what keeps it from being free?
- testosterone that is not bound to anything else and is active in the blood
- 2%
- will bind both albumin and SHBG
56
Testosterone replacement
- why not oral?
- how to make it last? importance?
- transdermal/topical gel
- do not do well with first pass metabolism
- add esters to prolong the effects of testosterone -> have to be hydrolyzed into their active form
- bypasses the first metabolism so goes right into systemic circulation
57
Kallmann syndrome
- classification
- what is the problem?
- common sxs? why?
- Hypogonadotropic hypogonadism
- GnRH neurons embryologically start in olfactory nerve in the cribriform plate, and if there's some type of underdevelopment, they don't descend properly, and you don't get primary menarche
- decreased smell, usually GnRH secreting neurons migrate from primordial, olfactory tissue to their correct location in the hypothalamus.
58
Parts of male reproductive tract in sequence through which sperm passes through? and role if any
- Seminiferous tubules: location of sertol and leyding cells
- Epididymis: H+ secretion which decreases luminal pH
- Vas Deferens
- Ejaculatory Duct
- Urethra
- Penis
59
Role of
| -
- Seminal vesicles: Secretion and storage of fructose-rich product, prostaglandins, ascorbic acid, fibrinogen, and thrombin-like proteins
- Prostate: Secretion and storage of fluid rich in acid phosphatase and protease (prostate specific antigen=PSA)
- Cowper glands: Secrete mucus upon arousal
60
Steps for Erection
- results from?
- innervation?
- end result?
- corporeal smooth muscle relaxation mediated by a spinal reflex involving central nervous processing allowing for increased blood flow into the corpus cavernosum
- Corporeal vasodilatation is mediated by the parasympathetic nervous system. Parasympathetic fibers directly innervating the corporeal smooth muscle and sinusoidal endothelial cells release acetylcholine, stimulating the production of constitutive endothelial nitric oxide which then act on smooth muscle and induce relaxation through activation of guanylate cyclase and increased production of cyclic guanosine monophosphate (cGMP) by cGMP-dependent protein kinase (PKG) activation culminating in a reduction in intracellular Ca2+ concentration and a decrease in the sensitivity of the contractile system to Ca2+.
- Smooth muscle relaxation leads to corporeal vasodilation which increases blood flow into the penis which causes erection to occur
61
Steps for Ejaculation
- 2 sequential processes and what are they?
- how do they happen?
- innervation
- emission and ejaculation
- Emission: the deposition of seminal fluid into the posterior urethra and is mediated by simultaneous contractions of the ampulla of the vas deferens, the seminal vesicles, and the smooth muscles of the prostate
- Ejaculation: results in expulsion of the seminal fluid from the posterior urethra through the penile meatus.
- controlled by sympathetic innervation of the genital organs and occurs as a result of a spinal cord reflex arc
62
Steps for Detumescence
- innervation
- how?
- definition
- produced by sympathetic corporeal in the absence of sexual arousal.
- Produced by sympathetic corporeal vasoconstriction and corporeal smooth muscle contraction by noradrenergic, neuropeptide Y, and endothelin-1 fibers.
- Detumescence definition: the process of subsiding from a state of tension, swelling, or (especially) sexual arousal.
63
ED treatment
- usual one, durg class, and MOA
- other type? MOA
- last type?
- Viagra/sildenafil: PDE5 inhibitor; inhibits the degradation of cAMP by PDE5 --> increase in cGMP which causes dephosphorylation of MLC which leads to relaxation in the corpora cavernosa to increase BF
- PGE (prostaglandin) analogs: Act via GalphaS and can cause increased vasodilation to smooth muscle
- Alpha-adrenergic receptor antagonists: inhibit sympathetic outflow that causes vasoconstriction, so it induces vasodilation
64
Hypo gonadism
- causes
- clinical presentation childhood
- clinical presentation adults
- Kallmann syndrome, Adrenal hypoplasia, Pituitary tumors (including prolactinoma), Mutations in GnRH receptors, FSH or LH Beta-subunits, trauma/surgery
- Early childhood onset: short stature, lack of deepening voice, female distribution of secondary hair, anemia, underdeveloped muscles, genitalia with delayed or absent onset of spermatogenesis and sexual function
○ Adults (after normal virilization has occurred): decreased bone density, decreased bone marrow activity --> anemia, alterations in body composition associated with muscle weakness and atrophy, changes in mood and cognitive function, regression of sexual function and spermatogenesis, loss of libido, ED
65
Hyper gonadism
| - causes
○ Hypothalamic tumors
○ Activating mutations of the LH receptors
○ Congenital adrenal hyperplasia (CAH)
Androgen-producing tumors
66
What is negative feedback?
- when a specific hormone at the end of an axis travels to the origins in the axis to downregulate production of those hormones
67
What is positive feedback?
when a specific hormone at the end of an axis travels to the origins in the axis to upregulate production of those hormones
68
inter-uterine weeks axis
- 0-10 wks
- 20 wks
- birth
- get positive feedback, the increased levels of estradiol that are being produced causes increased levels of FSH and LH to help development
- estradiol levels start to have a negative feedback on the axis and so now you start to get decreases in FSH and LH
- lose that negative feedback and get surge of LH again
69
inter uterine weeks development of ovary
- term
- first phase
- surrounded by
- difference between meiosis I and II
- when does it stop? name? what is it enclosed in?
- hormones that regular fetal stage?
- oogenesis
- germ cells (oogonium) undergo rapid mitosis to increase their number
- immature follicles
- Meiosis I is reduction division-your homologous chromosomes separate out
Meiosis II is similar to mitosis-it is separation of chromatids
- prophase of meiosis I; primary oocyte; primary follicle
- maernal LH and FSH
70
HPG axis at different ages
- from the age of 2-8 overall effect
- What happens from age 8-12? cause?
- Negative feedback --> suppresses the axis
- Axis is starting to be activated again, you start to get positive feedback
- Estradiol starts to increase, which increases FSH and LH levels which leads to increase in prepubertal and pubertal change
71
Puberty
- when does it start?
- influenced by?
- First change
- Second change
- Next
- How long does it take
- when does menarche start?
- How do you determine where patient is ?
- Importance of documenting tanner stages separately
- Variable-on average around age 8 or 9
- race and genetics
- thelarche (breast budding)-can be unilateral and this is common for about up to 6 months from starting puberty
- adrenarche:Maturation of adrenal system in relation to androgens -> You get body odor, axillary hair growth, acne, pubarche (pubic hair)
- Peak height velocity (growth spurt), followed by menarche, followed by maturation of all the secondary sex characteristics
- This process occurs over 4.5 years
- Period usually starts about 2 to 3 years after thelarche (breast budding)
- Tanner stages
- The breast development and pubic hair Tanner stages aren't always at the same stage
72
Tanner stages of breast development
- 0-what all children under the age of 7 look like
- 5-adult distribution of everything
- 2-breast budding (you see breast nodule right below areola)
- 4-Mound on mound (areola sticks out a little more than breast, but breast is also slightly enlarged)
- 3 is gonna be in the middle
73
Tanner stages of pubic hair
- 0-no pubic hair
- 2-sparse, thin, light colored pubic hair coming in
- 3-switches to coarser darker hair
- 4-adult type hair
- 5-adult hair spreads to medial thighs
74
3 phases of menstrual cycle
- which controls amount of hormones in each cycle?
- name cycle, how long, and amount of hormone
- estradiol
- Follicular: Starts at day 1 of menses; estradiol levels are low and there's also negative feedback on HPG axis so there's low levels of FSH ad LH
- Ovulatory: Starts about day 13 to 14 -> Ovulation occurs; dominant follicle starts to produce more estrogen, estradiol levels increase, and there's now increased responsiveness of ant pit to GnRH so there's positive feedback -> increase LH and FSH -> lead to ovulation
- Luteal: At day 14 to day 28 -> now even though estrogen and estradiol levels are now elevated, the axis becomes negative inhibition and FSH and LH levels start to decrease
75
endometrial phases
- proliferative phase (which menses is a part of)
| - Secretory phase
76
Follicular Maturation
| - stages, cells involved, and where
- primordial follicle: oocyte and 1 layers of granulosa cells
- primary follicle: fully grown oocyte, zona pellucida, and granulosa cells
- secondary follicle: fully grown oocyte, zona pellucida, granulosa cells and theca cells --> after puberty in the ovaries during menstural cycle; high FSH which bind to granulosa to slowly start increasing the estradiol
- early tertiary follicle: fully grown oocyte, zona pellucida, granulosa cells w/ antrum, theca interna and exerna -> thecal cells are responding to LH; granulosa and thecal cells work together to produce estradiol; FSH is low because of inhibin
- graafian follicle: fully grown oocyte, zona pellucida, corona radiata, cumulus oophorus, granulosa cells w/ antrum, theca interna and exerna
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What does antrum do?
| - importance
- concentrates a lot of FSH, estradiol, growth factor, and plasminogen activating factor.
- prevents follicular atresia -> so, the follicle that is selected to grow all the way into the graafian follicle will have a very well developed antrum with trapped gonadotropins and growth factors inside
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oogenesis at puberty
- stimulus?
- what stage is follicle at?
- what happens?
- what happens when graafian follicle matures before ovulation?
- when is meosis II completed
- what happens to follicle?
- LH surge
- grafian folllicle
- selected follicles will have primary oocytes finish meosis I -> reduction division (diploid to haploid)
- meosis II begins with secondary oocyte but stops at metaphase
- upon fertilization/ penetration of sperm
- forms corpus luteum
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Estradiol synthesis
- role of granulosa cells
- what does this lead to?
- role of theca cells
- difference in enzymes between granulosa and theca cells
- what about progesterone?
- FSH--> Gαs--> cAMP--> PKA--> P450 aromatase--> androstenedione and/or testosterone has to come over to the granulosa cells to undergo aromatization--> converted to estradiol
- very slow increase in estradiol -> positive feedback on FSH until a certain point then it goes to negative feedback
- LH receptors--> LH binds--> Gαs--> cAMP--> PKA--> CYP11A1 activated--> Cholesterol converted to Pregnenolone--> 17 α hydroxylase converts pregnenolone to 17OH pregnenolone--> 17, 20 lyase converts 17OH pregnenolone to dehydroepiandrosterone--> continues to androstenedione and testosterone which diffuses to the granulosa cells to be turned into estradiol
- granulosa cells do not have 17α-hydroxylase so cant convert pregnenolone into 17-hydroxypregnenolone so will not make androstenidione -> has to get it from theca cells
- made by granulosa cells in response to LH
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Female Pt , age 16, no PMH, mensturation starts at 13, cycle length is 28 days, cycle duration is 5 days, bleeding began 9 days ago
- current cycle day?
- what is happening to HPG axis
- what is happening in her ovary
- what is happening in endometrium
- what symptoms might she have
- Day 9
- Negative feedback--> increased levels of estradiol as well as inhibin so FSH is starting to go down… but as the estradiol levels start to increase through the rest of the follicular phase, it's now positive feedback on LH and the surge can occur
- non-dominant follicles undergo atresia and the dominant follicle can survive -> so ovary is in follicular phase with increased capillary density to increase cholesterol delivery
- Endometrium is in the proliferative phase, and in response to estradiol it is undergoing hyperplasia and hypertrophy of the stromal and epithelial cells causing a thickening of the endometrium -> causing elongation of endometrial glands and increase vascularization of the uterus
- none
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Female Pt , age 16, no PMH, mensturation starts at 13, cycle length is 28 days, cycle duration is 5 days, bleeding began 14 days ago
- current cycle day?
- what is happening to HPG axis
- what is happening in her ovary
- what is happening in endometrium
- what symptoms might she have
- Day 14
- LH surge due to estradiol positive feedback -> Increased responsiveness of the anterior pituitary to GnRH
by the Increased number of GnRH receptors and increased pulsitivity--> LH and FSH are increasing--> effect on ovary
- This surge is important because we're trying to cause rupture of the follicle in the ovaries -> Ovarian capillary density is increased and LH causes an increase in vasodilators (bradykinin and histamine) which increases blood flow and primary follicle is becoming edematous and hyperemic. FSH is also increasing proteolytic enzymes which causes disaggregation of granulosa cells and the basement membrane between theca and granulosa cells start to fall apart and granulosa cells luteinize. Oocyte starts to detach. Thinning of follicular walls.--> all leads up to rupture of the follicle.
- Highly vascularized, Glands becoming coiled, Storing glycogen, Release carbohydrate-rich mucus Thickening up and prepping for implantation in the instance that fertilization were t, o occur
- Cramping on one side, Increase cervicle mucus, Increase body temperature, Increased libido, Breast tenderness
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Female Pt , age 16, no PMH, mensturation starts at 13, cycle length is 28 days, cycle duration is 5 days, bleeding began 26 days ago
- current cycle day?
- what is happening to HPG axis
- what is happening in her ovary
- what is happening in endometrium
- what symptoms might she have
- Day 26
- LH and FSH are low (negative feedback) -> Decreased pulsitivity of GnRH
- Since she is not pregnant… regression of the corpus luteum occurs; Ovary in luteal phase
- Menstruation, Shedding of endometrial lining due to low progesterone; Cut off blood supply/ischemia--> tissue necrosis--> shedding endometrial tissue
- Mild-severe cramping, Moody, Food cravings, Muscle aches, joint aches, Fatigue, Migraines, Diarrhea/constipation (ovaries and uterus are releasing prostaglandins which can act on the intestinal tract which are anatomically in close proximity--> IBS symptoms
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OCP's
- MOA
- effects at ovary
- effects at uterus
- effects at breast
- effects of overall endocrine function
- adverse effects
- contraindications
- changing pulse frequency by giving the patient an elevated dose of either estrogen and progesterone or progesterone by itself. This means that now you would not see the ovary and endometrium changes that happened before. You may not get follicular development, no ovulation, and less bleeding. Cervical mucus can also change, making it hard for sperm to survive.
- Ovaries= suppressing ovulation, depressing ovarian function, minimizing follicular development
- Uterus= thicker, less copious cervical fluid. Stimulating proliferation of the endometrium.
- Breast= breast enlargement due to estrogen
- Overall endocrine function= inhibiting the HPG axis. Also, RAAs is also increased, cortisol binding globulin is increased, thyroxine binding globulin is increased
- Clotting, stroke, nausea, breast tenderness, headaches (from estrogen), weight gain (from progesterone), acne (estrogen can help acne while certain progesterones are more androgenic and tend to be worse for acne), gallbladder, depression, break-through bleeding (more common in progestin-only OCPs)
- History of thrombotic disease, Smokers, especially smokers over the age of 35, Breast cancer or tumor that is responsive to estrogen, Migraine with aura, Hepatic adenomas
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Female Pt , age 28, no PMH, mensturation starts at 13, cycle length is 28 days, cycle duration is 5 days, bleeding began 26 days ago, fertilization occurred.
- How did the conception occur? (cervical mucus, prostaglandins, acrosomal reaction)
- what is happening to HPG axis
- what is happening in her ovary
- what is happening in endometrium
- what symptoms might she have
- Increased quantity and capacity of the cervical mucus as well as favorable electrolytes made it ideal for fertilization, Prostaglandins in the seminal fluid help induce uterine contractions to help propel the sperm closer to the egg, Acrosomal reaction--> lysosome help the sperm penetrate the egg and fertilization occur
- She's pregnant and maintaining the corpus luteum which is continuing progesterone production
- Corpus luteum is growing
- The embryonic trophoblast is going to produce hCG which maintains this area so implantation can occur, Embryo implants on the endometrial wall
- Cramps, Minor spotting, Nausea, vomiting, GI symptoms, bloating (thank you prostaglandins), Mood swings
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Precocious puberty
- How early is too early?
- kinds?
- how to evaluate a patient with this?
- management
- consequences
- Secondary sex characteristics before the age of 8 for girls and 9 for males
- Heterosexual precocious puberty and Isosexual precocious puberty
- GnRH stimulation test to determine the pseudosexual vs the complete/true isosexual, For CAH, you can test for the different enzyme deficiencies, You can also test LH and FSH, for true precocious puberty order an MRI of the brain
- Suppress puberty with a GnRH agonist like glucuronide
- Earlier growth spurt, taller than peer initially but will finish growing sooner and be a shorter adult height
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Heterosexual precocious puberty
- what is it?
- causes
- Start to exhibit secondary sex characteristics opposite of what your genetic sex chromosomes are
- CAH (congenital adrenal hyperplasia), Virilizing tumor, Medications/ exogenous androgens
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Isosexual precocious puberty
- what is it?
- other name
- causes
- pseudoisposexual
- presentation
- Secondary sex characteristics are consistent with your actual genotypic sex
- Complete can also be referred to as true, central, or gonadotropin dependent
- Can be caused by things in the hypothalamus or pituitary (like CNS tumors, hydrocephalus, or something intracranial), Incomplete (isolated premature thelarche, pubarche, or adrenarche)
- Sometimes called peripheral, or gonadotropin independent-> Can be caused by exogenous estrogen, ovarian tumor-secreting estrogen, severe hypothyroidism
- Can see café au lait spots and fibrous dysplasia of the bone
