Estrogens, Antiestrogens, Progestins, Antiprogestins Flashcards
Endocrine Regulation of Female Reproductive Function
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
Hormone Levels During the Menstrual Cycle
(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
Biosynthesis of Estrogens, Progestins, Androgens
Cholesterol–> pregnenolone–>progesterone
Progesterone–>weak androgens–>Estriol, estrone and
estradiol
Estrogens are produced by androgenic precursors.
Key Enzyme: Estrogen Production
Aromatase
responsible for last conversion step
Classification of Estrogens, with examples
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
Localisation of Estrogen
Effects of Estrogen
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
Hepatic Effects of Estogen
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
Mechanism of Genomic Action of Estrogens
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
Mechanism of Non Genomic Action of Estrogens
- G protein coupled R
- Act on ion channels
- Interact with RAS system
Background Knowledge SERMs
Terminology
Basic Concepts
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)
Estrogens
Pharmacokinetics
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
Estrogens
Medical Uses
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
Estrogens
Side Effects
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
Estrogens: Natural and Steroidal
Drug Names and Characteristics
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
Estrogens: Synthetic and Steroidal
Drug Names and Characteristics
Ethinyl Estradiol (Prodrug: Mestranol) P.O.; intravaginally Very common in oral contraceptives
Quinestrol
Estrogens: Synthetic and Non Steroidal
Drug Names and Characteristics
Diethyl Stilbestrol
Vaginal cc in offspring if used during pregnancy
Methallenestril
Selective Estrogen Receptor Modulators (SERMs)
Drug Names and Characteristics
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
Antiestrogens: Drug Groups
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(!!)
Antiestrogens: Selective Aromatase Inhibitors
Drug Names and Characteristics
Formestan and Anastrozole
Inhibit in both ovaries and non glandular tissue
Th of estrogen sensitive breast cancer
Antiestrogens: Aminoglutathiamide
Characteristics
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
Antiestrogens: Long Acting GnRH Agonists and Antagonists
Characteristics
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
Progestins
Functions Physiologically
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
Progestins
Molecular Mode of Action
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
Progestins
Pharmacokinetics
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
Sources of Progesterone in Body
Corpus Luteum post Ovulation
Placenta during Pregnancy
Medical Uses of Progestins
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
Progestins: Side Effects
Headache Breast Swelling and Tenderness Hypertension Depression Breakthrough Bleeding Edema, Acne, decreased HDL, increased LDL Breast cancer with lasting PMHR Glucose Intolerance
Progestins: Endogenous Progestin
Drug Name and Characteristics
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
Progestins: Pregnane Compounds (1st gen)
Drug Names and Characteristics
Megastrol Acetate: P.O and IM
Medroxyprogesterone Acetate: P.O and IM
Chlormandinone Acetate and Cyproterone
have androgen antagonist effect
Progestins: Estranes (2nd gen)
Drug Names and Characteristics
Norethindrone (Norethisterone) and Ethynodiol Diacetate
Androgen derivatives with moderate activity
PO/IM/SC
Progestins: Gonanes (3rd gen)
Drug Names and Characteristics
Norgestrel, Levonogestrel, Gestodene, desogestrel, norelgestromine
Almost free from androgenic activity (first two still have slight)
PO/IM/SC
Antiprogestins
General
Progesterone R Antagonists
Recently: SPRMs
Antiprogestins
Mifepristone
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
Antiprogestins
Long Acting GnRH Agonist and Antagonist
Can drastically reduce progesterone production too
Antiprogestins
Ulipristal acetate
Prodrug–> Ulipristal
Partial Agonist and/or antagonist of progesterone
Popular emergency contraceptive