Estrogen and Progestins Flashcards
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
Q
Hormones + Menopause
A
- Decreased ovarian estradiol: increased adrenal estrone
- Increased androgen: estrogen
- Decreased progesterone
26
Q
Menopause: Potential Problems & Symptoms
A
- Vasomotor Symptoms: Hot flashes, Night Sweats
- Osteoporosis – major long term problem
- Genitourinary Syndrome: Vaginal dryness, burning, irritation, vaginal mucosa atrophy, impaired sexual function, urinary urgency
- Mood changes, sleep disturbance, dermal aging
- Increase in incidence of cardiovascular disease
- Increase in incidence of colorectal cancer
- More malignant forms of breast cancer
- Loss of neurons in brain leading to a decrease in cognitive function, Alzheimer’s disease?
- Macular degeneration, cataract formation possible
27
Q
MoA - Hormone Replacement
A
- 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
Q
Hormone Replacement Therapeutic Benefits
A
- Prevent osteoporosis - prevent bone loss (systemic)
- Prevent vasomotor symptoms - hot flashes/chills (systemic)
- Prevent genitourinary symptoms - dryness, burning, genital itching, frequent urination (intravaginal)
29
Q
Estrogen Toxicity/SE
A
- Vaginal bleeding, nausea, breast tenderness
- Cancer - increased risk of breast cancer - concern in women who have multiple risk factors for breast cancer
- Estrogen alone increases risk of endometrial cancer (preventable by addition of a progestin)
- Hypertension, gallbladder disease
- Thromboembolic disorders – greater in smokers
- Ischemic stroke
30
Q
Women’s Health Initiative Study
A
- 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
Q
Duavee
A
- 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
Q
Osphena
A
- 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
Q
Alternatives
A
- SNRI: venlafaxine, desvenlafaxine
- Gabapentin
- Clonidine
- Low dose paroxetine (SSRI), 7.5 mg
34
Q
Paroxetine
A
- Moderately effective for hot flashes
- No benefit for vaginal atrophies and bone density
- Black Box Warning: increased siucide risk
35
Q
Hormonal Contraception
A
- Most widely used drugs in US and worldwide
- SoA: hypothalamus, pituitary, endometrium
- Main site is anterior pituitary inhibition
36
Q
Contraception MoA - Combination Therapy
A
- Estrogen inhibits follicle growth
- Progesterone inhibits LH surge and ovulation
- Progesterone thickens cervical mucus and alters lining which is bad for sperm
37
Q
Contraception PK
A
- 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
Q
Progestin ALONE
A
- 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
Q
Contraception SE
A
- 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
Q
Risks with Oral Contraception
A
- Do not protect against STDs.
- Myocardial infarction and Ischemic Stroke:
substantially higher risk in women who smoke or have
hypertension and are over 35 yrs of age. - Hypertension - increase in blood pressure over time
in 1% to 5% of users. Resolves when discontinued. - 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
Q
CI for Estrogen-containing Contraceptives
A
- Patients with a history or presence of thrombophlebitis, thromboembolic disease, or stroke
- Smokers
- 35 years old, hypertension, diabetes with
end-organ damage, or severe migraine headaches - Breast cancer or other Estrogen-dependent cancer
- Congestive heart failure - may make edema worse
- Adolescents with incomplete epiphyseal closure
42
Q
Contraception Cautions
A
- Antibiotic use and reduce contraception efficacy
- Anticonvulsants can induce metabolism of contraceptives and decrease their effectiveness
- *Both can cause breakthrough bleeding and pregnancy**
43
Q
Too Much Estrogen SE
A
- Nausea
- Bloating
- Breast Tenderness
- Increased BP
- Melasma
- Headache
44
Q
Too Little Estrogen SE
A
- Early or mid-cycle breakthrough bleeding (before day 14)
- Increased spotting
- Hypomenorrhea
45
Q
Too Much Progestin SE
A
- Breast tenderness
- Headache
- Fatigue
- Changes in mood
46
Q
Too Little Progestin SE
A
-Late breakthrough bleeding
47
Q
Too Much Androgen SE
A
- Increased appetite
- Weight gain
- Acne
- Oily skin
- Hirsutism
- Decreased libido
- Increased breast size
- Breast tenderness
- Increased LDL cholesterol
- Decreased HDL cholesterol
