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RGU Exam 1 > Estrogens and Progestogens > Flashcards

Estrogens and Progestogens Flashcards

1
Q

Progesterone nomenclature

A
  • The endogenous progestogen
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2
Q

Progestins nomenclature

A
  • Synthetic progesterone (though sometimes used interchangeably w/ progestogen)
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3
Q

Natural estrogens and progesterone

A
  • Primary steroid hormones produced in the ovaries
  • Most common naturally occuring estrogen and progestogen

*17beta-estradiol

*Progesterone

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4
Q

Natural estrogen in humans from weakest to strongest

A
  • E3 (Estriol), E1 (Estrone), E2 (Estradiol)
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5
Q

Primary estrogen post-menopause

A
  • Estrone
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6
Q

Synthetic estrogen most common in birth control

A
  • Ethinyl estradiol

*Ethiny group renders molecule able to pass through stomach and liver making it orally active

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7
Q

Synthetic progestogens (progestins)

A
  • Ethinyl substitution of testosterone —> orally active compound ethisterone
  • Removing the 19 carbon from ehisterone —> class of progestins called 19-nortestosterone derivatives
  • 19-nortestosterone derivatives make up most of the synthetic progestins used as oral contraceptives
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8
Q

Food substances with estrogenic effects

A

Phytoestrogens

  • Major groups: Isoflavonoids and Lignans

*Isoflavonoids such as Isoflavones (found in soy) and Coumestans (found in alfalfa sprouts and certain legumes)

*Lignans found in flaxseed, berries, etc.

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9
Q

Phytoestrogens may bing more readily to what estrogen receptors?

A
  • ERbeta
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10
Q

Environmental substances w/ estrogenic effects

A
  • Bisphenol A (BPA)

*released as plastics degrade

*can bind to ERs; metabolite may have even stronger binding affinity

  • Polychlorinated hydroxybiphenyls (PCBs)

*banned in 1979, but small amts still occasionally detected

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11
Q

Steroid hormone biosynthesis

A

Circulating cholesterol (in ovaries, testis, adrenal gland) —> Progesterone —> Androgens —> Estrogens

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12
Q

Estrogen biodegradation

A
  • Occurs in liver
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13
Q

Cytochrome p450 (CYP)

A
  • Major enzyme family in drug metabolism
  • Catalyze oxidatio reactions, making a substance more water soluble so the body can remove it
  • Differences in CYPs = reaction variability to drugs
  • Responsible for most of the breakdown of gonadal steroids
  • Important in both biosynthesis and breakdown of estrogen

*CYP19A1 = aromatase (Testosterone —> Estradiol)

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14
Q

“Classical” estrogen signaling pathway (Genomic)

A

1) ER is bound to a heat shock protein in the cytoplasm (heat shock protein keeps estrogen receptor inactive until it binds w/ estrogen
2) Estrogen binds to ER causing a conformational change allowing for removal of heat shock protein
3) ERs form a dimer
4) ER dimer enters nucleus and binds either directly to the DNA thru the Estrogen Response Elements (ERE) which are nucleotide sequences of the gene or transcription factors on target gene to activate transcription

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15
Q

“Rapid action” estrogen signaling pathway (Non-genomic)

A

1) Activation of a cell surface receptor activates ER thru phosphorylation

*the receptor on the membrane is not an estrogen receptor so, the thing about the genomic pathway is that it can be activated by ligands that are not estrogen

2) Activation intracellular signaling pathways
3) Can set off rapid changes including Ca2+ and NOS release

*results in cell growth, motility, differentiation, survival or apoptosis

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16
Q

2 Classic estrogen receptors

A
  • ERalpha (NR3A1)

*high growth promoting properties

*endometrium, breast tissue (and often in breast cancer cells), stromal cells in ovary, brain (hypothalamus)

  • ERbeta

*has more anti-growth properties

*phytoestrogens bind more readly to

*granulosa cells in ovary, kidney, brain (hippocampus, cortex, thalamus), bone, heart, lungs, prostate, endothelial cells

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17
Q

G-protein coupled Estrogen Receptor 1 (GPER, GPR30)

A
  • Implicated in rapid, non-genomic E2 signaling
  • Found in endometrium w/ similar patterns as ERalpha
  • Also in spinde, brain, blood vessels, ovary, breast, heart, lung, adipose tissue
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18
Q

Progesterone signaling pathway

A
  • Very similar to estrogen pathway
  • PR instead of ER
  • PRE instead of ERE
  • Has both classical genomic and non-genomic pathways
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19
Q

Progesterone receptor

A
  • One classical receptor (called progesterone receptor, or PR)
  • 2 main isoforms: short (PRA) and long (PRB)
  • Expression seen in uterus, mammary gland, brain, pancreas, bone, ovary, testes, and tissues of the lower urinary tract
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20
Q

Estrogen physiological actions

A

Female reproduction

  • Reproductive organ growth
  • Secondary sexual characteristics
  • Regulates menstrual cycle
  • Fertility (also in males)

Metabolic/bone

  • Reduces bone resorption (break down of bone and release the minerals into the blood)
  • Stimulates closure of epiphyses in long bone shafts
  • Increase plasma triglycerides and HDL cholesterol
  • Decrease LDL cholesterol

Cognitive

  • Role in sexual behavior
  • Role in neurodegenerative disorders

*estradiol had protective effect for women at high risk

  • Learning and memory, possibly thru a role in synaptic remodeling
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21
Q

Progestogens physiologic actions

A
  • Induces secretory changes in endometrium
  • Progesterone (non synthetics) maintains pregnancy; name derived from “pro-gestational steroidal ketone”
  • Affect carb metabolism/fat deposition
  • High doses can block ovulation and gonadotropin secretion
  • May increase blood pressure
  • Decrease HDL cholesterol; increase LDL
  • Increases insulin and response to glucose
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22
Q

Therapeutic applications involving estrogen and progesterone pathways

A
  • Can give natural or synthetic estrogen and progesterone

*oral contraceptives (OC’s)

*hormone replacement therapy

  • Can give drugs that modulate estrogen or progesterone activity

*some emergency contraceptives

*selective estrogen receptor modulators (SERMS) in cancer and more

*aromatase inhibitors

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23
Q

Clinical uses of estrogens

A
  • Combination estrogen + progestin oral contraceptives

*contraception

*hyperandrogenism (often in polycystic ovary syndrome)

*menstrual disorders

  • Hormone replacement therapy (HRT); conjugated equine estrogens or synthetic estrogens

*premature ovarian failure

*menopause

*ovariectomy

  • Prevention of osteoporosis

*short-term (6mo - 5years)

*postmenopausal women

  • Primary hypogonadism in females
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24
Q

Clinical uses of progestogens

A
  • Contraception (w/ or w/o estrogen)
  • HRT (usually w/ estrogen)
  • Maintenance of pregnancy (prematurity risk, etc)
  • Assisted reproductive technology
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25
Q

Types of oral contraceptives

A

1) Combination/combined estrogen-progestin pills
2) Progestin-only pills
3) Emergency contraceptives

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26
Q

Combination OCs

A
  • Contain both an estrogen and a progestin
  • With perfect use = 0.1% failure rate
  • With typical use = ~8% failure rate

*most common problem = missed pills

*can take missed pill ASAP; after 2, additional contraceptive method recommended

  • Can be used as monthly or extended dosing
  • Mono-, Bi-, Tri-, or 4-phasic
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27
Q

Ethinylc estradiol

A
  • An orally active synthetic estradiol that is the most common estrogen component of OCs
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28
Q

Multi-phasic OC vs. Monophasic

A
  • Same efficacy as monophasic
  • Skipping any pills in a multi-phasic causes more disruption than skipping a monphasic
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29
Q

4-phasic combination OCs

A
  • Dosage changes 3x over the course of cycle
  • Uses bioidentical estrogen (estradiol valerate)

*may result in better absorption

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30
Q

Higher vs. lower doses of E2 in OCs

A
  • Lower dose = fewer adverse effects
  • Lower doses may result in amenorrhea or break through bleeding (safe but inconvenient)
  • High doses often needed to treat beyond contraception (e.g. excessive menstrual pain or bleeding)
31
Q

Variety of progestins in combination OCs benefit

A
  • Different progestins have diff. levels of androgenic activity
  • Can choose diff. progestins in pill to gain or avoid various side effects depending on the particular needs of each pt.
32
Q

Estrogen effects during follicular phase

A
  • Negative feedback to Hypothalamus and anterior pituitary

*LH and FSH stimulate several follicles to grow

  • Ovarian hormone effects: dominant follicle produces estradiol, which:

*inhibits GnRH, FSH, and LH production

*causes endometrium to thicken

33
Q

Estrogen effects during ovulation

A
  • Positive feedback to hypothalamus

*LH and FSH stimulate maturation of one of the growing follicles

  • Ovarian hormone effects: growing follicle continues to produce estradiol, which:

*stimulates GnRH, FSH and LH production

*LH surge triggers ovulation

34
Q

Estrogen effects during Luteal phase

A
  • Estrogen along w/ progesterone = neg. feedback to hypothalamus and anterior pituitary

*LH stimulates formation of a corpus luteum from follicular tissue left behind after ovulation

  • Ovarian hormone effects: The corpus luteum secretes progesterone, which:

*Inhibitis GnRH, FSH, and LH production

*Maintains the endometrium; as the progesterone declines, initiating sloughing of the stratum functionalis

35
Q

Normal fluctuations of progesterone and estrogen in the menstrual cycle diagram

A
  • Estrogen peak precedes the FSH and LH surge that signal ovulation
36
Q

Mechanisms of action of combination OCs

A
  • Blocks ovulation at the level of the pituitary

*suppresses midcycle LH surge

*also suppresses FSH (and possibly GnRH) pulses and lower FSH and LH levels)

  • Suppression of ovarian folliculogenesis

*result of FSH suppression

*more so with high dose estradiol OCs

*may take a full cycle to have effect

37
Q

Beneficial effects of combination OCs

A
  • Decreases incidence of amenorrhea, irregular periods, intermenstrual bleeding, reduce blood loss/anemia
  • Can decrease endometrial lining and decrease pain in endometriosis
  • Reduce incidence of benign breast disease, uterine fibroids, ovarian cysts
  • Less risk of ovarian, endometrial, and colorectal cancer
  • Preserves bone density
  • Can be used to treat severe acne
38
Q

Adverse effects of combination OCs

A
  • Side effects are dose- and type-dependent
  • Weight gain (fluid retention/anabolic effect)
  • Libido changes
  • Nausea, dizziness, headache, migraine, depression or irritability
  • Increased risk of breast cancer; does not appear to be dose-dependent
  • Cardiovascular problems

*venous thromboembolism

39
Q

Contraindications for combination OCs

A
  • Smokers >35
  • Pts w/:

*moderate/severe hypertension

*thromboembolic disorders

*ischemic heart disease

*valvular heart disease/cardiac complications

  • Systemic lupus erythematosus (pos. or unknown antiphospholipid antibodies)
  • Migraine w/ aura
  • Breast cancer
  • Cirrhosis
  • Hepatocellular adenoma or malignant hepatoma
40
Q

Major drug interactions w/ combination OCs

A
  • Any drug that induces P450 3A4 (CYP3A4)

*St. John’s wort

*certain antibiotics (rifampin)

*some antifungals (griseofulvin, ketoconazol) have risk of decreasing efficacy

  • Some anticonvulsants
  • Antiretrovirals (nevirapine and ritonavir)
  • Ulipristal acetate
41
Q

Progestin-only pill (POP)

A
  • Norethindrone, 0.35mg daily (less than in combo pills)
  • No inactive pills; constant level throughout cycle
  • Failure rate is likely higher than w/ combo pill

*not as effective at blocking ovulation

*cannot miss any pills and must take at same time every day (delay >3hrs requires back up contraception)

42
Q

POP’s MOA

A
  • Generally not as effective as combination OCs at delaying ovulation
  • Increases viscosity of cervical mucus, and alters tubal transport of ovum and endometrial development

*decreases conception probability

*decreases implantation

43
Q

Why would you use POPs over combination OCs?

A
  • Useful for women sensitive to estrogen (smokers, cardio risk)
  • Safe for breastfeeding mothers

*estrogen can cross over into breast milk whereas progesterone cannot

44
Q

Contraindications for POPs

A
  • Pts w/ breast cancer
45
Q

Adverse effects of POPs

A
  • Irregular bleeding and menstrual changes are the primary side effect
  • Can have androgenic side effects (acne, Hirsutism)
  • Follicular cysts
46
Q

Emergency contraceptives

A
  • Pill or copper IUD
  • 2 primary options for oral emergency contraception

*Levonorgestrel

*Ulipristal acetate

47
Q

Emergency contraceptives MOA

A
  • General mechanism for all is delaying ovulation; may also be some effect on sperm
  • Time dependent; only effective before implantation of embryo
48
Q

Levonorgestrel

A
  • Emergency contraceptive
  • Ex: Plan B
  • Best within 72hrs (longer you wait, less effective)
  • Higher failure rate in women w/ high BMI
49
Q

How do OCs w/ progestins prevent pregnancy

A
  • If taken immediately after intercourse:

*may thicken cervical mucus and slow sperm

*may alter where body thinks it is in menstrual cycle, delaying ovulation

50
Q

Ulipristal acetate

A
  • Selective progesterone receptor modulator (SPRM)- antiprogestin
  • One brand: Ella
  • Must use within 120hrs (5 days)- BUT it is just as effective at the end of this period as in the beginning
  • Blocks embryo attachement
  • More effective than levonorgestrel-containing pills
  • Also used to treat uterine fibroids
  • May be less effective in obese women
51
Q

Best alternative to contraception for obese women

A
  • Copper IUD
52
Q

Drug interactions w/ oral emergency contraception

A
  • Meds that reduce plasma levonorgestrel levels:

*Anticonvulsants

*Antituberculosis

*Antiretrovirals

*Antifungals

*St. John’s wort

  • Drugs that induce liver enzymes (elevated levels of lifer enzymes can persist for up to 28 days after discontinuing meds)
  • Drugs that increase gastric pH (Ulipristal acetate)
53
Q

Side effects of oral emergency contraception

A
  • Nausea
  • Vomiting

*patient can be offered a copper IUD or another dose (plus an anti-emetic)

  • Irregular bleeding
54
Q

Mifepristone

A
  • At low, single dose, can be emergency contraception (but not in the US)
55
Q

Possible future emergency contraception meds

A
  • Prostaglandin inhibitors (COX-1 and 2 inhibitors)

*Meloxicam- used w/ levonorgestrel; shows increased efficacy over levonogestrel alone

*Celecoxib

56
Q

Clinical uses for estrogen modulators

A
  • Cancer
  • Osteoporosis
  • Infertility
57
Q

Estrogen modulation in cancer treatment

A
  • Mostly used for (ER-pos.) breast cancers
  • Estrogen basically “turns on” gene expression programs in the cancer cells
  • ERalpha expression is assoc. w/ more differentiated tumors and a better prognosis
  • PR and ER expression together = good prognosis

*PR appears to directly interact w/ ERalpha

*PR activiation —> alters ERalpha —> decreases ERalpha pos. tumor growth

58
Q

2 major classes of drugs used to modulate estrogens in cancer

A
  • SERMs
  • Aromatase inhibitors
59
Q

Selective Estrogen Receptor Modulators (SERM’s)

A
  • Estrogen-related compounds
  • Bind and activate the estrogen receptor in some tissue (agonist), but…
  • Block the estrogen receptor in other tissues (antagonist)

So, SERM’s have diff. effects in diff. tissues

60
Q

SERM MOA

A
  • SERM or estradiol binding to the ER can change the structure alowing for diff. activators or repressors to bind as well
61
Q

SERM Drugs

A
  • Tamoxifen
  • Fulvestrant
  • Raloxifene
  • Clomiphene
62
Q

SERM’s primarily used in cancer treatments

A
  • Tamoxifen
  • Fulvestrant
63
Q

Tamoxifen

A
  • Competitive estrogen receptor antagonist in breast tissue

*used to treat breast cancer, and for cancer prevention in women at “high risk”

*inhibitis proliferation ER pos. breast cancer cells

  • Estrogen receptor agonist in uterus, bone, liver

*can increase risk of uterine cancer

  • Inhibits arterial accumulation of LDL degradation products
64
Q

Tamoxifen adverse effects

A
  • Menopausal estrogen deficiency
  • Hot flushes
  • Nausea, amenorrhea, menstrual irregularities
  • Increased risk of endometrial hyperplasia and cancer
65
Q

Tamoxifen drug interactions

A
  • Some antidepressants (SSRI’s and SNRI’s)
  • Benadryl
66
Q

Fulvestrant

A
  • Used to treat breast cancer women who:

*are postmenopausal

*have ER pos. breast cancer that has metastasized after treatment w/ other antiestrogens (usually tamoxifen)

  • Only antagonistic to ER’s- thus categorized as a a SERD (Selective Estrogen Receptor Down-regulator)
67
Q

Aromatase inhibitors used to treat cancer MOA

A
  • Inhibits estrogen synthesis from androgens
68
Q

Aromatase inhibitors indications

A
  • Indicated for treatment of women w/ breast cancer following tamoxifen therapy

*in postmenopausal women, aromatase inhibition is preferred w/o a course of tamoxifen

69
Q

Aromatase inhibitors adverse effects

A
  • Fatigue, GI, headache, muscle pain, estrogen-deficiency symptoms
70
Q

Aromatase inhibitors contraindications

A
  • Pregnancy
71
Q

Raloxifene

A
  • Similar to tamoxifen, but w/ stronger agonist activity in bone and liver, and weaker in uterus
  • Used to prevent osteoporosis post-menopause
  • May act as an antagonist in CNS and breast; no estrogenic effects in uterus
  • May aid in breast cancer prevention for very high risk pts
72
Q

Clomiphene

A
  • SERM drug
  • Used to induce ovulation
  • Partial antagonist at estrogen receptors
  • Can inhibit action of strong estrogens
  • Inhibits estradiol’s neg. feedback on LH, FSH, GnRH
73
Q

Aromatase inhibitors

A
  • Letrozole
  • In addition to being adjuvant therapy for breast cancer is also used in unexplained infertility to induce ovulations

RGU Exam 1 (14 decks)

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