Estrogens and Anti Estrogens

Estrogens

Chemistry

Steroids having phenol ring, many groups are attached, responsible for different pharmacokinetics and pharmacodynamics of different preparations

Source

• Natural/Synthetic
• Plants (fungi)

Present in animals and humans, main source is Stallion horse urine for clinical use

Synthetic are made from plastics, pesticides and many other industrial chemicals

Biosynthesis

Androstenedione has affinity for alpha receptors, action is different in different parts of body.

Classification

A. Natural Estrogens

–        Estradiol

–        Estrone

–        Estriol

–        Equilin

B. Synthetic Estrogens

  I. Steroidal

–        Ethinyl Estradiol

–        Mestranol

–        Quinestrol

 II. Non-steroidal

–        Diethylstilbestrol

–        Chlorotrianisene

–        Methallenestril

Pharmacokinetics

Routes of administration –can be given by oral/I/V/transdermal/topical applications/vaginal creams, gels

In body bind hormone binding globulin

Hydroxylation & conjugation occurs in liver to inactive metabolites

Enterohepatic circulation –pass to intestine and hydrolyzed, reabsorbed and reach liver again where conjugation occurs

If given through transdermal patch or topically, less liver effects are seen.

Mechanism of action

In body two forms of estrogen receptors are present:

α & ß

When estrogen binds these isoforms, stabilizing proteins, heat shock proteins, dissociate from receptor, estrogen receptor complex is formed. These receptors then form homo & Hetro-dimers.

Bind estrogen receptor element present on promotor region of gene to modify transcription.

Enzymes, growth factors, cytokines are involved. Transcription not only involves binding with response element, but also co-regulators – co-activators are required.

It takes longer for non-genomic effects to appear, e.g. change in blood supply of uterus, increased calcium uptake by granulosa cells.

Physiological & Pharmacological Effects

Developmental Effects

Female maturation

Development of essential internal genital organs, growth, primary and secondary sexual characteristics, development of mammary glands

Male maturation

Endometrial Effects

Required for both growth and development of endometrial lining, smooth muscles, stroma and ductal region of uterus.

Metabolic & Cardiovascular Effects

Bones / Skin / Blood vessels- suppress osteoclastic activity, inhibiting resorption of bone, required for stimulation and formation of blood vessels. In vessels cause formation of nitric oxide, nitric oxide synthetase, responsible for vasodilatation.

Proteins / Lipids –increased protein synthesis, increased plasma proteins like binding proteins, globulins (corticosteroid binding, etc.), increased formation of fibrinogen, renin substrate.

Decreased LDL and cholesterol, increased HDL and triglycerides

Effects on Blood Coagulation

1. Synthesis of clotting factors,
2. increased hypercoagubility,
3. decreased antithrombin III,
4. increased plasminogen,
5. decreased platelet adhesiveness

Effects on CNS

1. Feeling of well being
2. Stimulate sympathetic components esp. corticotropic release

Miscellaneous effects

Promote synthesis of progesterone receptors

Facilitate movement of intravascular fluid into extravascular space leading to edema. Decrease intravascular volume responsible for stimulation of aldosterone secretion and retention of sodium and water.

Therapeutic Uses

1. Replacement Therapy

a. Primary Hypogonadism – Turner’s syndrome

Estrogen is given to facilitate pubertal changes.

b. Castration / Oophorectomy

c. Postmenopausal Hormone Therapy

Given for different reasons:

i. Vasomotor symptoms

Hot flushes alternating with chills, very troublesome. As estrogen increases the chances of cancer, in high risk individuals, Clonidine can be given.

ii. Osteoporosis

Besides measures include:

1. Physical activity
2. Intake of calcium and vitamin D

Bone density at time of menopause determines.

iii. Vaginal & urogenital atrophy

Topical gels are used

iv. Cardiovascular disease

Beneficial effects on lipid profile.

v. Breast & endometrial cancers

Endometrial chances are decreased, breast cancer chances are increased if combination of estrogen and progesterone is given.

2. Colon cancer / Alzheimer’s

3. Contraception

4. Suppression of ovarian functions

5. Dysmenorrhea

Adverse Effects

1. Carcinogenic Effects

a. Breast cancer increased chances if progesterone is added

b. Endometrial cancer chances are decreased if given alone

c. Vagina –mothers treated with diethylstilbesterol if give birth to female child, increased chances of adenocarcinoma of vagina in child

2. Cardiovascular Effects

a. Thromboembolic disease increased chances

b. Edema

c. Hypertension

3. Miscellaneous Effects

Nausea / Migraine / Hyperpigmentation / Breast tenderness / Gallbladder / Cognition

Contraindications & Cautions

Care is taken in high risk individuals:

Patients having thromboembolic disease, liver disease, hypertension

Anti-estrogens

Antagonize effects of estrogens

Estrogen synthesis inhibitors

GnRH analogs 

• Buserelin & Nafarelin (suppress pulsatile release, decreased formation)
• Aminoglutethimide (inhibit conversion of cholesterol into pregnolone)

Aromatase inhibitors

• Anastrozole
• Letrozole
• Exemestane

Breast / Prostate Cancers inhibitors

Estrogen receptor antagonists

•             Fulvestrant

SERMs

SERMs

Selective Estrogen Receptor Modulators

• Tamoxifen (older used for treatment of infertility)
• Raloxifene
• Toremifene
• Clomiphene

Competitive partial agonist inhibitors

Tissue-selective actions

In some areas estrogenic activity, others anti-estrogenic activity, estrogenic activity on bones, liver (protein metabolism), endometrium whereas anti-estrogenic activity on breast so used in breast cancers.

Uses

1. Breast cancer – chemoprevention 

Treatment is given for around 5 years

2. Osteoporosis – Raloxifene has more effects on bones, advantage is that has antiestrogenic activity on breast, so chances of breast cancer are not there.