Estrogens, Progestins & Androgens Flashcards
What are the 5 phases of the female cycle?
- Menstruation
- Early Follicular Phase
- Late Follicular Phase
- Ovulation
- Luteal Phase
What is Menstruation?
- Uterine lining sheds.
- Hormones are STEADY (and low).
What is Early Follicular Phase?
- Steady levels follicle stimulating hormone (FSH) and luteinizing hormone (LH).
- Primary follicle develops in ovary and it produces estrogen.
- At low concentrations, estrogen inhibits the production of LH and decreases FSH.
What is Late Follicular Phase?
- The follicle matures to a point where it produces high estrogen concentrations.
- This has a positive effect on the production of LH and FSH (spike).
- Estrogen encourages endometrium development in uterus.
Hormone start to spike @ end of this phase
What is Ovulation?
- The spike in LH triggers the release of the ovum from the follicle.
What is Luteal Phase?
- Corpus luteum is left behind from the follicle.
- It produces progesterone, estrogen, and inhibin (not pictured).
- Inhibin blocks release of FSH. (to prevent further follicles from developing)
- Progesterone stimulates endometrial growth & blocks GnRH from hypothalamus.
- As corpus luteum degenerates, the hormone levels drop.
Female Hypothalamus-Pituitary-Gonad Axis:
(+) Feedback (Day 12-14):
- HIGH estrogen [ ]’s
(-) Feedback:
- LOW estrogen [ ]’s
Estrogen receptor’s?
1) Alpha receptor- uterus, ovaries, breast, testis, bone, heart and brain.
2) Beta receptor- prostate, immune system, brain, lungs, bones, blood vessels, bladder, intestine.
(has systemic effects)
Progesterone receptor’s?
- Limited distribution of receptor expression: female genital tract, breast, pituitary
- Weak testis and prostate expression (males)
- produce Progesterone as well but not as much
r. aren’t really found throughout the whole body
What are the effects of estrogen?
- Brain
- Heart & Liver
- Ovary
- Vagina
- Breast
- Uterus
- Bone
What are the effects of Progesterone?
- Substances that prepare the uterus for reception of fertilized ovum. (main place its acting on)
- Increase secretions from the endometrial tissue that has been primed with estrogen.
- Forms a “hostile” environment for sperm penetration (forming an envir. where sperm can penetrate)
- Continued action during pregnancy
- Luteal phase 20- 30 mg/day from ovaries (imp. for dosing drugs)
What is the Broad Drug Classes (General hormone agonists & antagonists)?
- Estrogens (ethinyl estradiol)
- Antiestrogens
- Progestine (L-norgestrel)
- Antiprogestins
- Androgens (testosterone)
- Antiandrogens
What are all the sex hormones produced from?
Cholesterol
Why would someone need drugs that affect female sex hormones (agonists/antagonists)?
- Contraception
- Menopause or Hypogonadism
- Fertility
- Abortion
- Hirsutism
- Acne
- Gender Conformation Therapy
- Osteoporosis
What is Withdrawal bleeding?
- Occurs when there is no progesterone and estrogen in the
blood. - i.e. Menstruation
What is Breakthrough bleeding?
- Any bleeding that occurs despite the presence of steroids.
- It is usually due to high levels of progesterone relative to estrogen.
(potential AE)
What are the 4 gen’s of Estrogen?
Ethinyl Estradiol (1st-4th)
What are the 4 gen’s of Progesterone?
1st - Norethindrone
2nd - Levonorgestrel
3rd - Desogestrel or Norgestimate
4th - Drospirenone
What is Progestin activity?
- Androgenic effects- 1st and 2nd generation progestins- can cause acne and hirsutism
– can also bind to ~ testosterone r. - Newer generations (esp. drospirenone) are more anti-androgenic
- blocks testoderone r. therefore ~ times better for ~ of those SE’s
What is Combination Pills?
3 weeks of hormones, 1 week of placebo (menstruation)
Triphasic - each week the level of P increase & E stays same
Biphasic - 1/2 of 3 weeks there’s 1 level of P & then higher
Monophasic - *most common - EE & NETH @ same
How does a combo of estrogen and progesterone work as an oral contraceptive?
trying to fool body that the woman is in the Luteal Phase
What is the MOA of Oral Contraceptives?
1) Prevent ovulation
* Estrogen and progesterone inhibit the secretion of LH & FSH
2) Prevent sperm entrance
* Thick tenacious mucus secreted under the influence of progesterone
3) Prevent implantation of the fertilized ovum
* Large doses of estrogen alter the motility of the oviduct and change the properties of the endometrium
What is the other benefits of Oral Contraceptives?
- Simple and effective
- Significantly improves menstrual symptoms &
regularity - Decreases relative incidence of disease
- Bacterial pelvic inflammatory disease
- Endometriosis
- ↓ risk of endometrial and ovarian cancer after long term use
- Osteoporosis
What are the risks of Oral Contraceptives?
- Venous Thromboembolism (VTE)
- Estrogen receptors in the liver are responsible for activating blood clotting
factors - Ethinyl estradiol is more potent than natural estrogen - it could hyperactivate the clotting pathway (=> causing blood clots)
- Arterial Thrombosis (MI & stroke) particularly if age >35 and smoking
- Slight increased risk of BREAST & CERVICAL cancer (controversial)
- Hypertension- may develop with age and long term use (b/c of estrogen on CV system)
What is Side Effects of Oral Contraceptives?
*Estrogen is blamed for most of the undesirable side effects.
What are the Side Effects Relating to Estrogen?
- Menstrual irregularities
- Breakthrough bleeding
- Nausea, vomiting
- Headache
- Breast tenderness (fluid
retention) - Weight gain (fluid retention)
- Coagulation risk
- Depression
- Photosensitivity
What are the Side Effects Suggesting Estrogen is Too High?
- Nausea
- Headache
- Breast tenderness
- Bloating
- High blood
pressure
What are the Side Effects Suggesting Estrogen is Too Low?
- Spotting
- Early, mid-cycle
breakthrough bleeding (Days 1-14)
What are the Side Effects Relating to Progestin?
- Menstrual irregularities
- Weight gain*
- Acne*
- Hirsutism*
- Fatigue
- Increased appetite
- Excessive androgenic effects
What are the Side Effects Suggesting Progestin is Too High?
- Headache
- Breast tenderness
- Fatigue
- Mood changes
What are the Side Effects Suggesting Progestin is Too Low?
- Late cycle breakthrough bleeding (Day 15-28)
What are the Other Side Effects of Oral Contraceptives?
May adversely affect fertility when the medication is discontinued after prolonged use.
* In 95% users ovulation resumes within 3 months of discontinuing medication.
* In small proportion of users – may take 1-2 years.
What are the Contraindications of Oral Contraceptives?
Absolute Contraindications
- Carcinoma of the breast known or suspected. (breast cancer - can make it worse)
- Undiagnosed genital bleeding.
- Suspected or known pregnancy
- Past history of cerebrovascular disease, thromboembolic disease, thrombophlebitis, or conditions predisposing to these disorders. (blood clots)
What are the Precautions?
- Smokers over age of 35
- Migraine headaches
- Hypertension
- Epilepsy (anticonvulsants decrease OC efficacy)
- Diabetes
- Cirrhosis
- Older age (more than 40) and obese
If vomiting and diarrhea (e.g. due to gastroenteritis or chemotherapy), then…
backup with another method may be required.
Vaginal delivery of the pill can be effective.
Drug that induce cytochrome P450 can cause contraceptive failure:
Rifamycin (antibiotic), anticonvulsants and antivirals (enzyme induction)
What is the hormonal contraceptive Patch method?
- Estradiol and norelgestromin
- 1 patch per week for 3 weeks, 1 week off
- Both have similar risks and benefits to oral contraceptives
What is the hormonal contraceptive Vaginal Ring method?
- Estradiol and etonogestrel
- Insert ring for 3 weeks, remove 1 week
- Both have similar risks and benefits to oral contraceptives
What is the continuous dosing of hormone contraception?
Consecutive active pills, patches, or vaginal rings (i.e. not removing etc.)
What are the advantages of Continuous Dosing of Hormone Contraception?
- less adverse symptoms
- convenient (sports, vacation)
- fewer heavy withdrawal bleeds
- shorter hormone free intervals may ↓risk of ovulation
What are the disadvantages of Continuous Dosing of Hormone Contraception?
- no long-term safety data
- Initially more breakthrough bleeding, but this decreases with time
- possible delay in recognition of pregnancy
- Increased cost (but less feminine hygiene product use)
What is new on the market?
Oral contraceptive containing estetrol and drospirenone
Estetrol
* has a long half life 20-28 hrs compared to ethinyl estradiol (1-2 hours).
* Minimal conversion to other estrogen forms (like estradiol)
* Fewer possible side effects
* Lower risk of deep vein thrombosis?
What are the Progestin Only Birth Control Options?
3) The “mini pills” containing only norethindrone (progestin)
4) Injection- medroxyprogesterone acetate (Depo-provera)
5) Intra-uterine devices (IUDs)
6) Implant (Nexplanon, now available in Canada)
The “mini pills” containing only norethindrone (progestin):
- Mechanism- action may be mediated by alteration of cervical mucus and endometrium without suppression of ovulation.
- Use- must be taken at the same time every day
- Somewhat less efficacious (up to 10% failure rate),
- Often – irregular bleeding during their use.
These can be an option for women who shouldn’t take estrogen (like smokers >35 years old, breastfeeding, etc.
Injection- medroxyprogesterone acetate (Depo-provera):
- Given every 12 weeks (slow release progesterone)
- works right away
** Similar benefits to mini-pills, but without having to remember to take a pill everyday
- usually preferred for younger women
- Major problems
- Decreases bone mineral density, can cause early osteoporosis
- Consider the family history, diet (calcium) and exercise before recommending
- Delayed return to fertility
Intra-uterine devices (IUDs):
a) With levonorgestrel- lasts up to 7 years
b) Copper- lasts up to 10 years
Can cause cramping, expulsion, uterine perforation (rare), pelvic inflammatory disease
- not implanted right & therefore comes out
-> Screening for STIs should occur before insertion
- if they have a STI, they’re more likely to get PID
Implant (Nexplanon, now available in Canada):
Etonogestrol (progestin)
Effective for more than 3 years
*IUDs and implants are the most effective, reversible methods available
- can return to fertility as soon as they are removed
The 3 most important points from the lecture so far:
- Oral contraceptives contain estogen & progesterin analogs that inhibit ovulation, DECREASE sperm enhance, prevent implanation
- VTE is the most dangerous SE of estrogen use
- Androgens can be used to treat andropause & hypoganidsm, but can cause permanent long term changes to the body (anabolic steroids)
What can be done if a patient has not been adhering to the contraceptive regimen and has had unprotected sex?
Emergency Contraception or “Morning After Pill”
Emergency Contraception or “Morning After Pill”:
Large doses of:
1) Levonorgestrel (Plan B; Rx no required)
2) Ethinyl Estradiol + Levonorgestrel (Yuzpe)
3) Ulipristal- selective progesterone receptor modulator
- Efficacy is greatest when taken within 24 hours, but can be taken up to 3-5 days later
- Delays or inhibits ovulation, but does not prevent implantation (less effective after ovulation).
- Does not terminate pregnancy or affect the fetus.
Estrogen/Progestin:
- monophasic, biphasic, triphasic pills
- patch, ring
Progestin alone (“Mini-Pills” and implants):
- pills, implants, injection
Emergency Contraception (“Morning after” pills):
- Plan B, ulipristal, etc.
What happens when estrogen and progesterone receptors are antagonized?
Anti-estrogen- A Fertility Agent
Anti-progesterone- An Abortive Agent
Mifepristone
Anti-estrogen- A Fertility Agent:
Clomiphene- Weak non-steroidal estrogen with moderate anti-estrogenic activity.
Action:
* Increases pituitary secretion of gonadotropins (FSH and LH)
* Interferes with estrogen “receptor sites” involved in feedback inhibition by estrogen on the secretion of LH- RH/FSH-RH.
Result:
* Significant enlargement of ovaries.
* Induces ovulation
Anti-progesterone- An Abortive Agent:
Mifepristone (RU 486)- competitive progesterone receptor antagonist
- given to induce abortion in early stages
Actions-
1. Causes detachment of the blastocyst.
2. Increases prostaglandin levels & uterine motility.
3. Causes cervical softening – facilitates expulsion blastocyst.
Mifepristone:
Result: termination of pregnancy in 1st trimester only.
Misoprostol (prostaglandin) ADDED to increase uterine
motility.
Success rate>90% for pregnancies if 49 days or less.
Side effects – Bleeding may last for 8 to 17 days. Abdominal cramps.
Can be used as a morning after pill - Post coital – prevents implantation and induces bleeding.
What are the Acne tx’s?
- All oral contraceptives with estrogen are helpful for acne
- Diane-35
- FOR ACNE ONLY (in other countries it is also used as a contraceptive)
- Ethinyl estradiol (0.035) and Cyproterone acetate (2mg), a progestogen W/ ANTI-ANDROGENIC PROPERTIES
- Reduces activity of sebaceous gland, excessive hair growth and deepening of voice.
- Only use until acne resolves.
Before Menopause (menstrual cycle):
HIGH E & P
After Menopause (no menstrual cycle):
LOW E & P
What are the Sx’s of Menopause?
- Hot flashes, flushing (vasomotor symptoms)
- Vaginal dryness
- Mood changes
- Insomnia
Most symptoms resolve after 5 years, but some patients have >15 years of symptoms
Hormone Therapy:
- Estrogen- at 1/3 to 1/6 the dose found in oral contraceptives
** Oral, transdermal patch, topical cream, vaginal (cream, suppository,
ring)
- Oral has the HIGHEST risk of adverse effects
- Start with a small dose and gradually increase (b/c of thrombo)
- Progestins (medroxyprogesterone, etc.) should be given in combination with oral estrogen to prevent endometrial cancer but may cause monthly withdrawal bleeding.
Beneficial Effects Estrogens in Menopause?
- Sleep (improvement)
- CV disease (protective effect; decrease LDL & increase HDL in plasma)
- Urogenital Tract (reverses postmenopausal atrophy)
- Osteoporosis (decreases resorption of bone; decreases freq. of hip fracture)
– must begin within 2-3 years of menopause, or earlier - Vasomotor (re-establishes feedback on hypothalamic control of NE secretion, leading to decreased freq. of “hot flashes”)
Why would someone need drugs that affect male sex hormones (agonists/antagonists)?
- Andropause or Hypogonadism
- Sports enhancement (anabolic steroids)
- Hirutism
- Gender Conformation Therapy
What are Androgens?
- Agents that have anabolic and masculinizing effects in both males and females.
- Testosterone – major androgen
- In males – Testis produce about 95% (8 mg daily, 0.6ug/dl),
Adrenals – 5% - In women- Testosterone concentration is 0.03 ug/dl - Responsible for libido, growth.
What is the Hypothalamus-Pituitary-Gonad Axis?
(-) feedback on Hypothalamus & Pituitary
What are the effects of Testosterone?
systemic effects
Skin:
- hair growth
- collagen growth
Sex Organs:
- sperm production
- erectile function
- prostate growth
Muscles:
- muscle growth
- increased strength
- increased endurance
Brain:
- increased sex drive
- improved mood
- confidence
- memory function
Bone Marrow:
- RBC production
Bones:
- maintenance of bone mass density
What is the MOA of Testosterone?
Testosterone is metabolized to estrogen and dihydrotestosterone (DHT). Changes transcription when bound to receptor.
changes gene expression throughout body
What are the Therapeutic Uses?
Replacement therapy
a) Hypogonadism in youth
* Large doses of intramuscular preparations are used until maturation is complete.
* Long acting preparations such the testosterone cypionate and enanthate are given biweekly.
b) Andropause or ADAM (Androgen Decline in Aging Male)
What are the Andropause Sx’s?
1) Loss of sexual desire and erectile function
2) Decrease in bone mineral density leading to osteoporosis
3) Altered mood (depression, irritability, etc.) and intellectual ability.
4) Other changes - Loss of muscle strength and volume, loss of body hair, increase in visceral fat
What is the Testosterone Tx - Andropause?
- Oral - Testosterone undecanoate, taken with meals in the morning.
- b/c T has a dinural rhythm like cortisol, therefore T is @ its highest effect in morning
- Transdermal preparations (Patch and gels) –
Best reflect the circadian rhythm (peak in morning).
Gel – 1% testosterone provides continuous transdermal delivery.
Has less skin irritation than patches. (therefore, better tolerated) - Injection- Testosterone cypionate- “yo-yo” pattern (higher spike in T, that tapers off before there next injection)
What are the risks of Androgen Therapy?
- Possible cardiovascular events (stroke, etc.)
- Fluid retention
- Increased prostate (which also naturally enlarges w/ age)
- Aggression or inappropriate behavior
What are the Anabolic Steroids?
- Synthetic testosterone analogs
- Abused by athletes to increase strength and muscle mass.
What are the adverse effects of Anabolic Steroids?
- Masculinization of the female, even with very low doses. Some effects irreversible
- Hepatic dysfunction, hepatocellular carcinoma, cholestasis.
- CNS effects, - aggressiveness, anger
- Impotence and decreased sperm count with higher concentration (b/c inhibiting pituitary & hypothalamus, therefore less hormones produced)
What is the Hormone therapy for Hirsutism?
Mild hirsutism- oral contraceptives
* Particularly with progestins with less androgenic properties (drosprinenone, desogestrel, etc.)
Severe hirsutism- anti-androgens
* Block androgen receptors or 5α -reductase
What are Anti-Androgens?
- Spironolactone
- Cyproterone acetate
- Finasteride
- Flutamide
Anti-Androgens - Spironolactone
competitive inhibitor of androgen receptor and 5α-reductase activity
* Considered 1st line anti-androgen for hirsutism therapy because it is most effective
* Also blocks mineralocorticoid receptors
Anti-Androgens - Cyproterone acetate
competitive inhibitor of androgen receptor and 5α-reductase activity
* 2nd line therapy
Anti-Androgens - Finasteride
inhibits 5α-reductase activity
* 2nd line therapy
Anti-Androgens - Flutamide
competitive inhibitor of androgen receptor
* Considered 3rd line therapy
* Has a high risk of hepatotoxicity
What are Anti-Androgen AE’s?
- In males:
- Feminization, infertility, sexual dysfunction (loss of libido
and erectile dysfunction), hot flashes, osteoporosis - In females
- Irregular bleeding, decreased libido
- Otherwise fairly well tolerated
