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Pharma 3 > Estrogens, Antiestrogens, Progestins, Antiprogestins > Flashcards

Estrogens, Antiestrogens, Progestins, Antiprogestins Flashcards

1
Q

Endocrine Regulation of Female Reproductive Function

A

Hypothalamus secreted GnRH–> Ant Pituitary
Ant Pituitary then secreted LH & FSH
Ovaries then secrete Estrogens/Progesterone

Estrogen has a negative feedback on ant. pituitary
Positive feedback under special conditions
Progesterone has a negative feedback on hypothalamus
and ant. pituitary

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2
Q

Hormone Levels During the Menstrual Cycle

A

(FSH) and Estrogens produced continuously, with changes in levels. Rise during ovulation

LH peaks during ovulation; is the immediate stimulus

Progesterone is produced by the corpus luteum therefore only secreted during the secretory phase

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3
Q

Biosynthesis of Estrogens, Progestins, Androgens

A

Cholesterol–> pregnenolone–>progesterone
Progesterone–>weak androgens–>Estriol, estrone and
estradiol

Estrogens are produced by androgenic precursors.

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4
Q

Key Enzyme: Estrogen Production

A

Aromatase

responsible for last conversion step

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5
Q

Classification of Estrogens, with examples

A

Natural and Steroidal
17b estradiol, estrone, estriol

Synthetic and Steroidal
Ethinyl Estradiol
Mestranol
Quinestrol

Synthetic and Non Steroidal (can still act on Estrogen R)
Diethyl Stilbestrol
Methallenstril

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6
Q

Localisation of Estrogen

Effects of Estrogen

A

Localisation:
Ovaries, placenta, adipose tissue, adrenal cortex, testes
adipose tissue imp post menopause

Effects:
1ary and 2ary sexual characteristic, maint of libido
Induction of proliferation phase of menstrual cycle
Endometrial Hyperplasia
Prep of mamma for lactation during pregnancy
Stimulation of long. bone growth and epiphyseal
closure; inhibition and decrease # of osteoclasts
Vasodilation, Na and water retention, anabolic on skin
Increase melanin content
Increase sebaceous gland content

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7
Q

Hepatic Effects of Estogen

A

Enhanced Homeostasis–> increased risk thrombosis
Decrease ATIII, increase vit K dep clotting factors
Weak fibrinolysis–> outweighed

Enhanced Hepatic Protein Synthesis: Increased
Angiotensinogen, transferrin, thyroxin binding globulin,
sex hormone binding globulin, transcortin

Alteration of Plasma Lipid Profile
Increase HDL and triglycerides
Decrease LDL

Altered Bile Composition –> increased bile stone risk
Decrease Bile Acids while increasing Cholesterol

REM: increased hepatic enzyme synthesis too; clinically not significant as free fraction unchanged but lab measurements are altered leading to diag. difficulties

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8
Q

Mechanism of Genomic Action of Estrogens

A

Receptor located in cytoplasm and nucleus
2 genes (ERa and ERb) code for the two types of IC R
Resting: R blocked by Heat Shock Protein (HSP)
removed when estrogen binds
Agonist-R Complex formation
Translocation thereof to nucleus, dimerisation with others
Dimer binds to specific DNA segment ex ERE
(estrogen response element)

ERE Actions:
+: with Co-Activator–> Increase transcription for estrog
-: with Co-Repressor–> Decrease transcription for estro

Indirect Interaction with TF (AP1, NFkB) also possible
–> inhibition

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9
Q

Mechanism of Non Genomic Action of Estrogens

A
  • G protein coupled R
  • Act on ion channels
  • Interact with RAS system
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10
Q

Background Knowledge SERMs

Terminology
Basic Concepts

A

Dual Behaviour
Behave as agonists in certain tissues and antagonists in
others (possibly partial agonistic)

But bind to same site within Estrogen-R (ERa and ERb)

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11
Q

Estrogens

Pharmacokinetics

A

Good oral absorption, highly lipophylic
Marked first pass metab–> high hepatic actions
Metabolic elim: Phase 1 reaction: CYP med oxidation
then conjugation and excretion: bile and urine
Estradiol binds to SHBG and albumin, synthetic to
albumin only
Enterohepatic circulation for (semi)synthetic

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12
Q

Estrogens

Medical Uses

A 
Substitution Th: Turners, castration, pituitary insuff
PMHT
Contraceptives (with progestin!)
Mentrual Bleeding Disorders
Premenstrual Syndrome
Delay Menstruation
Polycystic Ovary Syndrome
Suppression of Lactation
Prevention of Gigantism
Breast Cancer, Prostate Cancer
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13
Q

Estrogens

Side Effects

A

Mainly when oral prep:
Increased risk venous thrombosis
Elevated levels specific plasma transport proteins
Cholestasis, increased risk gall stones
Elevation of plasma TG levels

General:
Worsening of Endometriosis
Endometrial Hyperplasia and Cancer
Combo with progestin to eliminate risk
PMHT: increased risk of breast and ovarian cancer
Combo with progestin further increases
Premature Epiphyseal Closure
During pregnancy–> fetal genital malformations, vaginal
adenocc of offspring
Nausea/vomiting/breast swelling/ edema

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14
Q

Estrogens: Natural and Steroidal

Drug Names and Characteristics

A

17b Estradiol: Estradiol Valerate and Cypinoate
most potent estrogen, T1/2: short
transdermal patch, gel, nasal spray, vaginal tablet
ex estradiol valerate and cypinoate: IM depo inject.
Metabolised in liver–> estrone and estriol

Estrone: Estrone Sulfate
   Active metabolite of 17b Estradiol
   Conjugated w/ glucuronidate and sulfate then excreted 
      into bile and urine 
   P.O. or IM

Estriol
Active metabolite of 17b Estradiol
Conjugated w/ glucuronidate and sulfate then excreted
into bile and urine
P.O., intravaginally via tablet, suppository, cream

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15
Q

Estrogens: Synthetic and Steroidal

Drug Names and Characteristics

A 
Ethinyl Estradiol (Prodrug: Mestranol)
   P.O.; intravaginally
   Very common in oral contraceptives

Quinestrol

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16
Q

Estrogens: Synthetic and Non Steroidal

Drug Names and Characteristics

A

Diethyl Stilbestrol
Vaginal cc in offspring if used during pregnancy

Methallenestril

17
Q

Selective Estrogen Receptor Modulators (SERMs)

Drug Names and Characteristics

A

Tamoxifen
Antagonist in breast cancer cells
Agonist in endometrium–> endometrial cc

Raloxifen
Antagonist in breast cancer cells and endometrium
Agonist in bone–> used in osteoporosis

Clomifen
Antagonist in most tissues (inhibits negative feedback)
–>used for ovulation induction in infertile women
SE: multiple pregnancies, ovarial cysts

18
Q

Antiestrogens: Drug Groups

A

Selective Aromatase Inhibitors
Inhibit estrogen formation in estrogen and non
glandular tissues

Aminoglutathiamide
Inhibits aromatase along with other hormones of synth

Long Acting GnRH Agonists, Antagonists
Inhibit FSH and LH secretion–> reduce estrogen synth
only in ovaries(!!)

19
Q

Antiestrogens: Selective Aromatase Inhibitors

Drug Names and Characteristics

A

Formestan and Anastrozole
Inhibit in both ovaries and non glandular tissue
Th of estrogen sensitive breast cancer

20
Q

Antiestrogens: Aminoglutathiamide

Characteristics

A

Inhibits aromatase along with other enzymes involved in production of steroidal hormones

Th of estrogen sensitive breast cancer in combo with hydrocortisone to compensate for antiGC action

21
Q

Antiestrogens: Long Acting GnRH Agonists and Antagonists

Characteristics

A

Inhibit FSH and LH secretion==> reduction of estrogen (all gonadal hormones) synthesis in ovary only
FSH and LH don’t regulate hormone production in non
glandular tissue
Th of hormone sensitive breast cancer

REM: require overregulation of estrogen R to treat breast cancer with estrogens

22
Q

Progestins

Functions Physiologically

A

Induction of secretory phase
Viscous cervcal secretion, change in vaginal epithelium
Prolif of mammary acini; antiprolif in endometrium
Maint. of pregnancy
CNS: elevation of body temp
Decrease HDL, Increase LDL

23
Q

Progestins

Molecular Mode of Action

A

Receptor: 2 isoforms (PRa and PRb) due to alternative splicing

Receptor dimerisation, binding to PRE, then co activator or co repressor binds too.

Direct, Indirect, and Non Genomic Actions

24
Q

Progestins

Pharmacokinetics

A

Good oral absorption
Significant hepatic first pass
Progesterone binds to albumin and transcortin
Others to SHBG and albumin
Some, synthetic, undergo enterohepatic circulation
Progesterone metabolised-> pregnenediol-> conjugation with glucuronate and sulfate-> excreted in urine
Synthetics have longer T1/2

25
Q

Sources of Progesterone in Body

A

Corpus Luteum post Ovulation

Placenta during Pregnancy

26
Q

Medical Uses of Progestins

A

With an Estrogen:
Substiution th in hypogonadism ex Turners
PMHR
Acne

Alone or with an Estrogen:
   Hormonal Contraception (combo more typical)
   Menstrual Bleeding Disorders
   Delay of Menstration
   Endometriosis

Alone:
Corpus Luteum insuff–> infertility
Prevention of premies
Pubertas Praecox
Estrogen dep breast and endometrial cancer (downreg):
drawback if tumor also expresses progesterone R

27
Q

Progestins: Side Effects

A 
Headache
Breast Swelling and Tenderness
Hypertension
Depression
Breakthrough Bleeding
Edema, Acne, decreased HDL, increased LDL
Breast cancer with lasting PMHR
Glucose Intolerance
28
Q

Progestins: Endogenous Progestin

Drug Name and Characteristics

A

Progesterone
High dose formulations are effective orally
IM, intravaginal, intrauterine controlled release
Binds to albumin and transcortin
Metabolised-> pregnenediol-> conjugation with
glucuronate and sulfate-> excreted in urine

29
Q

Progestins: Pregnane Compounds (1st gen)

Drug Names and Characteristics

A

Megastrol Acetate: P.O and IM
Medroxyprogesterone Acetate: P.O and IM

Chlormandinone Acetate and Cyproterone
have androgen antagonist effect

30
Q

Progestins: Estranes (2nd gen)

Drug Names and Characteristics

A

Norethindrone (Norethisterone) and Ethynodiol Diacetate
Androgen derivatives with moderate activity
PO/IM/SC

31
Q

Progestins: Gonanes (3rd gen)

Drug Names and Characteristics

A

Norgestrel, Levonogestrel, Gestodene, desogestrel, norelgestromine

Almost free from androgenic activity (first two still have slight)

PO/IM/SC

32
Q

Antiprogestins

General

A

Progesterone R Antagonists

Recently: SPRMs

33
Q

Antiprogestins

Mifepristone

A

Prototype
Competitive progesterone R antagonist (in vitro agonist)
as well as GC R antagonist activity at higher dose

Mechanism:
Antagonises pregnancy maintaining effects of
progesterone
Upreg. Prostaglandin R in uterus–> more powerful
uterus contractions when combo with prostaglandins

Medical Use:
Induce medical abortion (until 8 weeks) in combo with
PG
Emergency contraception (few countries only)
Th of breast cancer to reduce prolif effect

34
Q

Antiprogestins

Long Acting GnRH Agonist and Antagonist

A

Can drastically reduce progesterone production too

35
Q

Antiprogestins

Ulipristal acetate

A

Prodrug–> Ulipristal
Partial Agonist and/or antagonist of progesterone

Popular emergency contraceptive

Pharma 3 (14 decks)

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