basic pharmacology of estrogen

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Estrogen and It’s Basic Pharmacology Made By: Haris Ahmed Talha

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Page 1: Basic Pharmacology of Estrogen

Estrogen and It’s Basic Pharmacology

Made By:Haris Ahmed Talha

Page 2: Basic Pharmacology of Estrogen

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.

Page 3: Basic Pharmacology of Estrogen

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)

Page 4: Basic Pharmacology of Estrogen

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.

Page 5: Basic Pharmacology of Estrogen

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

Page 6: Basic Pharmacology of Estrogen

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

Page 7: Basic Pharmacology of Estrogen

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

Page 8: Basic Pharmacology of Estrogen

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.

Page 9: Basic Pharmacology of 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

Page 10: Basic Pharmacology of Estrogen

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

Page 11: Basic Pharmacology of Estrogen

Estrogens Physiology

Page 12: Basic Pharmacology of Estrogen

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

Page 13: Basic Pharmacology of Estrogen

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

Page 14: Basic Pharmacology of Estrogen

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

Page 15: Basic Pharmacology of Estrogen

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

Page 16: Basic Pharmacology of Estrogen

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

Page 17: Basic Pharmacology of Estrogen

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

Page 18: Basic Pharmacology of Estrogen

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

Page 19: Basic Pharmacology of Estrogen

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

Page 20: Basic Pharmacology of Estrogen

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

Page 21: Basic Pharmacology of Estrogen

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

Page 22: Basic Pharmacology of Estrogen

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))

Page 23: Basic Pharmacology of Estrogen

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

Page 24: Basic Pharmacology of Estrogen

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)

Page 25: Basic Pharmacology of Estrogen

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

Page 26: Basic Pharmacology of Estrogen