Unit 02: Hypothalamic pituitary gonadal axis Flashcards
1
Q
what controls androgens and estrogens
A
- anterior pituitary gland gonadotropins LH and FSH
- these glycoprotein hormones are ultimately reg by hypothalamic release of GnRH
2
Q
what do gonadotropins do
A
- 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
3
Q
what type of hormone if GnRH, what influences its release? how is it secreted?
A
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
4
Q
describe inhibition of GnRH
A
- 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
-
5
Q
what is activin
A
paracrine factor produced and acts locally in both the pituitary and in the gonads
functions in the pituitary gland to stimulate primary FSH secretion
6
Q
what are roles of FSH and LH in overies and testes
A
- 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
7
Q
decsribe the hypothalamic pituitary gonadal axis
A
- 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
8
Q
GnRH and ovulation
A
- 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
9
Q
what is Gonadorelin
A
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
10
Q
What is menotropin
A
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
11
Q
what is Human chorionic gonadotropin hCG
A
- 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
12
Q
what is Leuprolide
A
- 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)
13
Q
androgen synthesis in men vs women
A
- 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
14
Q
how is testosterone transported?
A
- 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
15
Q
all effects of sex steroids in target cells occur by way of _____
A
steroid nuclear receptor mechanisms
- ex: dihydrotestosterone and testosterone bind to the androgen receptor (dihydrotestosterone shows greater affinity) and estradiol binds to the estrogen receptor
16
Q
what are androgens responisble for?
A
- 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
17
Q
describe the clinical applications of androgens
A
- 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
18
Q
toxicity/side effects of exogenous androgens in men and women
A
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
19
Q
what is the most common use of androgen preparations?
A
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
20
Q
androgen therapy for gynecologic disorders
A
- 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
21
Q
what is donazol
A
- type of androgen therapy
has hyperandrogenic effects can be used to alleviate symptoms of endometriosis.
22
Q
androgen prescription relating to puberty
A
- 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
23
Q
abuse of androgens
A
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
24
Q
5 clincial uses of androgens/anabolic steroids
A
- 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
25
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
26
what is leuprolide
anti androgen
acts as a GNRH agonist (continual delivery)
27
what are ketoconazole and spironolactone
anti androgen
Testosterone synthesis inhibition
28
what is finasteride
Inhibition of 5α-reductase
29
what are Flutamide, Cyproterone
anti androgens
- androgen receptor antagonists
30
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
31
what synthetic estrogens are commonly used?
ethinyl estradiol and mestranl (widel used in oral contraceptives)
32
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
33
examples of synthetic progestins
L-norgestrel, norethidrone and medroxyprogesterone (also used in oral contraceptives)
34
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.
35
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
36
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.
37
non repprductive roles of estrogen
- bone turnover and density
adipocyte deposition adn blood coagulation
growth during puberty
growth plate (epiphysis) closure
38
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
39
what are teh two categories of oral contraception
combination estrogens and progestins, and continuous therapy with progestins only
40
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
41
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
42
what are Norplant-2 and L-norgestrel
silicone capsules that are placed subutaneous in the arm and can last up to 5 years
43
what is Medroxyprogesterone
- intramuscular depot innjection of crystals every 3 months
44
what is an IUD
Progesterone intrauterine devices (IUD) are also available and they offer a low dose which is delivered continuously and locally.
45
levonorgestre
- plan B
- large dose of estrogens alone or combined with progestin can prevent pregnancy
- must be taken within 72 hours of intercourse in oder to make endometrium unreeptive to blastocyst for implementation
46
what is mifepristone
potent selective progesterone receptor modulator that blocks progesterone's actions on the endometrium and results in endometrial shedding and luteolysis
- used to induce abortion at up to 70 days of pregnancy
47
what is cogenital primary hypogonadism
- can occur due to failure of ovarian development and women are usually infertile a a result
- can use hormones as a replacement therapy to sub naturally occuring hormones
- treatment around puberty (11-13) in atempt to mimic the endocrine physiology of puberty
- therapy is low dose estrogen for 21 day then add progestin when initiual uterine bleeding occurs
48
describe hormone replacement therapy
- can be required in menopausal women or tho who had surgery to remove ovaries
- natural ovarian failure or surgical removal results in decreased estrogen and progesterone which can cause various physiologic and psychological changes
- menopause or removal of ovaries will cause a reduction in genitalia size which is known as atrophy (atrophy)
- ppl can experience depression, loss of libido, lack of energy, hot flashes (vasomotor spasm), loss of bone density (osteoporosis) and cardiovascular disease (astherosclerosis)
49
what do progestins do to estrogen
educe the amount of estrogen that is stimulated which can cause endometrial changes.
50
what are ovulatory induction agents
- may benefit infertile women
- apporx 20-30% of infertility is due to anovulatory conditions
- several classes of agents used to treat infertility such as GnRH analogues (asumes a functional pituitary glad/ovary( and FSH/LF analogues (assumes functional ovary)
**clomiphene citrate** is a partial estrogen receptor agonist that can be used to induce voulation by inhibiting negative feedback inhibition of estrogen on hypothalamic-pituitary-gonadal axis
- this causes FSH levels to increase which enhances follicular recruitment
- this type of therapy needs to be repreated until woman is preg bc normal ovulatory function will likely not return after a single dose
51
what are gonadal inhibitors
- can be used for people undergoing cancer therapy
- selective estrogen receptor modulators SERMs such as **tamoxifen** can be used in the treatment of early and advanced breast cancer in women of all ages
- tamoxifn acts as an estrogen receptor antagonist in estrogen receptor positive breast cancers
**Exemestane:** aromatase enzyme inhibitor, can be used alone or in combination with tamoxifen for the treatment of breast cancer.
Prostate cancer can be treated with 5-α reductase inhibitors (**finasteride**) or androgen receptor antagonists (**flutamide, spironolactone**).
52
what are the mild, moderate and severe effects of estrogens and progestins
mild: nausea, headaches, endocrine changes
moderate: weight gain, vaginal and uterine tract infection due to reduced mucus, breakthrough bleeding, depression
severe: hepatic dysfunction and dyslipidemias, breast cancer, thrombeombolic disease due to inc coagulation activity, myocardial ifnractions and atheroclersois, hypertension and cerebrovascular disease
53
what is secreted by the posterior lobe of the pituitary gland? whats its other name?
- also called neurohypophysis
- antidiuretic homrone (ADH) and oxytocin also secreted
- ADH = importnat regulator of plasma volume and osmolality
- oxytocin has physiologic effects on uterine contraction and lactation
54
what type of hormone is oxytocin? where is it synthesized? where is it secreted?
Oxytocin is a peptide hormone thats structurally similar to vasopressin (aka ADH)
- synthesized in paraventricular nuclei and to lesser extent the supra optic nuclei of the hypothalamus
- secreted from nerve endings of these neurons which end in the neurohypophysis
\*other sites of synthesis are luteal cells of ovary, uterus and fetal membranes
55
what causes release of oxytocin
follows sensory stimuli from the cervix and vagina at birth or suckling by a newborn
- oxytocin enhances the frequency and force of uterine contractions under the permissive effects of estrogen priming
- contraction of myoepithelium stimulates oxyotcin release for milk injection (coordination with rpolactin is also important for this process)
56
what is the effect of progesterone on oxytocin
antagonizes the effects of oxytocin
57
describe feedback regulation of oxytocin
follows postivie feedback regualtion
initial stimulus results in production of more hormone\*\*
58
what type of hormone is vasopressin, where is it synthesized and what is the stimuli for its release
Vasopressin is a peptide hormone, functioning primarily as an antidiuretic hormone in humans
- its synthesized in the same neurofibers as oxytocin
- stimuli for ADH are increasing tonicity through activation of osmoreceptors in the hypothalamus and decrease in bp through activation of baroreceptors
59
what does vassopresin do
(aka ADH)
- acts of kidney to promote water retention via the V2 receptors and constricts blood vessels via the Vi receptors
60
what is pitocin
synthetic oxytocin
- drug of choice for labour induction
- administered via IV infusion to augment dysfunctional labour and hypotonic contractions or control postpartum hemorrhage
61
adverse effects of oxytocin and contraindictions
- oxytocin rarely causes serious adverse effects but excessive stiulation of uterine contractions may occur
- contraindicted as a labour inductive inductive agent in situations where there is fetal distress, prematuirty, abnormal fetal positioning and cephalopelvic disproportion
62
what is atosiban
- oxytocin antagonist currently used outside of north america
- its an oxytocin analogue that blocks the oxytocin receptor which would prevent oxytocin from binding
- not approved in NA for safety concerns
63
what is Pitressin and DDVAP
pitressin = vasopresin and DDAVP = desmopressin
- treatment of pituitary diabetes insipidus and nocturnal enuresis
- DDVAP is a longer acting vasopressin analogue that does not result in vasocontriction - can be administered IV, IM or intranasal (desmopresin)
64
what are osteoblasts and osteroclasts
osteoblasts: synthesize or build bone (think b for build)
osteoclasts: resorb boney tissue
\*these are specialized cells that continually remodel the human skeleton in response to mechanical forces and endocrine and paracrine factors
65
concentrations of ____ and to a lesser extent ____ are maintained within ____ limits in the body
Calcium concentrations, and to a lesser extent phosphate, are maintained within tight limits in the body.
66
why is bone mineral hemeostatis important?
- abnormalities can lead to problems with neuromuscular excitability such as weakness and tetany,
skeletal structural support disturbances and loss of hematopoietic capacity
67
how is calcium balanced?
- absorbed in the small intestine and excreted by the kidneys
- levels are balanced through actions of key hormones like **parathyroid hormone** (PTH), **calcitriol,** **calcitonin and estrogens**
68
what does PTH do?
- increases serum calcium and decreases inorganic phosphate PO4
- continuous secretion of PTH increases bone formation and bone resorption and stimulates renal tubular reabsorption of calcium
\* once daily injection of PTH stimulates new bone formation or remodelling
69
what is calcitriol?
hormonally active form of Vitamin D (1,25 (OH) 2D3)
- capable of increasing serum calcium and inorganic phosphate
- accomplished by promoting calcium and phosphate absorption by the intestinal tract and kidnets and also promoting bone resorption
- secretion of PTH is directly suppressed by calcitriol production
70
describe calcitonin
- polypeptide hormone that is produced by the parafollicular cells of the thyroid gland
- actions oppose PTH
- secretion **lowers** serum calcium and phosphate levels by inhibiting osteclast activity and reducing calcium and phosphate reabsorption by the kidneys
\*estrogens can also oppose actions of PTH by producing increased levels of vitmain D and slowing down bone turnover
71
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
72
what is osteoporosis?
common disorder of bone mineral homeostasis where bone turnover is disrupted such that bone resporption exceeds bone formation
73
what are the risk facotrs associated with osteoporosis? what are the predisposing causes?
Risk factors: hormonally female, caucasian, smoking, history of prior fracture, age, low weight and body mass index and familial histroy
\* certain systemic illnesses and medications may induce secondary osteoporosis
Predisposing factors: poor diet, gastrointestinal disease, endocrine diseases (hyperthyroidism), liver disease, alcoholism, vitmain D deficiency and certain drugs like corticosteriods
74
75
what is the primary regualtor for adult bone mass?
physical activity, calcium intake, and reproductive endocrine status
= regulators are considered preventions for the development os osteoporosis
- pharmacologic agents can be used in the prevention and therapy of osteoporosis to decrease bone loss (resporption\_ and promote bone formation
76
what is raloxifene
selective estrogen receptor modulator (SERM) with actions on bone adn liver estrogen receptors
- used to treat and prevent osteoporosis but does not prevent hot flashes therefore it might not be prescribed to individuals suffering from hot flashes
77
what is Bisphosphate
ex: risdronate
- most successful therapy for prevention and treatment of osteoporosis
- agent inhibits osteoclast function and bone resorption but does not inhibit mineralization
78
what is teriparatide
PTH analogue used for the treatment of osteoporosis
- a recombinant PTH and needs to be administered daily thoguh subcutaneous inejction
- teriparatide stimulates bone formation rather than inhibit bone resorption when administered intermitently at low doses
79
calcitonin for treatment of osteoporosis
- inhibits bone resportion by osteoclasts in some aptients with osteoporosis
80
calcitriol for treatment of osteoporosis
(aka vit D)
- can be administered to indivduals that are vitmain d deficient
- imporves intestinal calcium absorption and can suppress bone remodeling to imporve mineral density
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