Estrogens and Antiestrogens

Dr. D. K. BrahmaAssociate Professor of Pharmacology

NEIGRIHMS, Shillong

Introduction• Substances which can produce estrus in spayed

animals• Oestrogens include the natural hormones as well as

semi-synthetic and synthetic (stilbene) agents• Oestrogens 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)

CH3OH

H

H

H

HO

ESTRADIOL

CH3

H

H

H

HO

O

ESTRONE

CH3OH

H

H

H

HO

OH

ESTRIOL

Oxidized in liver

hydr

oxyla

tion

Natural Oestrogens

1.

2.

3.

Synthetic oestrogens

• Natural - Inactive orally, short duration and rapid metabolism:

• Steroidal: – Ethinyl estradiol, Mestranol and Tibolone

• Nonsteroidal: – Diethinylstilbestrol, Hexestrol and Dienestrol

Regulation of Secretion

• Daily secretion: 10 to 100 mcg 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 mcg per day only

Actions of Oestrogens• 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

Oestrogens Physiology

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

• Oedema – 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

Mechanism of Action

• 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

Oestrogen - Kinetics

• Absorbed orally, but quick metabolism – natural ones except ethinyl estradiol

• All are absorbed transdermally• Bound to plasma protein (SHBG)• All 3 - Conjugated with glucoronic acid and

sulfated and excreted in urine• Enterohepatic circulation – deconjugation in

intestine

Oestrogen 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. – EE: 0.01, 0.05, 1 mg tab for menopause– Conjugated estrogens: 0.625,1.25 mg tab for DUB 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 - ADRs

• 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

Therapeutic Uses• 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, dysperunia, 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

HRT Indications• 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

Selective Estrogen Receptor

Modulators (SERMs)

Clomiphene Citrate (Antiestrogen)

• The “Fertility pill” - pure antagonist of ESTROGEN receptor in all human tissues

• MOA: Induce Gn secretion by blocking estrogenic feedback inhibition– 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 – contd.• 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)

• ADRs: 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

Tamoxifen – contd.

• Uses: – Breast carcinoma of pre and post menopause– Adjuvant therapy in early cases– Palliative therapy

• Side 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

CH2CH3

O(CH3)2N-CH2-CH2

TAMOXIFEN (NOLVADEX)

Raloxifen and Ormeloxifene

• Raloxifene:– Partial agonist in Bone and CVS – antagonist in Breast and

Endometrium– High affinity for both receptors – distinct DNA target – RRE– Decreases LDL cholesterol – no increase in HDL cholesterol– No stimulation of endometrial proliferation – risk of cancer

reduced– Extensive first pass metabolism– Uses: 1st line of drug in prevention of Osteoporosis in menopause

– Ca++ and Vit. D enhances benefit• Ormeloxifene: Estrogen antagonist in breast and uterus –

useful in Dysfunctional uterine bleeding

Aromatase Inhibitors

• Letrozole, Anastrozole and Exemestane• MOA: Letrozole– Non steroidal compound, reversible inhibition of

aromatization all over the body– Suppression of proliferation of estrogen dependant 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

Must Know

• Hormone Replacement Therapy• Clomiphene citrate• Tamoxiphene

Take Home !

Estrogens have been mainstay of HRT since long – However, need for HRT to a menopausal women should be assessed and individualized……