Lecture 13 - Hormones Flashcards
Describe the classical pathway of hormones
- Hormones are released from the cell sin which they are synthesized, then circulate in blood largely bound to sex hormone binding globulin (SHBG) (tightly bound) and albumin (loosely bound)
- Only unbound hormones enter cytoplasm of target tissue cells where they bind to a hormone receptor (HR) forming a hormone-receptor complex (HR-C) which then dimerizes and translocates into the cell nucleus.
- Specific cofactors (coactivators or corepressors) unique to each tissue interact with both the air-C and hormone response elements (HREs) on the target gene.
- Gene transcription is either activated or repressed depending on the hormone, the receptor, the tissue, and cofactors (>300 identified) involved
- Hormone activity depends on presence and density of specific hormone receptors, binding proteins, coactivators and corepressors
Describe other pathways for hormones
Intracellular signalling pathways and direct effects on cellular membranes via the estrogen receptors (i.e. non-genomic related)
What are the target tissues for ER-alpha?
prevalent in uterus, ovary, breast
also in liver, bone, adipose tissue, brain
What are target tissues for ER-Beta?
colon, vascular endothelium, lung, bladder and brain
What are target tissues for ER-alpha and ER-Beta?
ovary, central nervous system and CV tissues
What are target tissues for PR-alpha?
predominant in uterus and ovary
What are target tissues for PR-Beta?
predominant in breast
What are target tissues for AR?
Vagina, ovary, testes, bones, muscles
Urogenital tract
_____ = dominant female hormone
estrogen
What does estrogen do?
- sexual maturation and growth (females and males)
- development of endometrial lining
- maintain structure & function of skin and blood vessels (vasodilator, antioxidant)
- decrease rate of bone resorption
- liver alterations - increase production of CBG, SHBG, TBG, transferrin, angiotensinogen
- increase HDL, decrease LDL, slight decrease in plasma cholesterol, increase triglycerides
- enhances coagulability of blood: increase clotting factors 2, 7, 9, and 10, increase fibrinogen, decrease antithrombin 3, despite increase in plasminogen levels and decrease platelet adhesiveness
- induces synthesis of both estrogen and progesterone receptors
What does progesterone do?
- Precursor to estrogens, androgens, and adrenocortical steroids
- Downregulates ER & suppresses estrogenic stimulation of endometrium
- Induce maturation & secretory changes in endometrium
- High affinity for P receptors, differing affinities for androgen & glucocorticoid receptors
- Progesterone metabolites have a anxiolytic and hypnotic effect on brain
- Antagonizes the mineralocorticoid receptor - decreases sodium resorption and H20 retentions
What is the Hypothalamic-Pituitary-Gonadal Axis?
- Responsible for regulation of menstrual cycle in females and the regulation of testosterone production and spermatogenesis in males
- Gonadotropin-releasing hormone (GnRH) secreted from hypothalamus in pulses
- GnRH stimulates anterior pituitary gland to secrete follicle stimulating hormone (FSH) and luteinizing hormone (LH)
- FSH and LH stimulate ovarian synthesis of E and P respectively in females and spermatogenesis and testosterone production respectively in males
- Circulating levels of estrogen and progesterone in women and testosterone in men result in both positive and negative feedback of GnRH, FSH, & LH release
Briefly describe the menstrual cycle
GnRH releases FSH, stimulates release of estrogen
Increased estrogen leads to release of LH, LH continues to stimulate the follicle
LH releases corpus luteum
**see clinical notes
What types of patients is estrogen-containing contraceptives CI in?
- age 35 and over who smoke
- hypertension
- diabetes with severe vascular disease
- history of stroke or ischemic heart disease
- migraine headaches with focal neurological symptoms (aura)
- multiple risk factors for CVD (older age, smokers, obesity, DM, HTN)
- breast, endometrial, ovarian or cervical cancer
- active liver disease
- thromboembolic disorder (past or current)
- pregnancy
List the MOA’s of hormonal contraceptives
1) suppression of gonadotropin (FSH/LH) secretion - dose-dependent inhibition of ovulation
(COC work this way, POP do not always inhibit ovulation)
2) inhibits the development of the dominant ovarian follicle/suppression of ovarian steroid production by suppression of FSH (estrogen effect)
3) Endometrial effects (atrophy) making it less suitable for implantation (progestin effect)
4) Thickening of cervical mucus impeding sperm transport (progestin effect)
5) Impairment of normal tubal motility and peristalsis which interferes with ovum and sperm transport (progestin effect)
_____ ______ = synthetic estrogen used in most estrogen-containing COC
ethanol estradiol
What does addition of an ethanol substituent to estradiol inhibit?
first-pass metabolism and increases potency
_____ is a prodrug of ethanol estradiol
mestranol
Review slide 15-17
sounds g
List some well known benefits of oral contraceptive pills
- prevent pregnancy
- cycle regulation & decreased menstrual flow
- decreased peri-menopausal symptoms
- help relieve menstrual pain (decreased dysmenorrhea)
- relieve PMS-related problems and PMDD
- improve hirsutism & acne
- decreased risk of fibroids/possibly fewer ovarian cysts
- maintenance of bone mineral density
List some less known benefits of oral contraceptive pills
- treat PCOS; hypothalamic amenorrhea
- reduce pelvic inflammatory disease
- reduce ectopic pregnancies (exception POP’s can cause an increase risk of this)
- improve symptoms of endometriosis
- reduce risk of ovarian CA by 50% (after 5 years of use; persists for 10-20 yrs after discontinuation of OC)
- reduce risk of endometrial CA by 50-60% (after 8 years of use)
- possible reduction of benign breast disease (reduced biopsies)
- may be protective against colon cancer
Signs of too much estrogen
nausea, breast tenderness, headache, bloating
Signs of too little estrogen
spotting, breakthrough bleeding early/mid-cycle
Signs of too much progestin
breast tenderness, headache, fatigue, mood changes, bloating
Signs of too little progestin
breakthrough bleeding late cycle
Signs of too much androgen
weight gain, acne, hirsutism, increased LDL, decreased HDL
What are some common side effects of COC?
1) irregular/unexpected bleeding
2) breast tenderness and nausea
3) weight gain
4) mood changes
5) chloasma (skin discolouration)
List some less prevalent side effects of COC
- venous thromboembolism
- MI
- stroke
- gallbladder disease
- breast cancer
List some medications that may cause contraceptive failure
- enzyme-inducing anticonvulsants
- antifungals
- antibiotics
- HIV meds
- herbal (st. johns wort)
- bile acid sequestrants
List some medications that may increase OC activity
- strong CYP3A4 inhibitors (gluconazole, ketoconazole, itraconazole, grapefruit juice)
- vitamin C > 1 g doses
List some common myths about COC
1) women on the COC should have periodic pill breaks
2) the COC affects future fertility
3) the COC causes birth defects if pregnancy occurs while taking it
4) the COC must be stopped in all women over 35 years of age
5) COCs cause acne
Weight > _____ may increase risk of pregnancy & clots in patch users
90 kg (198 lbs)
The ____ is effective in obese women
ring
List some points about the POP
- Norethidrone 0.35 mg PO daily continuously (no HFI)
- Good for those CI to estrogen
- Good for those postpartum, breast feeding, and those with endometriosis
List the MOA behind the POP
1) thicken cervical mucus inhibiting sperm penetration
2) lowers the mid cycle LH & FSH peaks
3) alternations in endometrium and impairment of sperm motility
What is considered a missed pill for the POP
> 3 hrs
MOA of depo injection
1) suppress ovulation
2) increase cervical mucus & atrophy of endometrium
common side effects of depo injection ?
- early weight gain
- irregular bleeding
- headache
Others:
- decreased libido
- mood changes
- decreased BMD- improves when discontinued or can add back E
- delay of ovulation approx 9 months after last dose
What are the two IUS’s available in canada?
1) Mirena
- also approved for abnormal (heavy) menstrual bleeding
- 5 years
2) Jaydess
- smaller, better for nulliparous women
- 3 years
MOA of IUDs
- thicken cervical mucus
- high Ing conc in endometrium - decrease E and P receptors and strong anti proliferative effects
SE of IUDs
- mood changes (depression, nervousness)
- decreased libido
- could have irregular bleeding
MOA of emergency contraception
- thickens cervical mucus
- inhibits ovulation
- alters endometrium
Mifepristone is an ??
abortion agent
What is Mifepristone’s MOA
- synthetic steroid
- progesterone-receptor modulator (SPRM)
- competitively binds to both P receptors, blocks effects of progesterone
Mifepristone is typically used with ______
misoprostol
What is misoprostol?
prostaglandin analogue, it promotes contractions
How effective is the mifepristone/misoprostol combo?
> 95% effective within 1st 50 days of pregnancy
MOA of mifepristone/misoprostol combo?
- acts to degenerate endometrium
- decrease support for embryo
- softening & dilatation of cervix
- promotes release of endogenous prostaglandins
- increase uterine contractions
Adverse effects of mifepristone/misoprostol combo?
- vaginal bleeding
- abdominal pain and cramping
- N, V, D
In canada, ____ is used for ectopic pregnancies
methotrexate IM
How does methotrexate work?
- stops embryonic cells from dividing and multiplying through blockade of dihydrofolate reductase which decreases DNA synthesis
- followed by misoprostol to increase contractions
Ovulation inducers are known as _____-_________
anti-estrogens
When are ovulation inducers used?
In women with anovulatory cycles and PCOS (polycystic ovarian syndrome)
List 2 ovulation inducers
- Clomiphene citrate
- Letrozole
Clomiphene citrate is a ??
SERM (selective estrogen receptor modulator)
Describe the MOA of Clomiphene citrate (SERM)
- Competitive inhibitor of estrogen receptors in hypothalamus. Mixed agonist and antagonist activity depending on target tissue
- Occupies ER in hypothalamus, inhibits negative estrogenic feedback, increases GnRH secretion & subsequent FSH & LH release - leads to growth of ovarian follicles with subsequent ovulation
Letrozole is a ??
Aromatase Inhibitor (AI)
Describe the MOA of Letrozole (Aromatase Inhibitor)
-Blocks conversion of testosterone and androstenedione to E2 and E1 respectively, decreases negative estrogenic feedback at pituitary, resulting in increased FSH output
____ _____ is a GNRH agonist
Leuprolide acetate (Lupron Depot)
List some uses of Leuprolide acetate (Lupron Depot) (GnRH agonist)
- endometriosis or uterine fibroids
- advanced prostate cancer
MOA of Leuprolide acetate (Lupron Depot) (GnRH agonist)
Continuous administration of leuprolide interrupts normal pulsatile stimulation of GnRH receptors - inhibition of FSH & LH secretion; suppresses production of ovarian estrogen and testicular testosterone
main adverse effect of Leuprolide acetate (Lupron Depot) (GnRH agonist)
menopausal symptoms such as hot flashes
When is FMP (final menstrual period) confirmed by?
12 months of amenorrhea in women with a uterus
T or F: does premature menopause need hormone therapy treatment?
Yes - premature menopause (age < 40) needs hormone therapy treatment until at least age 51
What is perimenopause?
menopausal transition - usually begins 2-8 years prior to FMP
Symptoms of perimenopause
- irregular periods
- lack of energy
- loss of memory
- hot flashes
- night sweats
- insomnia
- vaginal dryness
- irritability
- depression
______ symptoms can occur during perimenopause (affects >75% of women)
vasomotor
- associated with disturbance in thermoneutral zone in hypothalamus
- increased sensitivity to core body temp changes
Narrowing of thermoneutral zone may be associated with what??
elevated sympathetic activation, mediated through alpha 2 receptors
What widens the thermoneutral zone?
Exogenous estrogen appears to widen the thermoneutral zone and is the most effective treatment of menopausal symptoms (up to 85% reduction in VMS)
VMS = vasomotor symptoms
How long is hormone therapy suggested for?
safe to use as long as symptoms persist at the lowest dose which controls the symptoms
Hormone therapies for menopause:
Indicated for ??
moderate-severe VMS
What is required to have progestins with it?
systemic estrogen treatment if uterus intact to prevent hyperplasia and possible uterine cancer
Hormone therapies for menopause:
Describe the continuous regimen
E & P given continuously (or E given continuously alone if no uterus)
Hormone therapies for menopause:
Describe the sequential regimen
E is given continuously but P is given in pulses for 10-12 days per month
read charts on slide 37 and 38
okay
What can vaginal estrogen therapies be used to treat?
urogenital atrophy due to low estrogen levels
*rapidly restores urogenital health within 3 months
Ulipristal acetate is a ??
SPRM (selective progestin receptor modulator)
What is ulipristal acetate (SPRM) used for?
treatment of moderate to severe signs/symptoms of uterine fibroids in women eligible for surgery
MOA of ulipristal acetate (SPRM)?
- prevents progesterone from binding to the PR, also has direct effect on endometrium and fibroids
- reduces the size of uterine fibroids by inhibiting cell proliferation and inducing apoptosis - decreases bleeding, improved Hbg, decreased pain
- partial progesterone antagonist in pituitary gland; partially suppresses FSH; may inhibit ovulation; maintains serum E2 levels in mid-follicular range in most women
ulipristal acetate (SPRM) has ____ VMS side effects than leuprolide acetate (GnRH agonist)
less
Male Reproductive Physiology:
___ interacts with receptors on Leydig cells in the testes to enhance testosterone synthesis
LH (leutenizing hormone)
Male Reproductive Physiology:
____ and ________ act on receptors in the sertoli cells in testes to regulate spermatogenesis
FSH and testosterone
**FSH also enhances synthesis of the aromatase enzyme (CYP19) that converts testosterone to E2, and of androgen binding protein
Male Reproductive Physiology:
The amount of LH & FSH released depends on frequency and magnitude of ____ pulses and responsiveness of the pituitary to ____
GnRH (both blanks)
Male Reproductive Physiology:
In normal men: __% plasma testosterone is unbound (free)
2
Male Reproductive Physiology:
In normal men: __% plasma testosterone is bound to SHBG
44
Male Reproductive Physiology:
In normal men: __% plasma testosterone is bound to albumin
54
Describe the MOA of testosterone (3 different effects)
1) Direct action of testosterone (T) on androgen receptor affects lean muscle mass and strength
2) Conversion to dihydrotestosterone (DHR) results in amplified action on external genitalia and sexual hair; DHT has 3-10x higher affinity for AR vs T
3) Conversion to estradiol necessary for much of its action on bone; to stimulate normal sexual function (libido and erectile function) and to decrease body fat in men
List some symptoms of androgen deficiency
- low libido
- decreased morning erections
- loss of body hair
- low bone mineral density (BMD)
- gynecomastia
- small testes
When is androgen therapy recommended?
Indicated for male hypogonadism
**also used off-label for hypoactive sexual desire disorder (HSDD) in women at 1/10 doses used for males
What does Hypogonadism refer to?
either a decrease in sperm or testosterone production
Primary hypogonadism
results from disease of testes
Secondary hypogonadism
due to a disease of the pituitary of hypothalamus
List some androgen therapies for hypogoadism in males
1) oral testosterone undecanoate
2) depot IM injections of testosterone
3) testosterone 1% transdermal gels
List some antiandrogens
- finasteride
- dutasteride
(5 alpha reductase inhibitors)
What do anti androgens do?
- block conversion of testosterone to dihydrotestosterone
- decrease size and growth rate of prostate
What are anti androgens used for?
the treatment of BPH (benign prostatic hypertrophy)
*improves urinary flow rate and decreases urinary retention and surgery rates
What is the major side effect of 5 alpha reductase inhibitors
sexual dysfunction (decreased libido and ejaculatory or erectile problems)
Flutamide and bicaltumide are ??
non steroidal antiandrogens
MOA of Flutamide and bicaltumide
- inhibits androgen uptake and/or inhibits binding of androgen in target tissues
- used for metastatic prostate cancer in combination with an LHRH agonist (goserelin)
How do androgenic steroids work?
naturally occurring or synthetic; increase lean body mass and decrease fat mass - include testosterone, stanozolol, nandrolone
