Endocrine Day 2- GH/Female reproductive Flashcards
What is the pathway for short loop negative feedback for GH?
- GH released from ant pituitary somatotrophs after stimulation by GHRH
- GH “feedbacks” to arcuate nucleus and ventromediolateral hypothalamus to decrease further output of GHRH and increase somatostatin release
- Somatostatin release from periventricular nucleus, reached somatotrophs and inhibits their release of GH
What does GHRH do at cellular level of somatotrophs?
Causes increase in cAMP which leads to GH synthesis
GHRH and somatostatin are released in _____ fashion from hypothalamus
alternating
What are the 3 main feedback functions for regulation of GH?
- Long-loop negative feedback
- Insulin-like growth factor is released from liver
- this feeds back to pituitary and hypothalamus to inhibit further GHRH release from hypothalamus and GH from pituitary
- also feeds back to increase somatostatin release from hypothalamus
- Short-loop negative feedback
- GH feedsback from pituitary to hypothalamus, inhibiting further GHRH release and increasing somatostatin release
- Ultra short loop negative feedback
- GHRH neuron feedbacks on itself at hypothalamus to decrease further output GHRH
- Also ultra short loop for somatostatin to decrease its further output
GH release is very ____ because of multiple layers of feedback
defined
The ___ ___ ___ is responsible for the pulsatile pattern of GH.
Ultra short loop
___ ___ is rapid acting, robust feedback of GH
short loop
____ is longer term, regulator of output of GH
IGF-1
What molecule is GH similar to in structure?
What can this be used for?
Prolactin
- When GH present in excessive amounts, can bind to prolactin receptors and cause increase in milk production in cattle
What are some effects of GH at adipose tissue?
Decrease glucose uptake
Increase lipolysis
Overall, decrease adiposity
What does GH do at liver?
- Increase RNA synthesis
- Increase protein syntheiss
- Increase gluconeogenesis
- Increase somatomedin C
What does GH do at muscle?
- Decrease glucose uptake
- Increase amino acid uptake
- increase protein synthesis
Overall, increase lean body mass
Remember, this is only in RESTING muscle cells
GH is a _____ hormone and ____ glucose concentrations
hyperglycemic; increases
Inhibits glucose uptake by adipotcytes and resting muscle cells
What is effect of somatomedin C and GH at bone, heart and lung?
- Incrase protein synthesis
- Increase RNA synthesis
- Increase DNA synthesis
- Increase cell size and number
Overall, increase organ size and increase organ function
What are some effects of GH and somatomedin C at chondrocytes?
- Increase AA uptake
- Increase protein synthesis
- Increase RNA synthesis
- Increase DNA synthesis
- Increase collagen
- increase chondrotin sulfate
- increase cell size and number
Overall, incrases linear growth
GH targets liver to produce IGF-1, this goes on to ____ ___ and ___ ___ release
Inhibit GHRH/GH ; Increase SS
Why was IGF-1 originally called somatomedin C?
Because it regulates effects of GH by increasing SS
Both IGF and GH work ____ and ____ on bone, heart, lung and chondrocytes
together and independently
What is a potential side effect of taking growth hormone (abusing GH)?
Can cause tumor growth.
Normally, immune system takes care of tumors, BUT with extra GH, tumors can proliferate in size and metastasize
What is IGFs role at bone, heart, lung, chondrocytes?
Stimulatory, like GH up until a point, then plays a role in inhibition
“stimulation then inhibition”
From med notes:
- A point of clarification on somatomedin C (IGF-1): it is often not the IGF-1 secreted by the liver that is mediating the effects of growth hormone, but rather, the IGF-1 production and secretion by the local tissues.
- In most cases, the growth hormone will travel to the target tissues, whether that is muscle, adipose, etc. and cause a local increase in the release of IGF-1, which then mediates the effects of growth hormones on tissues nearby.
- The two hormones work together – it is a combination of the direct effects of growth hormone and those effects mediated locally by IGF-1.
Growth hormone is thought of as a ____ hormone
anabolic
Increasing muscle mass while decreasing fat
What stimulates GH/GHRH release?
- Glucose decrease- triggers stimulation of GH so it can exert its hyperglycemic/lipolytic effect and increase BG in body
- FFA decrease
- AA increase- stimulate GH to uptake excess AA to enlarge/proliferate cells
- fasting (same as glucose/ffa decrease)- same as glucose/ffa decrease
- prolonges caloric deprivation
- stage 4 sleep- largest release of GH during 24 hour period
- exercise-
- stress-physiologic (Exercise) and psychological stress will trigger output of GH to increase BG available in blood stream
- estrogen/testosterone
- dopamine
- serotonin
- alpha adrenergic agonist
- GABA
- Enkephalin
bold= talked about in class
What inhibits GHRH/GH release?
- Glucose increase
- FFA increase
- cortisol
- low cortisol- increases GH synthesis
- high cortisol levels- (ie chornic stress)- inhibits GH
- ie child in abusvie
- obesity- inhibit GH secretion byincrease in FFA/glucose
- pregnancy-
- HCG is like GH- when placenta grows and makes HCG, gives negative feedback to decrease amount of GH
- somatostatin
- GH
What is the GH plasma concentration like in males?
- Male have more testosterone than females
- Testosterone highly anabolic and increase GHRH and somatostatin
- Causes high peaks of GH and very low troughs (caused by SS)
- Very regular, every 4 hours
What is the GH plasma concentraiton like in females?
- Somewhat elevated baseline
- more peaks of release and can be more erratic
- peaks of GH are not as high
Still overall positive effect on GH
- Estrogen causes less production GH compared to testosterone
Why are females, in general, shorter in stature than males?
- Males have more regular pattern, have larger growth in stature.
- Females will be taller at start of puberty
- due to fact that females enter puberty earlier
- making lots of estrogen before males making testosterone
- estrogen at epiphyseal plates- estrogen secreed and process growth sooner, but causes earlier closure of plates and cessagtion of growth
- In males, testosterone close the end plates, but males will have maximal hormone secretion and GH production
What is the difference in response of GH to acute stress and chronic stress?
- In acute stress, cortisol is elevated and leads to increase in protein syntheiss, including GHRH, leading to increase GH synthesis
- In chronic stress, long term elevation cortisol is catabolic
- this decreases protein synthesis and drops level of GHRH and therefore GH
When is the highest amount of GH released in a 24 hours period?
Deep sleep
What is prenatal growth dependent on?
- Non GH dependent
- GH does not stimulate fetal growth since it is not produced in adequate levels to yield enough IGF-1
- Is IGF-2 dependent
- IGF2 can stimulate growth without interaction of GH
What is output of GH in childhood?
- At birth, growth process switches to be mediated by GH and IGF-1
- During childhood, relative increase in GH and plateaus until puberty
What happens to GH production during puberty?
- Huge increase in sex hormones causes increase in GH
What is the adult level of GH?
- Rate of sex steroid produciton slows after puberty causing plateau to adult level
- Total GH output slows
What does GH production look like in senescence?
- Sex steroid levels decline with age, GH declines
- Leads to loss of muscle mass, increase fat deposits
- Research to counteract effects by pulsatile releases of GH as opposed to pill (which would cause more side effects due to constant level of GH)
What is acromegaly?
- Increased growth of soft tissues of face, increasing in tissue in hands d/t excess GH (can see enlargement of lip, jutting of jaw (prognathism), increased circumference of fingers)
- after puberty/closure of epiphyseal plates
What is gigantism or giantism?
- GH secreting pituitary tumor present at onset of puberty and continuing into adulthood
- epiphyseal plates have not yet closed and GH causes increase bone growth at accelerated rate
- If this condition is not corrected in childhood, can develop acromegaly once plates close
What is pituitary dwarfism?
- Due to deficiency of pituiatry somatotrophs or decreased somatoropic produciton of GH during childhood developement
- IGF-1 also low
- Cuases short stature
- IGF and GH at inadequate levels
What is laron drawfism?
- Due to defective GH receptors
- IGF-1 is also low, however GH levels may be elevated due to loss of IGF-1 negative feedback
- GH will be released at increasing quantities, but it doesn’t matter because the receptors don’t work
- IGF-1 low, BUT GH high
What is the master sex hormone? Where is the hormone released from? Acts on?
- Master sex hormone- LHRH aka GnRH
- Released form medial preoptic area and arcuate nucleus
- Act on gonadotrophs in anterior pituitary gland (gonadotrophs then release LH/FSH
LH and FSH are what kinds of hormones?
Glycoprotein hormones
LH/FSH, TSH and HCG all have what in common?
Identical alpha subunits
What is job of LH and FSH in the female?
Targets specific cell types in ovary to produce:
- 17-beta-estradiol (main ovarian estrogen)
- secretes progesterone
Most of the time, 17-b-estradiol feeds back to LH cell to ____ further output of LH/FSH
Reduce
(negative feedback most of the time)
Most of the time, 17-b-estradiol is _____, but at specific time in menstrual cycle, it produces a _____ feedback at level of medial preoptic area and pituitary.
negative; positive
The gonadotrophs are stimulated in ____ fashion by ____
pulsatile; LHRH
What are some modulatory inputs for LHRH neurons?
- Norepinephrine- positive stimulation of LHRH neurons (NE stimulates LHRH)
- Beta endorphin neurons (opioid type)- inhibit LHRH
- from med notes- this is an elevated hormone in times of stress.
- release of this hormone would cause reduced fertility and reduced sexual behavior
- Gonadotropin inhibiting hormone (GnIH)- inhibits LHRH
These inputs help let the body know when it is a “good time” to make sex hormone and when it is a bad time.
LHRH has a ____ rhythm
circhoral (aka hourly)
Estrogen causes a _____ feedback on LH release
Negative
- In monkey, they removed the ovaries and monitored LH concentration in plasma (top graph)
- monkey had continuous hourly peaks of LH
- when they administered estrogen, then LH plasma levels diminished, displaying negative feedback (bottom graph)
- med notes: the removing of the ovaries uncovered the circhoral rehythm of LH release
Pathway of follicle development?
- Starts as cohort of 6-10 primordial follicles
- Then develop into primary follicles
- Develop into secondary follicles
- Get “first among equals” from secondary follicles and becomes the graffian follicle (aka ovulatory follicle)
- Around day 14 LH surge causes physicla process of ovulation to occur
- extrsuion of ovum into peritoneal cavity
- ovum swept up into fallopian tube
- Remaining granulosa and thecal cells go on to form corpus luteum
- CL- becomes progesterone secreting body
- Remants of luteum (last 3-4 dyas of life) become the corpus albicans
What are primodial follices?
- 6-10 follicles recrutied by FSH stimulation
- these are undeveloped follicles
- oocyte surrounded by undifferenteiad layer of precursor cells
What are the primary follicles?
- Oocyte Surrounded by one layer of granulosa cells and basal lamina outside granulosa cells
What are secondary follicles?
- Oocyte surrounded by multiple layers of granulosa and thecal cells
- single layer of thecal cells on membrane surrounded by basal lamina
What is the grafian follicle?
- The one secondary follicle that races ahead of the other follicles
- has oocyte surrounded by multiple layers of granulosa cells and thecal cells
- has fluid filled center called antrum
- capable of ovulatin
What happens at day 14 in ovarian cycle?
LH surge which causes extrusion of ovum from ovary
What happens to ovum once extruded from the ovary?
Swept up by fimbria of falloptian into fallopian tube for possible fertilization in uterus
What do the remannts left behind after ovulation?
- THe granulosa and thecal cells that remina behind become the corpus luteum
The corpus luteum is a ____ secreting body
progesterone
- Preovulatory follicles are estrogen secreting
- after ovulation, follicles secrete progesterone
What happens durign follicular phase of ovarian cycle?
- Last approximately 14 days, but variable
- egg develops into follicle
- stimulated by FSH
- estrogen produced
What happens during ovulation phae of ovarian cycle?
- Egg released from follicle (LH surge)
- Egg in abdominal cavity
- picked up by fimbria of fallopian tube
- not necessarily halfway point
What happens during luteal phase?
- Postovulatory phase 14 days (more constant)
- corpus luteum develops from exploded follicle
- prodcues progesterone as well as estrogen
- progesterone stimulates uterus to be ready for a baby
- if no pregnancy, corpus luteum degenerates into corpus albicans
What does 17-beta-estradiol start as?
Cholesterol
What targets thecal cells? What is produced by thecal cells?
LH targets thecal cells
- Androstenedione
- testostrone
Once androstenedieone and testosterone are made in thecal cells (by LH stiulation) they easily ____ into ____ cells.
diffuse; granulosa
Inside granulosa cells is an enzyme called ______. What does it do?
aromatase
remember this enzyme!!!!
Converts androgens–> estrogen, primarily 17-b-eastradiol
What type of cells does FSH stimulate? What does this cause?
FSH stimulates aromatase activity inside the granulosa cels
What happens in the granulosa cells? What stimulates this reaction?
- Conversion of androstenedione and testosterone into estrogen (speicfically 17-beta-estradiol)
- Binding of FSH onto thecal cells stimulates aromatase and conversion of estrogen
What does high estrogen cause?
- High estrogen stimulates the positive feedback at LHRH neurons in MPOA/OVLT
- High estrogen causes synchronization of firing of all the LHRH to produce large pulse of LHRH out of hypothalamus and into anterior pituitary
- this large pulse stimulates ovulation (LH surge)
Low estrogen at the hypothalamus causes a ______ feedback
negative
- Low estrogen produces NEGATIVE feedback into LHRH neurons in arcuate nucleus and median emminence
What is the critical level of estrogen?
200 pg/mL
In the monkey experiment, what caused the initial dip in LH levels?
- Low estrogen (when they first started giving estrogen) causes a negative feedback to LH, causing levels to decrease
- Caused by binding of low estrogen at arcuate nucleus
What does estrogen have to do to cause LH surge?
- Be sustained greater than 200 pg/mL
- sustain for 36 hours
- in a rising slope fashion
As estrogen levels in monkey experiement drop below 200 pg/mL, what occurs?
Negative feedback resumes, decrase LH
What happens when LH surge reaches ovary and ovulatory follicle?
Causes biophysical changes in follicle
What does LH surge cause at the follicle?
- Large increase in local follicular steroid hormones aka progesterone
- Increases proteolytic enzymes (collagenase) as well as follicular hyperemia and prostaglandin secretion
- This weakens the follicle wall and causes plasma transudation into follicle
- This leads to degeneration of stigma and foolicle swelling causing…
- follicle rupture and evagination of ovum (aka ovulation)
General cycle of hormones involved in uterine cycle?
- Estradiol starts out low in first 3-5 days (menstruating in this graph)
- first 14 days= follicular, last 14 = luteal
- Frist 14 dyas, estradiol levels low d/t low LH/FSH
- low LHRH
- Then cohort premodial cells recruited (by FSH) and develop into primary, secondary, graffian cells.
- Increase in estrogen and estradiol as thecal/granulosa cells grow
- Add more LH/FSH receptors onto thecal/granulosa cells
- start to produce more estradiol
- When estrogen levels >200 pg/mL, then MPOA/OVLT have positive feedback estrogen to dump LHRH into protal vessels
- cause LH surge, causing ovulation to occur
- After extusion of ovum, progesterone levels rise from corpus luteum (high progesterone is also negative feedback for LH/FSH)
- Lower estrogen levels causes negative feedback on LHRH neurons,decreasing LH/FSH
- Inhibin also produced by CL and decreases FSH production
What is inhibin?
- Inhibits FSH secretion
- When inhibin is high, FSH remains low
- When inhibin levels drop, FSH has slight increasing
- this slight little bump in FSH recruits the next cohort of follicles to start the cycle over again
Why does ovulation cause a drop in estrogen?
Loosing granulosa cells causing a drop in estrogen
Why does LH/FSH increase after decrease of estrogen and progesterone (when corpus luteum degenerates)
Loss of negative feedback on LH/FSH
What are actions of estorgen on femal reproductive tract?
- Proliferation and enlargement of vaginal epithelium
- Increased vaginal secretions
- Increases water content of cervical mucus
- causing it to thin and become permeable
- Increases growth of uterine glands
What are effects of progesterone on femal reproductive tract?
- Antagonizes effects of estrogen on tissues
- Maintains a non-contractile uterus by inhibiting smooth muscle contractions
- Causes thickening of cervical mucus, creating barrier to pathogen invasion
- Stimulates uterine gland secretions
- Prog. and E withdrawal cause uterine cell lining sloughing and bleeding
What is the proliferative phase? Secretory phase?
Proliferative phase= follicular phase, day 7-14
Secretory phase= luteal phase, day 14-28
What is PCOS?
- Polysytic ovarian syndrome
- Condition with excess ovarian androgen production and some degree of virilization; hair, genetalia, increased muscle mass, menstrual cycle disruptions
What happens hormonally durign PCOS?
- High androgen secretion causes increase increase in estrogen caused by aromatase inside adipose tissue
- estrone (type of estrogen converted from androgens) at high levels disrupt normal pattern of LHRH form hypothalamus
- this results in excess LH and not enough FSH
- High LH level causes lots of androgen production from thecal cells
- HOWEVER, reduced FSH levels does not allow stimulation of thecal aromatase, so androgen in thecal cells does not convert estrone to estradiol. causing chronic anovulation (can’t build up ESTROGEN levels to cause surge to ovulate)
What are some treatments for PCOS?
- Clomifene, clomide- block effects of excessive estrone and return pattern to normal
- Obesity- insulin resistance, treat with metformin
- Androgen antagonist
- can also treat symptoms with birth contorl, but this will not restore fertility
What is role of obesity in PCOS?
- Obesity if sometimes associated with PCOS d/t high insulin levels typical of insulin resistance
- Insulin targets thecal cells, making them produce excess androgens, leading to PCOS symptoms
What is impact of stress on ovarian cycle?
- Elevated stress hormones (beta endorphins and CRH)
- make contact with LHRH/GnRH hormones causing inhibitiong
- leads to decrease LH/FSH, decrease E/P and causing amenorrhea and state of infertility
How does LH production change in various stages?
- Prepubertal: circhoral rhythm, LH/FSH at low level
- Midpuberty: noctrunal pulsations in LH/FSH but down durign daytime
- Adulthood: large pulses throughout 24 hours period
What regulates LH in prepuberty? Maturity?
- Prepuberty
- increase in GABA (inhibitory NT keeps LHRH low)
- decrease in glutamate (excitatory NT)
- Adulthood “sexual maturity”
- decrease in GABA
- increase in glutamate (both cause increase in LHRH/FSH and E/P)
“Resetting of gonadastat”
What is precocious puberty? How can it be treated?
- Early onset of puberty
- Treat with LHRH super agonist
- desensitization of LHRH causes decreased responsiveness of LHRH ligand (downregulation of LHRH receptors)
