Unit 02: Hypothalamic pituitary gonadal axis Flashcards
what controls androgens and estrogens
- anterior pituitary gland gonadotropins LH and FSH
- these glycoprotein hormones are ultimately reg by hypothalamic release of GnRH
what do gonadotropins do
- control hormone production by the gonads by promoting synthesis of androgens and estrogens
- in males gonadotropins are inhibited by negative feedback of testosterone
- in females, depending on rate of change, conc of estrogen and stage of menstrual cycle, estrogen can exert both inhibitory and excitatory effects on gonadotropins
what type of hormone if GnRH, what influences its release? how is it secreted?
GnRH is a decapeptide produced by hypothamic neurofibers
- release is influenced by other hormones such as cortisol, insulin, IGF-1, prolactina nd gonadal steroids
- hypothalamus secretes GnRH in a pulsatile manner and it travels via hypothalamic pituitary protal system to stim gonagotroph cells of anterior pit
*stimulation of gonaotroph cells via a G protein coupled cell surface recptor increases the synthesis of LH and FSH - although one cell type produces both LH and FSH their synthesis and release are controlled independently
describe inhibition of GnRH
- continuous stimulation and release of GNRH yields GnRH recepor down regulation
- Inhibin - hormone produced by the Sertoli cells of testes and granulosa cells of developing follicles inhibit further FSH release with little effect on LH secretion
-
what is activin
paracrine factor produced and acts locally in both the pituitary and in the gonads
functions in the pituitary gland to stimulate primary FSH secretion
what are roles of FSH and LH in overies and testes
- FSH and LH are structurally similar glycoproteins that bidn to surface recpetors on cells in ovaries and testes
- in ovary: FSH stimulates follicular development while LH stimulates ovulation
- both LH and FSH are neded for steroidogenesis by follicular cells
- in testes: LH is major regulator of testosterone production through activation of leydig cells, FSH acts on sertoli cells during spermatogenesis
decsribe the hypothalamic pituitary gonadal axis
- GnRH i secreted from hypothalamus in pulsatile fashion
- stimulates gonadotroph cells of ant pit to secrete LH and FSH
- LH and FSH stimualte ovaries or testes to produce sex hormones estrogen or testosterone which will inhibit further release of LH and FSH
- inc estrogen levels secreted from follicles during follicular phase of menstrual cycle induces positive feedback -> midcycle surge in LH adn fSH secretion
- inhibit is produced by gonads in response to FSH and exerts neg feedback on gonadotrophs to inhibit further FSH
- locally produced activin acts in paracrine fashion to stim FSH secretion
GnRH and ovulation
- exogenous pulsatile GnRH can be used to induce ovulation in women with infertility caused by dec production of sex hormones
- analogues of GnRH with inc metabolic stabilit and prolonged half lives take advantage of this effect and are used to suppress sex hormone production in clinicla conditions like precocious puberty and prostate cancer
what is Gonadorelin
aka Lutrepulse®, Factrel®
- therapeutic agent that is very similar to GnRH and causes the pituitary gland to release LH and fSH
- its used in both sexes to treat infertility caused by hypothalamic hypogonadotropic hypogonadism - result of GnRH deficiency
- these agents are les common now and FSH and LH analgues ar eprescribed instead
What is menotropin
aka menopur
- also known as human menopausal gonadotropin (hMG)
- has both FSH-like activity and LH-like acitivty (both a FSH and LH analogue, with high FSH activity)
- the substance is extracted from urine of postmenopausal women and used to stimulate ovarian follicular developent in women and spermaogenesis in men
- plays role in ovulation and implantation in women, and testosterone production in men
*hMG is often used in conjunction with LH analogues for infertility in box sexes
what is Human chorionic gonadotropin hCG
- simialr in structure to LH (analogue)
- produced by placenta and excreted in ruine of pregnat women
- recbominant FSH and LH are also available for use and do not require urine extraction - but nore expenive to produce
what is Leuprolide
- used in individuals with prostate cancer, uterine fibroids, endometriosis or assisted reproductive proecdures wehre sex hormone production is abnormally high
- leuprolide is an agonist at GnRH receptors, initially inc lH and FSH but unlike endogenous GnRH leurolife is administered continuously instead of in pulsatile fashion
- this desensitizes the GnRH receptors and decreases the LH and FSH production, leading to hypogonadism (diminished function of testes and ovaries, leading to reduced production of sex hormones)
androgen synthesis in men vs women
- in men androgen in secreted by the testis, stimulated by LH to secrete testosterone
- approx 95% is released by leydig cells and 5% by adrenal glands in men
*small amount of dihydrotestosterone (DHT) and androstenedione are also produced by testes
- in women, small amounts of testosterone are derived from ovaries and adrenal glands, it will be converted to estrogens in body fat and bones
- there is little to no storage of androgens upon synthesis in women
note testosterone is synthesized form cholesterol
how is testosterone transported?
- testosterone is delivered to target tissues in the blood and most of circulating testosterone is bound to sex hormone- binding globulin (SHGB)
- a small amount (1-2%) is found free in blood
- its metabolized in most target tissues via dihydrotestosterone by 5α-reductase at many sies and estradiol by aromatase in the liver, adipose, bone and brain
all effects of sex steroids in target cells occur by way of _____
steroid nuclear receptor mechanisms
- ex: dihydrotestosterone and testosterone bind to the androgen receptor (dihydrotestosterone shows greater affinity) and estradiol binds to the estrogen receptor
what are androgens responisble for?
- androgens are responsible for secondary sex characteristics, virilization and growth promotion
- more specifically, the actions and effects of androgens include spermatogenesis, genitalia, secondary sex glands, deepening of the voice, facial hair, libido, behavioural changes, lean body mass, erythropoiesis and a decrease in HDL
- estradiol also plays a pivotal role in closure of growth plates in long bones
describe the clinical applications of androgens
- androgen preparations like testosterone have been used for androgenic and anabolic effects
- Test has a 1:1 androgen:anabolic ratio - attempts have been made to alter preparations to product more anabolic effects
ex: tanazolol, nandrolone decanoate and oxandrolon - oral preps of androgens must by pass the liver
- half life of testosterone can be varied by adding esters, allows for formulation of depot preparations like enanthate, cyprionate and undecanoate
- transdermal also available with patch or organogel
toxicity/side effects of exogenous androgens in men and women
men: prostatic enlargement, acne, moodiness and other behaviour problems, hepatic dysfunction, cancer, suppression of spermatogenesis which can cause sterility, atherosclerosis and heart disease
women: masculinisation can occur and androgens are contraindicted in pregnancy
what is the most common use of androgen preparations?
for androgen replacement therapy
- used o replace or augment endogenous androgen secretion in hypogonadal men which can result from testis or pituitary deficiency
- oral, intramuscular and transdermal testosterone preparations are available
- for indivduals where spermatogenesis is requires, donagotropins can be used until puberty and then testosterone cna be aplied
androgen therapy for gynecologic disorders
- androgen therapy can be administered to reduce best engorgement post partum because androgens antagonise the growh promoting effects of estradiol on the breast
- patients undergoing chemotherapy for inoperable best cnacer or post menopausal women might also receive androgen preparaions
- danazol which has hyperandrogenic effects can be used to alleviate symptoms of endometriosis
what is donazol
- type of androgen therapy
has hyperandrogenic effects can be used to alleviate symptoms of endometriosis.
androgen prescription relating to puberty
- for ndividuals requiring growth stimulation such as boys with delayed puberty, androgens can be prescribed
- androgens decreae with age and therefore supplementation might occur ebcause the hormone has shown to increase lean mass and hematocrit while reducing bone turnover in older men
abuse of androgens
in form of anabolic steroids
- desirable bc they inc strength, aggressiveness and performance
- possible side effects include behavious problems, aggresion, depression ,liver dysfuntion and lvier cancer
5 clincial uses of androgens/anabolic steroids
- most common for androgen replacement therapy - used in hypogonadal men (have testis or pituitary deficiency)
- used for gynecologic disorders: reduce breast engorgement post partum, alleviate symptoms of endometriosis
- used as a protein anabolic agent following surgery, trauma or other debilitating disease
- for growth stimulation in boys with delaed puberty
- abuse in sports of anabolic steroids
what instnaces would you want to suppress androgens
- treatment of male prostatic cancer, benign prostatic hyperplasia, endometriosis, hirsutism in women, male pattern baldness, excessive sex drive or behavious problems in men and precocious puberty
what is leuprolide
anti androgen
acts as a GNRH agonist (continual delivery)
what are ketoconazole and spironolactone
anti androgen
Testosterone synthesis inhibition
what is finasteride
Inhibition of 5α-reductase
what are Flutamide, Cyproterone
anti androgens
- androgen receptor antagonists
describe synthesis of estrogen
- most important natural estrogen secreted in premenopausal women is estradiol produced by ovary
- steroidal estrogens (estrone, estradiol and esriol) are formed from testosterone or androstenedione precursors in the follicular grnaulosa and theca cells in ovaries by aromatase
- estrone and estriol are synthesized from estradiol, largely by the liver but some peripheral conversion of nadrogens ocur by aromatase in other tissues
- in post menopaudal woman adipose tissues produces estrogen and the adrenal glands produce estrone from DHEA (dehydroepiandrosterone).
*in men most estrogens occur from extra-gonadal conversion of testosterone, DHEA and androstenedione
what synthetic estrogens are commonly used?
ethinyl estradiol and mestranl (widel used in oral contraceptives)
what is the most important natural progestin? describe tis synthesis
- most important naturlly produced progestin is progesterone
- produced in the ovaries and adrenal gland, as well as placenta during pregnance
- progesterone serves as a precursor for estrogens, androgens and adrenocorticoids
- in men progestins are produced in the testes
examples of synthetic progestins
L-norgestrel, norethidrone and medroxyprogesterone (also used in oral contraceptives)
what do estrogens bind? what do progestins bind?
circulating estrogen binds to SHBG
progestins bind to corticosteroid-binding globulin (CBG)
- some binding (1-2%) to albumin
- the hormone effects by estrogens and progestins are mediated by nuclear receptor events resulting in protein synthesis and responses in target tissues
*there are two estrogen receptors α-estrogen and β-estrogen receptors.
what are the roles of estrogens and progestins - reproductive
- important in normal sexual maturation and contribute to female secondary sex characteristics, breast development, the reproductive tract and behaviours like a sense of well being
- hormoens are als involed in menstrual cycle, specifically ovulation and development of endometrial lining
- critical for control of parturition or birth
non reproductive roles of progesterone
modulation of carbohydrate metabolism
control of pregnancy
suppression of ovulation
adipocyte depositio
sexual maturation of the breasts and reproductive tract and behaviour and mood.
non repprductive roles of estrogen
- bone turnover and density
adipocyte deposition adn blood coagulation
growth during puberty
growth plate (epiphysis) closure
why use oral contraceptives
- control fertility, could reduce risk of ovarian and endometrial cancers, reduce risk of ovarian cysts, and lower the incidence of ectopic pregnancy
- can also help regualte acne and treat symptoms or hirsutism and endometriosis
what are teh two categories of oral contraception
combination estrogens and progestins, and continuous therapy with progestins only
describe combined oral contraception
- most common
- includes synthetic estrogen combined with 1 of 9 progestins
- 21 day cycle of steroids followed by 7 days off
- MOA is suppression of gonadotropin (LH, FSH) suppression which inhibits ovulation by estrogen and proestin feedback inhibition on the hypothalamic pituitary axis
- cervical mucus thickens and inhibits sperm penetration and reduces motility in fallopian tubes
describe the progestin only contraceptive
- reffered to as “mini pill” developed to aovid adverse effects of estrogens in combination preparations
- has slightly higher failure rate and women tend to have high instnaces of menstrual disturbances (irregular bleeding and amenorrhea)
- contrain either norgestrel or norethindrone
what are Norplant-2 and L-norgestrel
silicone capsules that are placed subutaneous in the arm and can last up to 5 years
what is Medroxyprogesterone
- intramuscular depot innjection of crystals every 3 months
what is an IUD
Progesterone intrauterine devices (IUD) are also available and they offer a low dose which is delivered continuously and locally.
describe daily whole calcium balance
- net uptake of 200 mg/day from the GI tract and excretion of 200 mg/day by the kidneys
- calcitriol enhances absorption of Ca+ from the GI tract
- continuous secretion of parathyroid hormone increases bone formation and (even more) bone resorption and stim renal tubular reabsorption of calcium
* both effects raise plasma Ca2+
- cont secretion of PTH also enhances renal clearance of inorganic phosphate
Note: once daily inejction of PTH (blue) stim new bone formation (accetion) more than it stim bone resorption and has only transient (and consequentlyminor ) effects on renal clearance of Ca2+ and PO4
*exogenous calcitonin inhibits bone resporption
