Reproductive Hormonal Pharm
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How is GnRH secreted and what does it stimulate?
GNRH is secreted from the hypothalamus and it stimulates the relieseog LH and FSH from the anterior pituitary. In general, when a pulse of GnRH is secreted then a pulse of LH is secreted also.
What is the half life of GnRH and why?
It is short because it is a small peptide.
Can we check for GnRH in the blood?
It is not measurable in the peripheral circulation
How is GnRH supposed to be secreted and what happens if it doesn't happen that way?
So it is supposed to be secreted in a pulsatile fashion, if it doesn't happen that way and it is secreted in a continuous way then there is a decrease in LH and FSh due to the desensitazion and the down regulation of the GnRH receptor on the pituitary gonadotrophes by the presence of GnRH.
What is the difference in the making of an GnRH agonist and antagonist?
Agonists usually have 1 substitution while an antagonist requires more substitutions.
What is the general function of the GnRH agonists and antagonists?
To increase the half life of the molecule
What are the short term effects of the GnRh agonists?
it is very similar to that of GnRH. GnRH agonists binds to the receptors initiating a cascade of events that culminate int he synthesis and secretion of gondadotropins (LHand FSH).
What are the long term effects of GnRH agonsists?
So short term we have them increasing LH and FSH but long term the gonadotropes become desensitized to the continuous presence of GnRH agonist due to the down regulation of the GnRH receptors and via the uncoupling of any remaining receptors from the intracellular machinery so, this results in the reduced circulating gonadotrophin levels.
The effect GnRH agonists have on the pituitary increasing the FSH and LH in the body.
What can GnRH agonists be used for?
They can either be used to stimulate or inhibits the pituitary and gonadal function. In the short term it stimulates it and in the long term it inhibits it.
What is the mechanism of action of GnRH?
GnRH antagonists out-competes GnRH for the GnRH receptors and blocks the ability of GnRH to initiate the intracellular cascade that allows for there to be a release of FSH and LH. So the FSH and LH drop automatically. So as long as there is enough GnRH antagonist present, there is a suppression of FSH and LH. HOWEVER the GnRH receptors remain functional in the pituitary so there can be a rapid reversal if needed.
So a child got into her mother's GnRH something.. She can't remember if it is Agonist or antagonist. When would you be expected to see a reversal of the LH and FSH decrease in each?
- Antagonist: immediate reversal as soon as the GnRH is high enough to outcompete because the receptors are ok, they are there and functional.
- Agonist: There will be a slow increase in the LH and FSH because there is a down regulation of the GnRH receptors and there is an uncoupling of any of the remaining receptors, so the increase of LH and FSH will take some time.
We have a patient that tried to commit suicide and took pills which she thought to be pain killers but were really GnRH antagonists.. What would we expect her LH and FSH levels to be a couple hours later how would this be different if she had taken agonists?
They will be near undetectable with the antagonists but had she taken agonists the levels of LH and FSH would be increased and then after a couple of days they would slowly decrease.
We have a patient with delayed puberty in which the activation of Hypothalamic- pituitary-gonadal axis is delayed, what medication would you give her?
Pulsatile GnRH or Pulsatile GnRH agonist.
When would you use GnRH agonist?
- Stimulate LH and FSH: delayed puberty
- ovulation induction in hypoginadotropic hypogonadism
- Suppression: prostate/breast cancer
- precousious puberty
What are the long term side effects of takin GnRH agonists for suppression and what is done to help this?
osteoporosis and bone fractures and usually GnRH agonist administration is accompanied by an 'Add back" therapy that includes a low dose of estrogen or progestin to help out.
When are GnRH antagonists used and what is the goal?
- females: invitro and goal is to prevent unwanted LH surges. It allows for there to be stimulation of the ovary while preventing the estrogen from causing a premature surge of GnRH.
- males: help treat prostate cancer and the goal is to suppress testicular androgen production
During menopause what is elevated and why?
Circulating gonadotropins are elevated sue to lack of negative feedback from the ovaries
What do gonadotropins do and why are they used?
- they are used clinically to stimulate gonadal function
- males: the administration of them can stimulate spermatogenesis and restore fertility in males with hypogonadotropic hypogonadism and the hCG is administered because it has LH like activity and has a longer half life and hCG stimulates testosterone production which is essential for spermatogenesis.
- females: stimulate ovarian function for in-vitro fertilization. FSH is the choice since LH is not necessary for follicle growth. If resumption of meiosis and ovulation is desired then hCG is administered since it has the same biological activity as LH and has a longer half life.
What is the most powerful androgen and how is it made?
testosterone is converted into dihydrotestosterone by the enzyme 5-alpha reductase in selected peripheral tissues such as prostate, penis, scrotum, liver and skin.
What are androgens clinically used for and how is it given?
- effects on bone mass, erythorpoetin pxn and libido
- it is usually given via a patch or as a transdermal gel applied to the underarm or inner thigh (oral not uses due to liver or go issues)
What are some of the sideffects of using testosterone bc you actually need it?
- infertility: feedback suppression of LH and FSH which are needed for spermatogenesis
- gynecomastia: T is precursor for E
What is testosterone used for?
Anrogen replacement and anemia
What are the common abused anabolic steroids and what are the side-effects?
- Testosterone androstrnedione and dihydrotestosterone.
- Common side effects are infertility, liver damage, hypertension, increased risk of heart disease, prostatic hypertrophy and testicular atrophy.
What are the categories of anti androgens? What are they used for?
5Ar inhibitors are the most common since the prosate and the hair follicles contain active 5Ar enzymes. They are mainly used to tray BPH (benign prostate hyperplasia) and male pattern bladness.
inhibits type 2 5A reductase (its a antiandrogen) approved for treatment of BPH and allopecia
inhibits both type 1 and 2 5 alpha reductase and is approved for the treatment of BPH.
What are the different types of 5 AR?
- Type 1: found in skin and liver and it is responsible for 1/3 of it
- Type 2: localized in the reproductive tissues and counts for the 2/3 of 5AR
What are the androgen antagonists?
Flutamide, bicalutamide and nilutamide and spiranolactone.
What is the mechanism of the androgen antagonists?
- Fluatime, bicalutamide and nilutamide: these bind to androgen receptors and inhibit stye interaction of testosterone and dihydrotestrosterone with the androgen receptor so they block the action of androgen in the target tissues including the hypothalamus and the pituitary. so the levels of testosterone may be normal or even elevated following androgen antagonist administration.
- Spiranolactone: competitively binds to the androgen receptor and inhibits 17 alpha hydroxyls which results in decreased synthesis of androsternedione and testosterone.
What androgen is used in the treatment of prostate cancer?
flutamide, bicalutamide, and nilutamide.
Why do most contraceptives have both estrogen and progesterone? (like what do each do?)
estrogen will both inhibit gonadotropin secretio and stimulate endometrial proliferation and since unopposed endometrial proliferation can lead to cancer, they add progestin to oppose the estrogen stimulation
What are the clinical uses for estrogen?
- Birth control
- hormone replacement for menopasuse
- maintain bone density- inhibits osteoclast activity and antagonizes parathyroid hormone
- invitro- estrogen and progesterone to prepare endometrium for implantation
selective estrogen modulators: some compounds act as estrogen agonists in certain tissues and antagonists in others.
What is the Perfect SERM and why?
- Bone- er agonist- to prevent osteoporosis and reduce fracture risk
- CNS- er agonist- reduce menopause symptomes
- Cardo- ER agonsit- lower cardiovascular risk
- breast- er neutral or antagonist- prevent or no incase in breast cancer
- uterus- er antagonist- prevent or no increase in endometrial cancer
- Bone- er agonist
- breast- er antagonist
- uterus- er antagonist
- used to prevent osteoporosis and breast cancer in postmenopausal women
- breast: antagonist
- uterus: agonist
- used to treat cancer in HER2 positive breast cancer in premenopausal women
- estrogen antagonist in the CNS
- used in treatment of infertility to stimulate gonadotrophin secretion an ovarian follicle growth
TSEC and why is it useful
tissue selective estrogen complex is a combo of SERM and estrogen
- estrogen antagonist of the endomentrium and breast but has little activity in the bone
- this and estrogen has been approved for the treatment of post menopausal women with vasomotor symptoms and the prevention of osteoporosis in women with an intact uterus.
Aromatase inhibitors what do they do?
- there is competitive and irreversible inhibitors.
- They are used to treat breast cancer in post menopausal women
What are the competitive inhibitors of aromatase?
anastrozole and letrozole
irreversible aromatase inhibotors
exemestrane and formestane
What is the role of progestins?
- regulate gonadotropin secretion
- thciken cervical mucus
- inhibit endometrial growth
- myometrial contractions
- inhibit lactation during pregnancy
- increase basal body temp
What is the role of progestins clinically?
- Low dose- contraception by thickening mucus
- High dose (depo)- inhibit ovulation
- used in post menopausal women to inhibit estrogen induced endometrial proliferation when on hormone replacement therapy
What is the role of progestin antagonists?
Main one is Mifepristone (RU486) used as abortificient. It blocks the action of progesterone resulting in the sloughing of the endometrium and contraction of myometrium and 2 days later misoprostol is given.
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