Estrogen and Progestins Flashcards
(47 cards)
1
Q
Estrogens
A
- 17B Estradiol = E2 = Estrogen
- Most affinity for receptor
- Major secretory from ovary
- Synthesized from androtenedione or testosterone - Estriol - metabolite of estradiol
- principle placental estrogen, pregnancy - Estrone - metabolite of estradiol
- metabolite of estradiol, ovaries
2
Q
Progesterone
A
- precursor to androgens and estrogens
- secreted by corpus luteum (ovulated follicles)
3
Q
Weak Female Androgens
A
- DHEA and androtenedione
- Small amounts of testosterone
4
Q
Estrogen Hormone Levels
A
- Follicular: 200 pg/mL
- Ovulation: 1000 pg/mL (peak level)
- Luteal: 500 pg/mL
- Pregnancy: 20,000 pg/mL
- Menopause: 5-20 pg/mL
5
Q
Progesterone Hormone Level
A
- Follicular: <1.5 ng/mL
- Ovulation: <1.5 ng/mL
- Luteal: 35 ng/mL
- Pregnancy: 150 ng/mL
- Menopause: <0.4 ng/mL
6
Q
Follicular Phase
A
- Menses: endometrium shedding
- FSH increases early and stimulates estrogen production (+LH) - follicular recruitment/growth (6-12 follicles)
- Day 6 - one follicle dominates and secretes estrogen which inhibits FSH and follicle development
- Increases LH receptors late in cells and granular cells to produce progesterone
- Ovulation 24-36 hours after estrogen peak and LH surge (ovulation tests)
- Oocyte has ~24 hours to be fertilized or DEATH
7
Q
Luteal Phase
A
- Corpus luteum (follicle remnant) - estrogen and progesterone secretion increases
- FSH and LH inhibited
- Consistently last 14 days to thicken endometrium and mucus for implantation
- Not pregnant? Corpus luteum reaches peak steroid production at about day 7 and degenerates, hormone levels drops and period start
- Pregnant? Produces HCG (pregnancy tests) which sustains pregnancy by stimulating the corpus luteum to continue secreting progesterone/estrogen (placenta takes over at end of first trimester, high risk of miscarriage)
8
Q
Steroids
A
- Made from cholesterol
- Carried in blood bound to carrier proteins
- Passes through cell membranes
- Bind to steroid receptors
- Estrogen receptors: ERalpha/ERB
- Progesterone receptors: PR B (main) and PR A
9
Q
Estrogen MoA
A
2 different receptors for estradiol:
- ERalpha - uterus, mammary gland, ovary, bone, liver, and adipose
- ERB - ovary (granulose cells), colon, adipose, and immune system
* *2/3 of breast cancers express ERalpha, drug target**
10
Q
Estradiol Functions
A
- Uterine/menstrual cycle
- Development of secondary characteristic
- Bone
- Lipid metabolism
- Blood vessels
- Liver
- CNS
11
Q
Uterine/Menstrual Cycle
A
- Stimulates proliferation of endometrium
- Increase progesterone receptor in endometrium
- Increase sensitivity to oxytocin leading to increased uterine motility
- Increase level prior to ovulation stimulate LH surge to cause release of follicle
- Decrease viscosity of secretions in cervix
- Also watery, alkaline secretions good for sperm survival
- Inhibits GnRH, FSH, and LH - main mechanism for contraception
12
Q
Development of Secondary Sex Characteristics
A
- Growth/development of labia, vagina, cervix, Fallopian tubes, and uterus
- Breast enlargement, pubic hair, skeleton shaping, growth spurts, fusion of epiphyses
13
Q
Estrogen + Bone
A
- Osteoclasts block resorption of bone
- Balance leans toward osteoblast which increases bone formation but NOT direct effect
14
Q
Lipid Metabolism + Estrogen
A
- Mainly beneficial
- Increased serum TG and HDL
- Decreased TC and LDL
15
Q
Blood Vessels
A
- Promotes vasodilation by increased NO synthase
- Stimulates renal Na+/H2O retention
- Promotes vascular healing by increasing endothelial cells and decreasing smooth muscle proliferation
- Inhibits development of atherosclerosis
16
Q
Liver + Estrogen
A
- Stimulates production of many proteins
- Hormone binding proteins increases
- Clotting factors increase and may cause thromboembolic disorders
17
Q
CNS + Estrogen
A
- Neuroprotection
- Increase vasodilation and decreases vascular inflammation
- Protect against stroke
- Mood, cognition
18
Q
Progesterone Functions
A
- Thicken uterine lining for fertilized eggs for uterine differences
- Antagonizes estrogen-driven growth in endothelium and decreases myometrial contactility
* *Prepares and maintains pregnancy**
19
Q
Progesterone
A
- Low in uterine/menstrual’s follicular phase
- Increases in luteal phase and remains high post-ovulation
- Counteracts/antagonizes estrogen effects on uterus
- Increases conversion of proliferation to secretory typed endometrium
- Viscous acidic mucus = hostile to sperm, increases body temperature by 0.5-1 degrees
- Maintains pregnancy by suppresses contraction, stabilizes uterine membrane, synergizes with estrogen in increase mammary gland growth and development
20
Q
Progesterone + Mammary Glands
A
- Stimulates proliferation/vascularization drug pregnancy
- Suppresses milk protein synthesis until near delivery (prolactin)
21
Q
Progesterone + Bone
A
Prevents bone loss
22
Q
Synthetic Hormones
A
- Increases oral effectiveness
- Micronized formulations (better absorption)
- Extensive liver metabolism from oral administration
23
Q
Estrogen/Progesterone PK
A
- Oral: extensive gut/1st pass metabolism, micronized form increases absorption
- Transdermal/topical/implants/injections - bypass gut/liver, directly to systemic circulation
- IUD: in uterus, bypass gut/liver
- Intravaginal: also bypass gut/liver, local vaginal effects, [higher] gut systemic effects
24
Q
Hormone Replacements
A
- For postmenopausal
- No functional follicles, so no estrogen/progesterone is produced
- Menstrual cycles ends, FSH/LH levels increases and physiological benefits of estrogen are lost
25
Hormones + Menopause
- Decreased ovarian estradiol: increased adrenal estrone
- Increased androgen: estrogen
- Decreased progesterone
26
Menopause: Potential Problems & Symptoms
1. Vasomotor Symptoms: Hot flashes, Night Sweats
2. Osteoporosis – major long term problem
3. Genitourinary Syndrome: Vaginal dryness, burning, irritation, vaginal mucosa atrophy, impaired sexual function, urinary urgency
4. Mood changes, sleep disturbance, dermal aging
5. Increase in incidence of cardiovascular disease
6. Increase in incidence of colorectal cancer
7. More malignant forms of breast cancer
8. Loss of neurons in brain leading to a decrease in cognitive function, Alzheimer’s disease?
9. Macular degeneration, cataract formation possible
27
MoA - Hormone Replacement
- Goal: provide physiological levels of estrogen, reestablish relatively physiologic levels of circulating estrogens to get benefits
* *Use lowest dose for shortest time ideally**
- Estrogens alone can cause uterine hyperplasia and increased risk of endometrial cancer (add progesterone to help prevent)
- Generally lower doses used compared to birth control
- SoA: bone, CV, CNS
28
Hormone Replacement Therapeutic Benefits
1. Prevent osteoporosis - prevent bone loss (systemic)
2. Prevent vasomotor symptoms - hot flashes/chills (systemic)
3. Prevent genitourinary symptoms - dryness, burning, genital itching, frequent urination (intravaginal)
29
Estrogen Toxicity/SE
1. Vaginal bleeding, nausea, breast tenderness
2. Cancer - increased risk of breast cancer - concern in women who have multiple risk factors for breast cancer
3. Estrogen alone increases risk of endometrial cancer (preventable by addition of a progestin)
4. Hypertension, gallbladder disease
5. Thromboembolic disorders – greater in smokers
6. Ischemic stroke
30
Women's Health Initiative Study
- Studied Prempro (conjugated estrogen and medroxyprogesterone)
- Showed increased risk for: CV disease/stroke, breast cancer, venous thromboembolic disease, pulmonary embolism
- Showed decreased risk: osteoporosis and fractures, colorectal cancer
- Increased interest in therapy with SERMs
31
Duavee
- Bazedoxifene
- 3rd generation SERM
- Uses: treat moderate-severe vasomotor symptoms of menopause, prevent postmenopause osteoporosis
- Agonist to bone to prevent bone loss and osteoporosis
- Antagonist to endometrium to prevent hyperplasia
- SE: muscle spasms, N/V, diarrhea, indigestion, dizzines
- Warning: Endometrial cancer, CV disorders, probably dementia
32
Osphena
- Ospemifene
- SERM, 3rd generation
- Approved estrogen agonist/antagonist for vulvovaginal atrophy symptoms of dysparenia (pain with intercourse)
- May help retain bone and be antiestrogenic in the breast
- Agonist for vaginal epithelium and bone
- Antagonist for breast
- SE: hot flashes, vaginal discharge, spasms, sweating
- Warning: endometrial thickening, thrombolic/hemorrhagic strokes, and DVT
33
Alternatives
- SNRI: venlafaxine, desvenlafaxine
- Gabapentin
- Clonidine
- Low dose paroxetine (SSRI), 7.5 mg
34
Paroxetine
- Moderately effective for hot flashes
- No benefit for vaginal atrophies and bone density
- Black Box Warning: increased siucide risk
35
Hormonal Contraception
- Most widely used drugs in US and worldwide
- SoA: hypothalamus, pituitary, endometrium
- Main site is anterior pituitary inhibition
36
Contraception MoA - Combination Therapy
1. Estrogen inhibits follicle growth
2. Progesterone inhibits LH surge and ovulation
3. Progesterone thickens cervical mucus and alters lining which is bad for sperm
37
Contraception PK
- 99.9% effective
- Estrogens: ethinyl estradiol
- Progestins: norethindrone
- Decrease doses over years to decrease AE (increases contraception failure chances if dose missed)
- Ethinyl estradiol is one of the most potent estrogens, greater oral bioavailability, more slowly metabolized
38
Progestin ALONE
- Contraception: 99% effective
- SoA: hypothalamus, pituitary, and endometrium
- MoA: inhibits GnRH and LH surge to prevent ovulation, thickens cervical mucus, endometrial activity goes out of phase to disrupt implantation
39
Contraception SE
- Nausea, breast fullness, and fluid retention; related to
level of estrogen and can be helped by using a pill with
less estrogen
- Failure of normal menstrual bleeding and amenorrhea
after ending the medication
-Weight gain, Depression (cause 6% of women to discontinue)
-May increase the incidence of migraine headache, diabetes mellitus, gall bladder disease
-If breakthrough bleeding (<35 mcg ethinyl estradiol) may need higher dose
40
Risks with Oral Contraception
1. Do not protect against STDs.
2. Myocardial infarction and Ischemic Stroke:
substantially higher risk in women who smoke or have
hypertension and are over 35 yrs of age.
3. Hypertension - increase in blood pressure over time
in 1% to 5% of users. Resolves when discontinued.
4. Venous Thromboembolism and Cerebral Venous
Thrombotic disease (3 - 4 x). (lower than pregnancy) due to increase in coagulation proteins
**May need to stop contraceptive medication before
elective surgery**
41
CI for Estrogen-containing Contraceptives
1. Patients with a history or presence of thrombophlebitis, thromboembolic disease, or stroke
2. Smokers
3. 35 years old, hypertension, diabetes with
end-organ damage, or severe migraine headaches
4. Breast cancer or other Estrogen-dependent cancer
5. Congestive heart failure - may make edema worse
6. Adolescents with incomplete epiphyseal closure
42
Contraception Cautions
- Antibiotic use and reduce contraception efficacy
- Anticonvulsants can induce metabolism of contraceptives and decrease their effectiveness
* *Both can cause breakthrough bleeding and pregnancy**
43
Too Much Estrogen SE
- Nausea
- Bloating
- Breast Tenderness
- Increased BP
- Melasma
- Headache
44
Too Little Estrogen SE
- Early or mid-cycle breakthrough bleeding (before day 14)
- Increased spotting
- Hypomenorrhea
45
Too Much Progestin SE
- Breast tenderness
- Headache
- Fatigue
- Changes in mood
46
Too Little Progestin SE
-Late breakthrough bleeding
47
Too Much Androgen SE
- Increased appetite
- Weight gain
- Acne
- Oily skin
- Hirsutism
- Decreased libido
- Increased breast size
- Breast tenderness
- Increased LDL cholesterol
- Decreased HDL cholesterol
