What are examples of negative feedback?
- TSH from anterior pituitary stimulates secretion of T3/T4. T3/T4 have negative feedback on hypothalamus and pituitary.
- Calcitriol on the vitD receptor will negatively feedback on PTH secretion, a factor that CaSR will use in times of hypo and hypercalcemia.
- CRH > ACTH > Adrenal Cortex > Cortisol and then cortisol negatively feedbacks on CRH production in the hypothalamus.
- Sertoli cells upon stimulation by FSH secrete inhibin which inhibits FSH secretion by the anterior pituitary.
Compare hypoPTHism, Secondary hyperPTHism, Primary hyperPTHism.
HypoPTHism: there is low calcium and and HIGH phosphate in blood. Urine: HIGH levels of calcium and low phosphate in urine as well.
SecondaryPTHism: there is high PTH but it has no effect on the kidneys. Due to high PTH there is high levels of phosphate in blood. However, there is no reabsorption of calcium so calcium blood levels are LOW. Therefore calcium levels in urine is high. As for phosphate, despite a large filtered load, there is no inhibition of reabsorption so there is high phosphate in blood while low levels of phosphate in urine.
Primary: there is high PTH, so high calcium and high phosphate in blood initially. The high phosphate will be temporary as the PTH leads to high phosphate in urine and its excretion. Filtered load of calcium is high so also hypercalcuria.
what naturally causes the endometrium to shed?
Profound drop of estrogen and progesterone in a short time. Progesterone keeps estrogen proliferation in check and it has to be a drop of estrogen and progesterone together. This is why there is a placebo period for birth control pills.
What is visceral fat significance in PCOS.
Visceral fat makes alot of stuff that affects sensitivity to insulin. Cytokines and metabolites from bad fat gets to tissues, cells that need insulin binding, will disrupt insulin signaling. If you can’t use the insulin effectively, that person will need to make more insulin.
Insulin (IGF) helps LH stimulate androgen production in theca cells.
Then increased testosterone will have negative feedback. It causes follicles to be cystic, granulosa cells don’t function normally, and no ovulation. If you have no have no ovulation, you will have no progesterone. Without progesterone induced negative feedback, more LH
You will see increased LH/FSH ratio. She has a lot of insulin and even more LH and they drive androgen production.
In the middle of all that is hyperglycemia.
She is still producing estrogen and it may even be elevated and hey, thats why PCOS is vulnerable to uterine cancer.
How does growth hormone lead to hypertension?
GH leads to fluid retention and in excess has some effect on aldosterone.
Why do we need pituitary gondatropins during pregnancy?
The women bypasses the pituitary contribution, the fetus and the placenta takes over for it.
The central pathway is shut down because that is metabolically wasteful. She doesn’t need to menstruate and shit.
Cortisol helps us function over the long term….
It will make sure we have enough sugar right now but enough for later (muscle is the ideal area for glycogen storage)
Liver is also a large warehouse. Especially when we are metabolically active and skeletal muscle is working.
What is SHBG and how is it regulated?
SHBG - binds testosterone.
In the event of elevated androgens, SHBG goes down and that has more free testosterone.
In women, elevated estrogen would increase SHBG keeping her free testosterone bound.
Whenever testosterone goes up, that favors more free testosterone.
why does lower albumin, increase measured calcium.
Because our assay is on bound calcium, there may be more than we actually measured.
Free and ionized calcium may still be normal.
What five tests could be used in someone you suspect has GH deficiency?
- Arginine stimulation
- Exercise stimulation
- Insulin induced hypoglycemia
- Dopamine stimulation
- Clonidine (alpha2) stimulation
All promote the production of GH.
How would you test for congenital adrenal hyperplasia and similarly adrenal insufficiency?
CAH - you would use ACTH stimulation.
in someone suspected of CAH, 17alpha-hydroxylase will be working and cause the production of androgens without the expected rise in cortisol and aldosterone.
Adrenal insufficency - you should see increased production of all adrenal corticol steroids
Cosyntropin (ACTH analogue)
A woman’s period ended 8 days ago. Relative to the last day of her period, where would her serum activin, inhibin, estradiol and FSH levels be?
Menses end on day 4 of the follicular phase. 8 days later would place her at day 12, right before ovulation. Inhibin B will drop off and activin will elevate. Activin will promote FSH secretion, increasing FSH levels. Increasing FSH, increases estrogen levels. The only thing that went down is inhibin B.
What are the symptoms of prolactinoma?
Female: breast discharge and irregular menstrual periods in women.
Men: decreased sexual desire, breast enlargement.
a 40 year old wants a child. Which will likely decrease her changes of achieving a live birth pregnancy.
Oocyte quality profoundly decreases after age 36. So aneuploid oocytes is a likely possibility. You wouldn’t think depletion of the ovarian follciular reserve.
Why do some women with PCOS have elevated estrogen?
Peripheral fat androgen aromatization.
What is CYP 17
CYP 19
17B-HSD
5- alpha-reductase
CYP17: the steroid enzyme in adrenal gland
CYP19; aromatase
17B-HSD - enzymes that converts androstenedione into testosterone;
5-alpha-reductase: it acts in androgen responsive target tissues by converting testosterone to the more bioactive DHT.
What are the 12 steps of the cycle
Step 1: FSH independent development of follicle switches to FSH dependent development
Step 2: The FSH/LH surge from the previous cycle stimulates the maturation of the follicle
Step 3: FSH/LH drops and low levels knock out the GnRH pulse generator so estrogen levels are low as well
Step 4: selected follicle expresses more FSH follicles and secretes inhibin B which decreases FSH secretion.
Step 5: Suddenly dominated follicle starts secreting lots of estradiol. This increase in estradiol signals the switch to positive feedback.
Step 6: Inhibin B levels fall. This releases negative feedback on activin. Activin promotes FSH secretion, contributing to surge.
Step 7: GC start expressing LH-receptor. LH will start the luteinization (terminal differentiation) of the follciles. Progesterone starts being produced
Step 8: LH surge leads to changes in the follicle that release the oocyte
Step 9: Remnant of the follicles terminally differentiate into the corpus luteum. Secreting progesterone and estrogen.
Step 10: Progesterone will keep the uterus quiet but also is leading to changes in gene expression that prime the uterus for shedding.
Step 11: Fast drops in estrogen and progesterone cause shedding
If a woman becomes pregnant, hcG will keep the corpus luteum alive and continue progesterone secretion. Progesterone will keep the myometrium quiet. It will knock out all the gonadotropins and eventually the placenta will take over all the neuroendocrine functions. Then progesterone withdrawal and a E3>E2 ratio, will stimulate contractions.
A women underwent a successful pregnancy. 8 months later she has galactorrhea and amenorrhea. What is causing this symptom?
Lactation and irregular menses are classic signs of hyperpolactinemia. Dopamine suppresses PRL secretion so a lack of it will lead to elevated PRL
Which hormone is THE sign of normal ovulation and so which test would you do first?
Progesterone is only possible due to the CL which is only possible if ovulation occurs.
Progesterone leads to increase in basal body temperature.
A man has benign prostate hyperplasia. Which hormone is elevated?
DHT is elevated . Growth and maintenance of the adult prostate is entirely the role of DHT.
A cell has high CYP17, CYP11A, no CYP19 and expresses 17-beta HSD
all points to androgenic cell. Theca. CYP11A is the enzyme that converts cholesterol to pregnenelone.
What is a diagnostic test you would do fore CAH (hypovolemia with 21 hydroxylase defect)?
ACTH stimulation
A girl has hyperandrogenemia leading to hirsutism. What would be a good idea to give her
Estrogen-progestin
Together they greatly inhibit FSH and LH secretion which decreases androgen production.
Estrogen will increase SHBP - sex hormone binding protein which decreases free testosterone
What are the classic signs of PCOS?
Hyperandrogenism, hirsutism, obese phenotype, anovulation
Secondary hyperparathyroidism. What happens to calcium, phosphate and calcitriol?
Sick kidneys that don’t respond to PTH.
Low calcium, high phosphate, and low calcitriol (which with PTH stimulation is made in the kidneys.)
What do sertoli cells secrete
AMH, inhibin, activin, and ABP
What are the effects of hyperphosphatemia?
Commonly the result of acute renal failure.
The high phosphate inhibits calcitriol synthesis and bone reabsorption.
TOgether with calcium, phosphate will form metastatic calcifications in cardiovascular tissue.
The inhibition will lead to hypocalcemia.
What are the clinical features of 5-alpha-reductase deficiency.
5-alpha-reductase forms DHT which is critical for the formation of external genitalia.
Karyotype is male
Wollfian duct is present
Genitalia - is ambiguous, could be a small penis or vaginal pouch.
What are the clinical representation of complete and partial androgen resistance.
Complete: they have female internal genitalia. External genitalia is female. Testosterone cannot act on the Wolffian duct.
Partial: can develop female secondary characteristics, testes can still make testosterone and be converted to estrogen.
What is cyptoorchidism?
Undescended testes, a process that is the final event of male development and dictated by testosterone.
It is the most common birth defect in male babies. It usually corrects itself with the surge of testosterone in the first year of life.
Problems: infertility, high risk for testicular cancer, high risk for inguinal hernia.
Describe Kleinfelter’s Syndrome?
Describe Male XX syndrome.
Karyotype is 47 XXY.
Presentation: small penis, weak muscle tone, ADHD, elevated gonadotropins, low testosterone, elevated estrogen,
Karyotype is 46 XX. There is a translocation from SRY to X chromosome. So a male inherits an X and a X with the translocated SRY. The presentation is that of a male.
How does cortisol affect the reproductive neuroendocrine pathway?
Cortisol not only blocks ACTH which diminishes some androgen production (in males this production is negligable),
Cortisol will block FSH and LH secretion, therefore preventing the testes from making testosterone and sperm.
IN the case of prostate cancer, glucocorticoids are a potential treatment. This is because prostate cancer initally depends on androgens for growth and survival.
Describe the general testosterone signaling pathway
Testosterone circulates bound to SHBG. When it is unbound it enters the cell easily as a steroid.
Then 5-alpha-reductase converts it to DHT which binds more potently to AR> The AR receptor is coupled to heat shock proteins.
The binding of DHT releases the heatshock proteins which then homodimerize to bind to androgen response element, recruiting coactivators and stimulating gene expression.
Testosterone can also be aromatized into estradiol and bind to estrogen receptor.
What is the role of osteocytes
Primarily FGF23 secretion.
2 things are said to stimulate osteocyte activity.
- elevated phosphate levels
- and calcitriol (the opposite)
FGF-23 will inhibit both calcitriol and PTH ultimately for Phosphate excretion
Estrogen from granulosa cells / or sertoli cells will positively stimulate FGF23 production as well but not directly at the level of osteocytes.
Describe CaSR activity. In high calcium and low
High calcium:
- in the parathyroid gland, CaSR senses there is high calcium and inhibits PTH secretion. It also ramps up VitD receptors which via negative feedback will decrease PTH secretion
- in the proximal tubule, high calcium inhibits calcitriol
Low calcium
- in parathyroid gland, CaSR senses low calcium and promotes PTH secretion and inhibits vitD receptor so there is no negative feedback.
- in proximal tubule, calcitriol is also made
