Estrogen, Progesteron and Androgen-1

8/22/2019 Estrogen, Progesteron and Androgen-1

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Estrogen, Progesterone,

Androgens

farmakologifkub


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Antiprogestins


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Mifepristone (RU486)

Competitive inhibitor of the progesterone

receptor.

The drug can also bind to the

glucocorticoid receptor.

It is used as an abortifacient to terminate

early pregnancy.

Drug administration is usually followed by

a prostaglandin.


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Danazol

Partial or weak agonist at androgen,glucocorticoid, and progesteronereceptors.

Appears to act centrally to reduce ovarianproduction of steroids.

Used in the treatment of endometriosis

and fibrocystic disease of the breast.Adverse reactions are due to its weakandrogenic properties.


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Androgens & Anabolic steroids


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Regulation of secretion

Testosterone is the principle androgen

secreted by the testes (Leydig cells).

Testosterone and other androgens are

also secreted by the adrenal cortex and in

small amounts by the ovaries.

Once secreted, testosterone is 99% bound

to plasma proteins, mostly to sex

hormone-binding globulin.


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Regulation of secretion

Secretion of testosterone is regulated by

the hypothalamic-pituitary system.

LH stimulates the Leydig cells to

synthesize and secrete testosterone.

Testosterone and FSH act to increase

spermatogenesis.

Testosterone provides negative feedback

to the pituitary.


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Mechanism of action

Similar to other steroid hormones.

Binds to cytosolic receptors, which are

translocated to the nucleus where they

regulate gene expression.

In some organs (e.g., prostate),

testosterone is converted to

dihydrotestosterone (via 5alpha-reductase

activity), a more potent receptor agonist.


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Physiologic effects

Necessary for the development of

secondary male sex characteristics and

male sexual behavior.

Required for spermatogenesis.

Promotes protein anabolism and growth.

Enhances linear bone growth andmuscular development.


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Physiologic effects

Causes an increase in the size of the

larynx and deepens the voice.

Increases sebaceous gland activity, which

may result in acne, and stimulates

erythropoiesis.


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Indications for Use

Used in replacement therapy forhypogonadism and hypopituitarism.

Used to accelerate growth and to promote

anabolism.In breast cancer, androgens are used aspalliatives.

Also used in the treatment ofangioneurotic edema and endometriosis(danazol).


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Specific agents

Compounds with androgenic and anabolic

activity include testosterone and

methyltestosterone.

Synthetic analogs with greater anabolic thanandrogenic properties include fluoxymesterone,

nandrolone, and oxandrolone.

These "anabolic steroids" were first produced for

treatment of patients with debilitating diseases or

prolonged immobilization to prevent negative

nitrogen balance.


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Side Effects

Include masculinization in women.

Prostatic hypertrophy, priapism, and

feminization in men.

Testicular atrophy and gynecomastia are

problems in chronic users.

The most common adverse reactions areedema, jaundice, local irritation, urinary

obstruction, and steroid fever.


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Side Effects

Other adverse effects include:

Premature epiphyseal closure in children.

Liver dysfunction.Hypercalcemia.

Alteration of serum lipids.


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Androgen Antagonist

Have been synthesized for the treatment

of prostate cancer and benign prostatic

hyperplasia.


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Androgen Antagonist

GnRH analogs (e.g., leuprolide).

Long-term therapy reduces the secretion

of FSH and LH, thus reducing testosterone

production.

Used for advanced prostate cancer.


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Androgen Antagonist

Flutamide

Nonsteroid competitive antagonist at

androgen receptors.

Used in metastatic prostate cancer to

block testosterone.


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Androgen Antagonist

Cyproterone acetate.

An androgen receptor antagonist with

progestin-like activity.

It is being tested for the treatment of

hirsutism in women.


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Androgen Antagonist

Finasteride.

Inhibitor of 5a-reductase and, thus, inhibits

the production of dihydrotestosterone.

It is used in the treatment ofbenign

prostat ic hypert rophyand male pattern

baldness.


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Androgen Antagonist

Ketoconazole.

Imidazole type antifungal agent.

Inhibits steroid synthesis.Used in androgen receptor-positive cancer

therapy.


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Other Drugs

Anastrozole.

An aromatase inhibitor used in breast

cancer.

Danazol.

Inhibits ovarian steroid synthesis.Used in endometriosis and breast

fibrocystic disease.


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Figure 4. Control of androgen

secretion and activity and some

sites of action of antiandrogens. (1)

competitive inhibition of GnRH

receptors; (2) stimulation (+) or

inhibition (-) by GnRH agonists; (3)inhibition of testosterone synthesis

by ketoconazole; (4) inhibition of

dihydrotestosterone production by

finasteride; (5) inhibition of

androgen binding at its receptor byflutamide and other drugs.


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Estrogens

Act at estrogen receptors

Actions at many tissue in the body.


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Clinical Uses

Oral contraceptives.

Hormone replacement therapy.

Female hypogonadism (congenital,acquire)

Dysmenorrhea.

Abdnormal uterine bleeding.


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Estrogens

17 B-estradiol most potent natural strogen.

Synthetic estrogen objective. Increase oral bioavailability.

Increase therapeutic half-life.

Conjugated equine estrogens

Conjugated means sulfate esters.

Used for hormone replacement therapy,Ethinyl estradiol.

Component of the oral contraceptives.


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Side Effects

Nausea, Bloating.

Headache, Mastalgia.

Thromboembolism Synthetic estrogens more thrombogenic.

Breast cancer.

Endometrial cancer.Hepatic adenomas.


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Diethylstilbestrol

Synthetic estrogen used long time ago for

the prevention of threatened abortions.

Removed from the market due to

deleterious effect on fetuses.

Clear cell adenocarcinoma of the vagina.


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Diethylstilbestrol

Urogenital tract abnormalities.

Persistance of Mullerian glands on upper

vagina.

Male genital tract defects.


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Selective estrogen receptor

modulators (SERMs)

Compounds with tissue especific activity.

Agonist activity in some tissues.No activity or antagonist in other tissues.


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SERMs

The Goal is to

Produce beneficial effects in targettissues.

Bone, Brain, Liver.

Avoid deleterious effects in other tissues. Breast, Endometrium.


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Tamoxifen

Antagonist activity at breast ERs.

Partial agonist activity at endometrial ERs.

Agonist activity at bone ERs.

Used in breast cancer

Estrogen receptor expressing tumors.


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Tamoxifen

Side Effects

Result from estrogen antagonism. Hot flashes.

Vaginal discharge or bleeding.

Menstrual irregularities.

Impotence.


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Raloxifene

Selective estrogen agonist in bone.

Used to treat osteoporosis.

Does not increase the risk of estrogendependent cancers.

Lowers LDL


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Clomiphene

Estrogen receptor antagonist at all tissues.

Fertility drug.

Blocks anterior pituitary estrogen

receptors.Decreases feedback inhibition of FSH byestradiol.

Increases ovulation.Increases the incidence of multipleconceptions.


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Progesterone

Progesterone (natural).

17 a-acetoxyprogesterone.

19-norgestel derivatives.Norgestrel.


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Clinical Uses

Combination with estrogen hormone

replacement.

Decrease risk of estrogen-sensitive cancers.

Oral contraception.

Alone

Combination with estrogens.


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Progesterone

Agents

Medroxyprogesterone.Norethindrone

Norgestrel.


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Progesterone

Adverse effects.

Weight GainHirsutism.

Acne

TirednessDepression.


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Figure 5. Autonomic control of erection. The use of drugs to produce cavernosal smooth muscle

relaxation. Smooth muscle tone is the prime determinant of the degree of erection (NO, nitric oxide;

NE, norepinephrine; ACh, acetylcholine; PGE1, prostaglandin E1; VIP, vasoactive intestinal

peptide).


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Proposed mechanism underlying the antioxidant effect of sildenafil in relation to ED. (1) Risk factors promote the

endogenous expression of NADPH oxidase which generates superoxide (O2-) in pudendal arterial and cavernosal tissue (as

well as associated neural and microvascular support tissues. (2) The increased formation of O2- negates the protective

effects and proerectile activity of NO through direct chemical reactions. (3) As Sildenafil inhibits type 5 phosphodiesterase

(PDE5), the hydrolysis of cGMP is blocked. Increased cGMP levels promote erection through augmentation of smooth

muscle cell relaxation, despite reduced NO formation. (4) However, since the NO-cGMP axis also inhibits NADPH oxidase

expression/activity, it follows that augmentation of cGMP levels would also promote the inhibition of this enzyme. Reduced

O2- would further augment NO bioavailability, which would feed back into the loop to enhance the inhibition of NAPDH

id i d i i (5) NO d i ild fil (NCX 911) ld l i i h d

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Estrogen, Progesteron and Androgen-1