Estrogens, Progestins and Androgens Flashcards
How do hormones circulate through the body?
Hormones that are released from cells circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin
Where are ER-beta receptors found?
Colon, vascular endothelium, lung, bladder and brain
17-beta estradiol and phytoestrogens bind
Where are PR-alpha receptors found?
Uterus and ovary
Binds progesterone
Where are AR receptors found?
Both male and female genitals, bones, muscles
Binds testosterone and dihydrotestosterone (more potent form of testosterone)
What are the physiological effects of estrogens?
Sexual maturation and growth, development of endometrial lining, maintain structure and function of skin and blood vessels, decrease rate of bone reabsorption, antioxidant, induce synthesis of both estrogen and progesterone receptors
What are the effects of estrogens on the liver?
Increased production of CBG, SHBG, thyroid binding globulin, transferrin and angiotensinogen
What is the effect of angiotensinogen?
Increased Na reabsorption and water retention (bloating) and increased blood pressure
What are the effects of estrogen on fats?
Increased HDL, lowered LDL, slight decreased plasma cholesterol and increased triglycerides
What are the effects of estrogen on coagulation?
Enhances the coagulation of the blood. Increases clotting factors, fibrinogen and plasminogen, decreases antithrombin III and platelet adhesiveness
What are the physiological effects of progesterone?
Precursor to estrogens and androgens, downregulates estrogen receptor and it’s stimulation of the endometrium, induce maturation and secretory changes in the endometrium in preparation for pregnancy, antagonizes the mineralcorticoid receptor to decrease Na resorption and water retention
What are the effects of progesterone metabolites?
Anxiolytic and hypnotic effects on the brain
What are the contraindications for estrogen containing estrogens?
> 35 and smoke >15 cigarettes/day, hypertension, diabetes with severe vascular disease, history of stroke, migraine headaches with an aura, multiple risk factors for CVD, women cancers, active liver disease, thromboembolic disorder and pregnancy.
What are the effects of estrogen in hormonal contraceptives?
Inhibition of development of dominant ovarian follicle and suppression of ovarian steroid production by suppression of FSH
What are the effects of progestin in hormonal contraceptives?
Atrophy of the endometrium, making it less suitable for implantation
Thickening of cervical mucus, impeding sperm transport
Impairment of normal tubual motility and peristalsis
What form of estrogen is in combined oral contraceptives?
10-35 mcg Ethinyl estradiol, a synthetic estrogen
Addition of ethinyl inhibits first-pass metabolism and increases potency
Mestranol is a pro-drug
What are some examples of 1st generation progestins?
Norethindrone, Norethindone acetate and ethynodiol diacetate
Medium androgen activity
What are some examples of 2nd generation progestins?
Levonorestrel, norgestrel
Strong androgen and anti-estrogen activity
What are some supposed additional effects of 2nd generation progestins?
Improved libido, negative lipid effects, increased acne and weight gain
Lower VTE risk
What are some examples of 3rd generation progestins?
Norgestimate, Desogestrel, Gestodene
Low androgen activity
What are the supposed additional effects of 3rd generation progestins?
Higher VTE risk, better for acne
What is drospirenone?
A spironolactone analogue, anti-androgenic/anti-mineralcorticoid activity
Improves PMDD symptoms, hirsutism and acne, higher VTE risk, increase s serum potassium
What is cyroterone?
An anti-androgen
How is ethinyl estradiol bound to proteins?
Highly bound to plasma albumin but not SHBG so unbound distribute rapidly and extensively
How are progestins bound to proteins?
Extensively but weakly bound to albumin and moderately but strongly bound to SHBG (can displace testosterone and lead to increased acne and lipid effects
Some strongly bound to CBG
What are the types of typical OC combinations?
21 days of monophasic, biphasic and triphasic (increased progestin), resulting in 13 bleeds each year unless taken continuously
What are the types of extended cycle OC combinations?
24 days, 26 days (estrogen)/24 days (progestin) resulting in 13 bleeds each year, 84 days resulting in 4 bleeds each year
What do progestin only pills contain and cause?
Norethindrone 0.35 mg taken continuously (no off days) resulting in 13 bleeds per year
What are the well-known benefits of oral contraceptive pills?
Prevent pregnancy, cycle regulation and decreased menstrual flow, decreased per-menopausal symptoms, decreased dysmenorrhea, relief of PMS and PMDD, improve hirsutism and acne, decreased risk of fibroids/fewer ovarian cysts, increased bone mineral density
What are the less known benefits of oral contraceptive pills?
Treat polycystic ovary syndrome, reduce PID, reduce ectopic pregnancy, improve symptoms of endometriosis, reduce risk of ovarian and endometrial cancer, possible reduction of benign breast disease, protective against colon cancer
What are some side effects of estrogen?
Too much: Nausea, breast tenderness (take at bedtime with food), headache, bloating
Too little: Spotting, breakthrough bleeding early/mid cycle (should improve with time)
What are some side effects of progestin?
Too much: Breast tenderness, headache, fatigue, mood changes, bloating
Too little: Breakthrough bleeding late cycle
What are some side effects of androgen?
Too much can cause weight gain, acne, hirsutism, increased LDL and decreased HDL
What are some other side effects from oral contraceptives?
Most common in first 3 cycles, most are minor
Mood changes, chloasma (darkening/pigmentation of facial skin)
Which medications may cause oral contraceptive failure?
Rifampin (back up contraception 1 month after), Carbamazepine, Phenobarbital, Phenytoin, lamogatrine, topiramate, griseofulvin, ketoconazole, ritonavir, st. john’s wort, garlic, bosentan, modfinil, cholestyramine, colestipol (take OC 1-4 hours before or 4-6 hours after bile acid sequestrant)
What medications may increase oral contraceptive activity?
Fluconazole, fluvoxamine, vitamin C, atorvastatin
Which medication’s clearance or metabolism can be decreased by oral contraceptives?
Amitriptypline, Imipramine, theophylline, cyclosporine, benzodiazepines that undergo oxidation, selegiline
How soon can fertility be restored after stopping combined oral contraceptives?
1 to 3 months
What are the pharmacokinetics of the combined hormonal contraceptive patches?
Avoids 1st pass metabolism, similar lipid effects to oral
Constant rate of release with less fluctuations in serum levels
1 patch weekly for 3 weeks followed by 1 hormone free week
Local skin reaction may occur, less effective in obese
What are the pharmacokinetics of the combined hormonal contraceptive vaginal ring?
Constant medication release rate (absorption is quite high), avoids 1st pass metabolism, effective in obesity
Insert 1 ring for 3 weeks then remove for 1 week (or use continuously)
May cause vaginal discharge/irritation
How is the progestin only pill different?
Use continuously (no HFI)
Chief mechanism is making cervical mucus more difficult to be penetrated by sperm, may induce endometrial changes and impair sperm motility
Some continue to ovulate with regular cycles, can be used by those with estrogen contraindications
Can cause irregular bleeding (decreases with time)
Missed pill >3 hours require back up for 48 hours
How is the injectable progestin-only contraception different?
Administered intramuscularly every 12 weeks
Equally effective in obese
Main mechanism is suppression of ovulation, increases cervical mucus and atrophy of endometrium
Some have early weight gain, decreased libido, mood changes, decreased BMD
Few drug interactions, no increased risk of CV disease, stroke or MI
Ovulation doesn’t begin until 9 months after last injection
How is this progestin-only intra-uterine system different?
Releases constantly, as time goes on it will release less. Can remain for 3 or 5 years.
The high concentration in the endometrium will decrease estrogen and progesterone receptors and a strong antiproliferative effect is seen, weak foreign body reaction, thickening of cervical mucus (ovulation is not affected)
Minimal drug actions, mood changes, decreased libido, irregular bleeding for 1st 3-6 months the bleeding decreases usually, but may be regular, stop or irregular
Fertility restored after removal
How does emergency contraception work?
Take 1.5 mg dose of levonorgestrel within 72 hours of unprotected sex (up to 5 days after, best in 24 hours)
Thickens cervical mucus, inhibits ovulation and alters endometrium
Not effective if the implantation process has begun
Efficacy reduced if >75 kg (copper IUD more effective)
What is an example of an abortion agent? How does it work?
Mifepristone, which is a synthetic steroid, progesterone-receptor modulator which competitively binds to both P receptors
Used with misoprostol within 1st 50 days of pregnancy.
Acts to degenerate endometirum, decreasing support for embryo, softening and dilation of cervix, promotes release of prostaglandins and increase uterine contractions
What are the adverse effects of mifepristone?
Vaginal bleeding, abdominal pain and cramping, nausea, vomiting, diarrhea
What is used in Canada for ectopic pregnancy?
IM methotrexate (stop embryonic cells from dividing and multiplying through dihydrofolate reductase block) followed by misoprostol to increase contractions
What are some examples of ovulation inducers? What are they used for?
Clomiphene citrate, letrozole
For women in anovulaory (failure of ovary to release eggs) cycles and polycystic ovarian syndrome (PCOS)
How does clomiphene citrate work?
A selective estrogen receptor modulatory (SERM) that is a competitive inhibitor of estrogen receptors in the hypothalamus and mized agonist/antagonist activity based on target tissue.
Occupies ER in hypothalamus to inhibit negative estrogenic feedback to increase GnRH secretion and this FSH and LH to cause growth of ovarian follicle
Use for 5 days around cycle day
How does letrozole work?
It is an aromatase inhibitor that is used off label for ovulation induction.
It blocks the conversion of testosterone and androsteinedione to E2 and E1 respectively, decreasing negative estrogenic feedback at the pituitary, causing increased FSH output
Take once daily on cycle days 3-7
How does leuprolide acetate work?
A gonadotropin releasing hormone agonist at GnRH receptors in the pituitary.
Continuous administration interrupts normal pulsatile stimulation of GnRH receptors to inhibit FSH and LH secretion and suppression of the production of ovarian estrogen and testicular testosterone
What are the side effects of leuprolide?
Menopausal symptoms (hot flashes) can give add-back therapy with low dose estrogen or norethindrone
What is leuprolide used for?
Endrometriosis or uterine fibroids
Higher dose for advanced prostate cancer
When does menopause occur?
12 months after the final menstrual period at about 45-55 years of age (51)
Perimenopause begins 2-8 years prior to final menstruation
What are some symptoms of perimenopause/menopause?
Hormonal variablities, irregular periods, lack of energy, loss of memory, hot flashes, night sweats, vaginal dryness, irriatability, depression, narrowing of thermoneutral zone, elevated sympathetic activation, vasomotor symptoms
What is the most effective treatment for menopausal symptoms?
Exogenous estrogen that widens the thermoneutral zone to reduce vasomotor symptoms
When are progestogens required for menopause treatment?
Required with the estrogen treatment if the uterus is intact to prevent hyperplasia and possible uterine cancer
Continuous or sequential regimen
How does the continuous regimen for menopause work?
Estrogen and progestogens given continuously (or estrogen continuously alone if no uterus)
Associated with unpredictable bleeding or spotting
How does the sequential regimen for menopause work?
Estrogen is given continuously but progestogens are given in pulses for 10-12 days per month
Associated with predicatble bleeding or spotting
What is the difference between transdermal and oral estrogen for menopause treatment?
Transdermal: No increased VTE or stroke risk, no change in libido (no SHBG change), Part II EDS
Oral: Increased VTE or stroke risk, increased SHBG (can decrease libido), no restrictions
Who is eligible for transdermal estrogen for menopause?
Current smokers, increase triclycerides, history or cholelithiasis or cannot tolerate oral estrogens (intolerable side effects) ro can’t take oral medications
Patients should have tried at least 2 different oral estrogen products
What are the differences between micronized progesterone (MP)and medrozyprogesterone acetate (MPA) for menopause?
MP: No breast cancer risk when used with estrogen for 5 years, negative effect on lipids with estrogen, higher incidence of uterine bleeding
What makes a patient eligible for use of micronized progesterone?
Post menopausal patients unable to tolerate oral MPA or in patients with low HDL cholesterol
How do vaginal estrogen therapies work?
Local treatment of urogenital atrophy due to low estrogen levels. Will restore urogenital health within 3 months
Conjugated estrogen cream, estradiol vaginal ring or tablet
What can be used with concomitantly with vaginal estrogen therapies and when?
Can use concomitantly with low dose systemic hormone therapy if still having vaginal symptoms
Progestogens are not necessary with low dose vaginal treatments on their own
What are some examples of selective estrogen receptor modulators (SERMs)? Where do they act as agonists or antagonists?
Estrogen acts as an agonist in the breast, endometrium and bone.
Tamoxifen is used in breast cancer and acts as an antagonist in the breast and slight agonist in endometrium and bone.
Raloxifene is used in osteoporosis and acts as an antagonist in the breast and endometrium and agonist in bone.
What is ulipristal acetate?
A selective progestin receptor modulator (SPRM) used to treat moderate to severe signs and symptoms of uterine fibroids in women eligible for surgery (only eligible for 3 months of treatment per lifetime)
How does ulipristal acetate work?
Prevents progesterone from binding to the PR, direct effect on endometrium and fibroids to reduce size by inhibiting cell proliferation and inducing apoptosis (decreased bleeding and pain)
Partial progesterone antagonist in pituitary, partially suppressing FSH, and maintaining E2 levels in follicular range
Less vasomotor side effects than leuprolide
What is the male reproductive physiology?
LH interacts with receptors on Leydig cells in the testes to enhance testosterone synthesis. FSH and testosterone act on sertoli cells in testes to regulate spermatogenesis, enhances synthesis of androgen binding protein and aromatase enzyme that converts testosterone to E2.
What is testosterone responsible for?
Development and maintenance of secondary sex characteristics in males at puberty and beyond
How does testosterone act as 3 different hormones?
Direct action of T on androgen receptor affects lean muscle and strength
Converted to dihydrotestosterone (DHT) resulting in amplified action on external genetalia and sexual hair
Converted to estradiol to work on bone, stimulate normal sexual function and decrease body fat in men
What are some symptoms of androgen deficiency?
Low libido, decreased morning erections, loss of body hair, low bone mineral density, gynecomastia and small testes.
When is androgen therapy used?
For male hypogonadism (decrease in sperm or testosterone) or hypoactive sexual desire disorder in women
Oral, IM or gel testosterone
What are some examples of antiandrogens?
Finasteride, dutasteride, flutamide, bicalutamide and cyproterone acetate
How do finasteride and dutasteride work?
They are 5-alpha reductase inhibitors that block conversion of testosterone to dihydrotestosterone, decreaseing size and growth of the prostate
Used to treat BPH
Side effect is sexual dysfunction
How do flutamide and bicalutamide work?
Non-steroidal antiandrogens that inhibit androgen uptake and/or inhibits binding of androgen in target tissues
Used for metastatic prostate cancer with an LHRH agonist
How does cyproterone acetate work?
A steroid with antiandrogenic, antigonadotropic and progestin-like activity. It blocks the binding of dihydrotestosterone to prostatic cancer cells and inhibits LH secretion through negative feedback which decreases testosterone production
May be combined with LHRH agonists
What are anabolic steroids?
Androgenic steroids that can be naturally occurring or synthetic
Testosterone, stanozolol, nandrolone, etc.
Androsteinidone (precursor to androgens) has little effect
DHEA is not androgenic but is converted to testosterone in women only, questionable claims to increase muscle strength
What are the effects of androgenic (anabolic) steroids?
Increase lean body mass and decrease fat mass, improves overall strength and appearance
Performance enhancement
What are the adverse effects of anabolic steroids?
aggression, violence, dependence, CHD, acne, cardiomyopathy, hypertension, dyslipidemia, coagulation abnormalities,
Male: gynecomastia, enlarged prostate, hypogandism, impotence
Female: Hirsutism, deepening of voice, clitoromegaly, irregular menses
Hepatic cancer, cholestasis (only with oral 17-alpha-alkylated androgens)
