Estrogens and Progestogens Flashcards
What do steroid hormones (estrogens and progetins) look like chemically?
tetracyclic (4 ringed) structure
What is the most common naturally occurring estrogen and progestin?
- estrogen= 17B-estradiol (aka estradiol; E2)
- progestin= progesterone
- primary steroid hormones produced in the ovaries
What are the weaker estrogens?
- estrone (E1) and estriol (E3)
How are estrogens made again?
- from circulating cholesterol (in ovaries, testes, and adrenal glands) to progesterone, to androgens, and finally via AROMATASE to estrogen!
- remember mineralocorticoids and glucocorticoids are also made from progesterone
Where are both estradiol and progesterone broken down?
in the liver
What are phytoestrogens?
phytoestrogens= from plants in our diet:
- polyphenols (reservatrol in red wine)
- flavonoids (citrus, chocolate, and green tea)
- isoflavonoids (soy)
- bind to ER-beta receptor more than ER-alpha, which makes these GOOD for you :)
What are environmental estrogens?
mostly BAD; endocrine disruptions:
- bisphenol A (BPA; released as plastics degrade)
- bind to ERs stronger than metabolic estrogens.
- polychlorinated hydroxybiphenyls (PCBs; banned in 1979 but some are still found in children’s toys, plastic bottles, and aluminum cans).
*** What is the main synthetic estrogen?
- ETHINYL ESTRADIOL= most common in birth control
* ETHINYL GROUP (C triple bonded to CH) allows it to pass through stomach and liver; aka allows it to be taken ORALLY.
*** What are the main synthetic progestins?
- 19-NORESTOSTERONES and are classified as either:
1. ESTRANES= first-generation progestins.
2. GONANES= greater progestational activity, so you can use a lower dose.
How are the synthetic progestins made?
- by removing the 19 carbon from ethisterone (a derivative of testosterone).
What are the 3 specific GONANE progestins?
- Desogestrel
- Norgestrel
- Levonorgestrel
What are the 5 specific ESTRANE progestins?
- Norethynodrel
- Lynestrenol
- Norethindrone
- Norethindrone acetate
- Ethynodiol diacetate
What is the “classical/direct” (genomic) steroid signaling pathway?
- hormone passes through the lipid membrane and bind to steroid receptor in the cytoplasm.
- translocation of hormone-receptor complex to nucleus.
- binding of complex to DNA regulatory site
- transcription of mRNA
- translocation of mRNA to cytoplasm to be translated to protein.
** What is the “rapid action” (non-genomic) steroid signaling pathway? (newly discovered pathway)
- hormone binds to plasma membrane receptor.
- MAP kinase or cAMP, PKC, Ca2+ activation
- activation of biological responses (or to a lesser degree gene expression)
*** How does the ESTROGEN GENOMIC signaling pathway work?
- Estrogen enters the cytosol and binds to the ER (receptor, which is already bound to a HEAT SHOCK PROTEIN).
- upon binding hormone-receptor complex forms a DIMER.
- move into the nucles and binds to ESTROGEN RESPONSE ELEMENT (ERE) activating gene transcription.
*** How does the ESTROGEN NON-genomic signaling pathway work?
- activation of a cell surface receptor (TKR or other) activates ER through PHOSPHORYLATION.
- activation of intracellular signaling pathways.
- rapid changes including Ca2+ and NOS release
What are the 2 types of estrogen receptors (ERs)?
- ER-alpha (NR3A1)= endometrium, hypothalamus, breast tissue (often BREAST CANCER), and stromal cells of ovary.
- ER-beta (NR3A2)= hippocampus, cortex, thalamus, granulosa cells of ovary, bone, heart, lungs, prostate, andendothelial cells.
What is important to know about the G-protein coupled estrogen receptor 1?
- responds only to estradiol and functions via the rapid (non-genomic) signaling pathway.
Is the progesterone signaling pathway similar to the estrogen signaling pathways?
YES and has both classic (genomic) and rapid (non-genomic) pathways.
What are the 2 types of progesterone receptors?
- PRA (short)= more rapid pathway.
2. PRB (long)= more classic (genomic) pathway
** What are the physiologic functions of estrogens?
- female reproductive development= reproductive organ development, secondary sexual characteristics, and regulates menstrual cycle.
- metabolic= REDUCES BONE RESORPTION; aka strengthens bones, increases plasma triglycerides, but lowers LDL and increases HDL.
- cognitive= protects against neurodegenerative disorders, and helps learning and memory through synaptic remodeling.
** What are the physiologic functions of progestins?
- progesterone= induces secretory changes in endometrium and maintains pregnancy.
- progestins= fat deposition, block ovulation and GnRH secretion, may increase BP, decrease HDL, increase LDL, increase insulin and response to glucose.
What are the clinical uses of ESTROGENS?
- ORAL CONTRACEPTIVES (always with progestins).
- hormone replacement therapy (HRT) for premature ovarian failure, menopause, or ovariectomy.
- HYPOGONADISM in females.
- prevention of OSTEOPOROSIS.
What are the clinical uses of PROGESTINS?
- ORAL CONTRACEPTIVES (with or without estrogen).
- HRT (with estrogen)
- Progesterone= MAINTENANCE of PREGNANCY (prematurity risk…) or assisted reproductive technology.
What are the 2 different mechanisms of action of oral contraceptives (OCs)?
- BLOCK OVULATION at the level of the PITUITARY= suppress FSH, LH, and GnRH pulses, lowering their levels and thus suppressing the mid-cycle LH SURGE.
- BLOCK OVULATION at level of OVARY and UTERUS= alters cervical mucus, tubal transport of of ovum, and endometrial development.
*** What are the 2 roles of ESTROGEN (produced by the ovaries) during the FOLLICULAR phase of the ovarian cycle?
- provides NEGATIVE FEEDBACK to the hypothalamus and anterior pituitary to keep FSH and LH levels low.
- stimulates the endometrium of the uterus to grow.
*** What are the 2 roles of ESTROGEN (produced by the ovaries) during OVULATION of the ovarian cycle?
- STIMULATES the hypothalamus to increase GnRH and thus LH and FSH from the anterior pituitary; this LH surge is what causes ovulation
- continued stimulation of the endometrium of the uterus to grow.
*** What are the roles of ESTROGEN (produced by the ovaries), and PROGESTERONE (produced by the corpus luteum) during the LUTEAL phase of the ovarian cycle?
- BOTH provide NEGATIVE FEEDBACK to the hypothalamus and anterior pituitary to decrease GnRH, LH, and FSH.
- PROGESTERONE will maintain the endometrium until the corpus luteum degrades, causing the endometrium to slough off.
So how do OCs work at the hormonal level?
- stop the estradiol flux, thus preventing the LH surge and subsequent ovulation.
What are the 3 types of OCs?
- combination (estrogen-progestin pills)= 99% of women.
- progestin only
- postcoital contraceptives (plan B)
*** What are the combination (estrogen-progestin) OC pills?
- can be used as monthly or extended dosing
- mono-, bi-, tri- or 4-phasic (aka how many times the estrogen-progestin dose changes throughout the cycle).
Do monophasic combination OC pills have the same efficacy as multiphasic?
YES, however skipping any pills in a multi-phasic course causes more disruption than skipping a monophasic
What is one thing that is different about the 4-phasic combination pill?
- uses a bioidentical estrogen (estradiol valerate) instead of ethinyl estradiol.
Why are there so many types of combination pills?
- lower doses of E2 (estradiol)= fewer adverse side effects. but amenorrhea.
- Higher doses of E2 (estradiol)= treat excessive menstrual pain and bleeding.
- progestins can be tailored to gain or avoid different side effects.
Do the progestin-only pills have inactive pills like the combo pills?
NO
Why would you take the progestin-only pill (Norethindrone) over the combo pill?
- useful for women sensitive to estrogen (smokers, cardio risk).
- safe for breastfeeding mothers.
What must you be wary of in progestin-only pills?
- will not always block ovulation.
- cannot miss any pills (must take at same time every day).
What are the 2 oral postcoital/ “emergency contraceptives”/ “morning-after pills”?
- LEVONORGESTREL (Plan B)= best within 3 days, but the sooner the better; however, won’t affect an attached embryo.
- ULIPRISTAL ACETATE= selective progesterone receptor modulator (SPRM; Ella). Must use within 5 days. This one will be just as effective on day 5 as day 1. Thus, more effective than levonorgestrel.
What postcoital contraceptive is also used to treat uterine fibroids?
- ulipristal acetate
What is Mifepristone?
- another rarely used form of postcoital contraceptive that is a Norethindrone derivative acting as a progestin antagonist. This is known as the abortive pill because it will cause abortion up to day 49.
What are some beneficial effects of the combo pill?
- decreases incidence of amenorrhea, irregular periods, intermenstrual bleeding, and reduces blood loss/anemia.
- decrease pain in endometriosis.
- reduce benign breast disease, uterine fibroids, and ovarian cysts.
- reduces risk of ovarian, endometrial, and colorectal cancer.
- preserves bone density
- treats severe acne
What are some ADRs of the combo pill?
- weight gain, libido changes (usually decrease), nausea, dizziness, headache, iritability and increased risk of breast cancer.
- VENOUS THROMBOEMBOLISM.
What are some ADRs of the progestin-only pill?
- irregular bleeding
- acne, hirsutism (RARE)
What are the major drug interactions with OCs?
- EPILEPSY MEDICATIONS
- certain antibiotics (RIFAMPIN).
- some antifungals have a slight risk of decreasing efficacy.
- CYTOCHROM P450 INDUCERS (St. john’s wort is an herbal supplements).
What are some other uses for estrogen/progesterone modulators?
- ER-positive breast cancers= SERMs (agonist and antagonist properties depending on tissue) and AROMATASE INHIBITORS to decrease estrogen.
- osteoporosis
- infertility
What are the main SERMs used for cancer treatment? (PICMONIC)
- TAMOXIFEN= ER antagonist in breast tissue :) but agonist in uterus, bone, and liver.
- FULVESTRANT= antagonist ONLY (so technically SERD; selective estrogen receptor down-regulator). Used in POSTmenopausal women only after failure with Tamoxifen.
What are aromatase inhibitors? (PICMONIC)
- Anastrozole and Letrozole= inhibit estrogen synthesis from androgens.
- indicated for breast cancer following treatment with Tamoxifen.
Can you use aromatase inhibitors in pregnancy?
NO
What drug is used to treat osteoporosis? (PICMONIC)
- RALOXIFENE= SERM similar to Tamoxifen, but with STRONGER AGONIST activity in BONE.
What drug is used to treat infertility?
- CLOMIPHENE= SERM that can induce ovulation by inhibiting estradiol’s negative feedback.
- Letrozole (aromatase inhibitor) can also be used to induce ovulation.
