Post on 20-Mar-2017
transcript
Estrogen and It’s Basic Pharmacology
Made By:Haris Ahmed Talha
Estrogen and It’s Basic Pharmacology
This presentation is about the basic functioning of the estrogen in the body. The receptors of the estrogen, the mechanism of action, The role of estrogen if female puberty, Its agonist and antagonist.
Introduction to Estrogen Substances which can produce estrus in spayed
animals Estrogens include the natural hormones as well as
semi-synthetic and synthetic (Stilbene) agents Estrogens are used as hormone:
Replacement Therapy (Menopause) In Oncology Contraceptives
Most estrogen in the female is produced in the ovaries by the Theca Interna and the Granulosa cells of the follicles
Also in males from Testosterone (Aromatization)
Natural Estrogen's
CH3OH
H
H
H
HO
ESTRADIOL
CH3
H
H
H
HO
O
ESTRONE
CH3OH
H
H
H
HO
OH
ESTRIOL
Oxidized in liver
hydroxyla
ti
on
1.2.
3.
Synthetic Estrogen's
Inactive orally, long duration and Slow metabolism.
Stored in adipose tissues of body and slowly released.
They are of two types:Steroidal:
Ethinyl estradiol, Mestranol and TiboloneNonsteroidal:
Diethinylstilbestrol, Hexestrol and Dienestrol
Estrogen Synthesis
Estrogen is produced primarily by developing follicles in the ovaries, the corpus luteum, and the placenta
Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) stimulate the production of estrogen in the ovaries
Some estrogens are also produced in smaller amounts by other tissues such as the liver, adrenal glands, and the breasts
The ovaries are the principal source of circulating estrogen in premenopausal women, with estradiol being the main secretory product
In postmenopausal women, the principal circulating estrogen estrone, which is synthesized from dehydroepiandrosterone and secreted by the adrenals
Estrogen Synthesis
The most potent naturally occurring estrogen in humans for both the Estrogen Receptor alpha- and beta-mediated actions is 17beta-estradiol, followed by estrone and estriol
Each estrogen contains a phenolic A ring with a hydroxyl group at carbon 3 and a beta-OH or ketone in position 17 of ring D
The phenolic A ring is the principal structural feature responsible for selective, high-affinity binding to both receptors
Synthesis of estrogen begins from the synthesis of androstenedione from cholesterol
Androstenedione crosses the basal membrane into surrounding granulosa cells, where its converted to estrone or estradiol wither immediately or through testosterone
The conversion is catalyzed by aromatase
Bio-pathway of Estrogen
This figure shows the major metabolic intermediates in the usual synthesis of estrogen, starting with cholesterol, proceeding to pregnenolone, an androgen, and then estrogen.
Estrogen Receptors Estrogens exert their effects by interaction with receptors that
are members of the super family of nuclear receptors The two estrogen receptor (ER) genes are located on separate
chromosomes: ESR1 encodes ER-alpha and ESR2 encodes ER-beta
Both ERs are estrogen-dependent nuclear transcription factors that have different tissue distributions and transcriptional regulatory effects on target genes
Both ERs are ligand-activated transcription factors that increase or decrease the transcription of target genes
After entering the cell by passive diffusion through the plasma membrane, the hormone binds to an ER in the nucleus
In the nucleus, the ER is present as an inactive monomer bound to heat-shock proteins, and upon binding estrogen, a change in ER confirmation dissociates the heat-shock proteins and causes receptor dimerization, which increases the affinity and the rate of receptor binding to DNA
Regulation of Secretion Daily secretion: 10 to 100
mg per day – starts from graffian follicle under influence of FSH
Depends on phase of cycle – increases with FSH in surge – preovulatory
Continue to secrete by corpus luteum after ovulation
During pregnancy – large quantity by placenta – upto 30 mg per day
Post menopausal: 2 – 10 mg per day only
Estrogens Physiology
Actions of Estrogen On sexual organs (primary and secondary sexual characteristics) Brings about pubertal changes in vagina, fallopian tube and uterus –
growth Vagina: cornification of epithelial cells with thickening and stratification of
epithelium Endometrium: Proliferation of endometrium – preovulatory (progeterone) Absence of progesterone – anovulatory cycles – withdrawal of estrogen –
menstruation Continued estrogen without progesterone – delayed menstruation (but breakthrough bleeding) Normal event – progesterone withdrawal – cannot be suppressed by estrogen
Cervix: Rhythmic contractions of uterus and fallopian tube - increase of cervical mucous and alkaline watery secretion with a lowered viscosity (favoring sperm access)
Secondary Sex Characters: Also acne Metabolic effects: Anabolic but weaker than testosterone – pubertal
growth Continued exposure – fusion of epiphyses
Other Pharmacological Actions
Bone: Important for maintaining bone mass – increased expression of bone mass proteins (osteonectin, collagen, osteocalcin, alkaline phosphatase) Reduce the maturation and activity of osteoclasts – by modifying
regulatory cytokines from osteoblasts Positive Ca++ balance Generation of vit.D3 – induction of renal hydroxylase enzyme
Edema – salt and water retention Decreased LDL and Increased HDL level – HDL:LDL ration
increased Increased coagulability: II, VII, IX and X Lithogenicity of Bile Increased SHBG, TBG and CBG
2 ERs are – ERα and ERß ERα - uterus, vagina, breast and blood vessels ERß – Prostate and Ovaries Work via a steroid hormone mechanism. Entering the target cells and binding to specific cytosolic receptors -
dimerization The steroid-receptor complex is then translocated to the nucleus –
EREs of target genes Where it alters gene expression - Coactivator proteins Antagonist binding- Corepressor proteins – inhibits transcription
Mechanism of Action
Estrogen Preparations
Preferred route is oral, but sometimes parenteral when large doses are required
All estrogen preparations are available – tablet and injections
Some examples: Estradiol – 2.5 mg to 10 mg/ml IM inj. Ethinyl Estradiol: 0.01, 0.05, 1 mg tab for Menopause Conjugated estrogens: 0.625,1.25 mg tab or injections 25
mg/ml Mestranol: 0.1 mg tabs to convert to EE Estriol succinate: 1mg/gm cream
Transdermal Patches Estradiol-TTS/Estraderm/Estragest - TTS Sizes: 5, 10 and 20 sq. cm – 0.025, 0.05 and 1 mg/day Menopausal women Usual dose: 0.5 mg/day Cyclic therapy – 3 weeks on – 1 week off + Progestin 10-12
days during last days ADV: Less hepatic delivery VS Oral – CBG, TBG,
angiotensinogen and clotting factors are not elevated
Estrogen – Adverse Effects
Suppression of libido, gynaecomastia and feminization – in Male
Fusion of epiphyses – reduction of stature Stilbestrol – increased incidence of Carcinoma of
cervix in female offspring Irregular bleeding – endometrial carcinoma Accelerated growth of Breast cancer Gall stones and hepatomas Migraine, epilepsy and endometriosis - worsens
Menopause - Adverse Effects
Hormone Replacement Therapy to Menopause woman Problems of menopause: Physical, psychological and emotional
Vasomotor disturbances: Hot flash, chilly sensation, inappropriate sweating, aches and pains etc.
Urogenital atrophy: vaginitis, dyspareunia, dryness and shrinkage etc. Osteoporosis and fractures Psychological and cognitive disturbances: Irritability, depression, loss
of libido etc. Dermatological changes Risk of cardiovascular diseases: CAD, Stroke MI etc.
Dosage: Estrogen equivalent to 0.625 mg of EE/day in cyclical manner Progestin preparation (medroxy progesterone/norethisterone) is used – 2.5
mg daily TTS preparations may be preferred
Hormone Replacement Therapy Benefits: (Indications):
Vasomotor and other symptoms of perimenopausal period – smallest effective dose
Post hysterectomy patients – estrogen only Young woman with premature menopause Perimenopausal women – cyclical HRT
Demerits: No improvement of cognitive disturbances – risk of dementia Does not protect against Cardiovascular diseases: increased venous
thromboembolism, MI and stroke etc. (NO synthase and PGI2 production) Not good for Prevention of osteoporosis and fractures Combined HRT increases the risk of Breast cancer, gall stones and migraine Should be assessed individually
Tibolone: Developed specifically for HRT Estrogenic and progestitional property Dose is 2.5 mg daily Lesser chance of Breast cancer
Anti-estrogens and SERMs
Anti-estrogens
Pure antagonists Clomiphene is for
treatment of infertility in anovulatory women
Fulvestrant is used for the treatment of breast cancer
Selective Estrogen Receptor Modulators (SERMs) Compounds with tissue-
selective actions The goal of these drugs
is to produce beneficial estrogenic actions in certain tissues (ex. Brain, bone, liver) during postmenopausal hormone therapy
Tamoxifen, Raloxifen, Toremifine
Clomiphene Citrate (Antiestrogen)
The “Fertility pill” - pure antagonist of ESTROGEN receptor in all human tissues Used in women with unexplained infertility or
anovulatory infertility Bind to both, ERα and ERß receptors Blocks estrogenic feedback inhibition of pituitary
and induces Gn secretion Increase in amount of secretion of FSH/LH at
each secretary pulse Creates favorable atmosphere (ovarian
stimulation) for ovulation in ovaries Hot flashes – antagonism of peripheral actions
Clomiphene Citrate Dosage:
50 mg OD from 5th day onwards for 5 days Continued for 2-3 cycles Conception occurs within 4-6 cycles If no, dose increased However – antiestrogenic effect may modify developing follicle,
endometrial and cervical secretion Luteal phase dysfunction – failure (HCG and Menotropins added)
Adverse Effects: Polycystic ovaries, multiple pregnancy, gastric upset, hot flushes and vertigo, allergic dermatitis
Other Uses: Assisted reproduction (to develop multiple eggs) Artificial insemination (irregular ovulation) (Clomiphene Challenge Test) Oligospermia (25 mg daily for 6 months – 6 days rest))
Tamoxifen (SERM)
Actions: Is a competitive antagonist to estrogen at receptors in the breast. Partial agonist at other estrogen receptors (thus minimizing side effects
due to estrogen deprivation) - bone, uterus, liver and pituitary Hot flushes – antiestrogenic action Stimulation of endometrial proliferation and lowering of Gn and prolactin
levels – agonistic action Decrease in LDL level but no change in HDL level
Other benefits: Improvement in bone mass and lipid profile Kinetics: Absorbed orally and has biphasic half life – 10 Hrs
and 7 days – long duration of action Excreted in Bile Dose is 10 to 20 mg BD
Uses: Breast carcinoma of pre and post menopause Adjuvant therapy in early cases Palliative therapy
Adverse effects: The drug has a low incidence of adverse reactions Hot flashes, nausea, vomiting, rash, menstrual irregularities and
bleeding, infrequent depression, headache, hypercalcemia, edema, and blood dyscrasias
Less toxic than anticancer drugs Endometrial carcinoma: thickening of endometrium
Other SERM: Raloxifene, ormeloxifene etc. Raloxifene is estrogen antagonist of breast and endometrium while
partial agonist of bone and CVS
TamoxifenCH2CH3
O(CH3)2N-CH2-CH2
TAMOXIFEN (NOLVADEX)
Aromatase Inhibitors
Letrozole, Anastrozole and Exemestane Letrozole:
Non steroidal compound, reversible inhibition of aromatization all over the body
Suppression of proliferation of estrogen dependent breast carcinoma cells
Rapid oral absorption – 100% bioavailability, large Vd, t1/2 – 40 Hrs.
2.5 mg BD Uses:
Early breast carcinoma and Advanced breast carcinoma