Sunday 26/ 4 / 2015
©Ali Kareem 2014-2015
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مكتب اشور لالستنساخ
SEX-HORMONE DRUGS
Lecture 6
Total lectures NO. 57
Dr. Najeeb
Gonadal hormones & inhibitors
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Androgens
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Testosterone & related androgens are produced in the testis,,,the
adrenal cotexs,,,& to a small extent , the ovary.
In the plasma, testosterone is bound to sex hormone-binding globuline
(SHBG).
The hormone is converted in several organs including the prostate & hair
follicles to dihydrotestosterone(DHT) by the enzyme 5-alpha
reductase.DHT is the active hormone in those tissues.
Available forms
-Because of rapid metabolism by the liver ,testosteron given orally has little
effects.It may be given by injection in the form of long-acting esters or
transdermal patch.Orally-active variants are also available.
-Oxandrolone & stanazolol are drugs that in laboratory testing have
inreased ratio of anbolic-androgenic action.However all the so called
anbolic steroids heave full androgenic effects when used in humans.
Mechanism of action
Androgens ,like other steroids, enter cells & bind to cytosolic receptors.The
hormone-receptor complex enters the nucleus & modulates the expression
of target genes.
Effects
1-Testosterone is responsible for the normal development of the male fetus
& infant.
2-It is responsible for the major changes in the male at puberty (1-Growth
of penis ,larynx & skeleton.2-Development of facial,pubic & axillary
hair.3.Darkening of skin.4-Enlargement of muscle mass).
3-After puberty ,testosterone acts to Maintain 1- secondary sex characters
2-Fertility 3-libido .
4-anabolic action that involve 1-Increased muscle size &
strengh.2-Incrased red blood cells production.
5-Testosterone helps maintain normal bone density.
Clincal uses
1-Replacement therapy in hypogonadism.
2-The anabolic effects have been explotied illicitly by athletes to increase
muscle bulk & strength & perhaps athletic performance.
Adverse effects
1-Use of androgens in women leads to virilization & menstrual irregularity.
2-in women who are pregnant with a female fetus,exogenous androgens
can cause virilization of of the fetus`s external genitalia.
3-Excessive dose of androgens in men can result in feminization
(gynecomastia,testicular shrinkage & infertility) as a result of feedback
inhibition of the pituitary & conversion of exogenous androgens to
estrogens.
4.High doses also cause behavioral effects including hostility & aggression.
5.High doses of anaboic steroids can cause cholestatic jaundice,elevation
of liver enzyme levels & possibly hepatocellular carcinoma.
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Antiandrogens
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Uses
1-Benign prostate hyperplasia.
2-Malignant prostate disease.
3-Precocious puberty.
4-Hair loss.
5-Hirsutism
Antiandrogenic drugs
1-inhibitors of steroid synthesis
Ketokonazol,an antifungal drug inhibits gonadal & adrenal steroid
synthesis.The drug has been used to suppress adrenal steroid synthesis in
patients with steroid-sensitive tumors
2-Gonadotrpin-releasing hormone analogs
Reduction of gonadotropins,especially LH reduces the production of
tesosterone.This can be done by long-acting Leuprolide or similar
gondotropin-releasig hormone agonists.These analogs are used in
prostatic carcinoma.
3-Receptor blockers
-Flutamide & bicalutamide are nonsteroidal compounds tha act as
competitive antagonists at androgen receptors.These drugs are used to
decrease the action of androgens in patients with prostate carcinoma.
-Spironolactone,an aldosterone receptor blocker, also blocks androgens
receptor & is used in hirsutism.
-Cyproterone
4- 5-alpha reductase inhibitors
Tesosterone is converted to DHT by the enzyme 5-alpha reductase
.Some tissues notably prostate cells & hair follicles depend on DHT rather
than testosterone for androgenic stimulation.
Finasteride & related drugs inhibit this enzyme & used to treat benign
prostatic hyperplasia & at a lower dose to prevent hair loss in men.
5-Combined hormonal contraceptives
Combined hormonal contraceptives exert an antiandrogenic effect when
used in women with hirsutism resulting from excessive production of
androgenic steroids.The estrogen in the contraceptives acts in the liver to
increase the productin of SHBG which in turn acts to reduce the
concentration of free androgens in the blood.
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Estrogens
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The major ovarian estrogen in women is estradiol.
Available forms
--Estradiol is available as transdermal patch,oral micronized form,vaginal
cream or intramuscular injection.
--Long acting esradiol esters as estradiol cypionate can be administered
by IM injection.
--Conjugated estrogen from biological sources as premarin are used for
hormone replacement therapy (HRT).
--Synthetic estrogen with high bioavailability as mestranol & ethenyl
estradiol are used in hormonal contraceptives.
Estrogen receptors major sites
.....Hypothalamus .....Pituitary.....Breast.....Bone.....Uterus.
Effects of estrogen
---It is responsible for the growth of the gonadal organs ( Vagina...Uterus
& Fallopian tubes ) during childhood.
---It is responsible for the appearance of secondary sex characteristics in
puberty & for the growth spurt asociated with puberty.
---It reduces bone resorption.
---It modifies serum protein levels.
---It enhances the coagulability of blood.
---It increses plasma triglyceride levels.
---It reduces LDL cholestrol.
---Continuous intake of estrogen especially in combination with progestins
inhibits the secretion of gonadotropins from the anterior pituitary.
Uses
1-Treatment of hypogonadism in young females.
2-HRT in women with 1.premature ovarian failure.2.menopause.
3.Surgical removal of the ovaries.HRT ammeliorates hot flushes & the
atrophic changes in UGS.
3-HRT is effective in preventing osteoporosis .
4-Hormonal contraception.
5-Other uses.
Adverse effects
1---Premature closure of the epiphysis of the long bones & short stature in
girls with hypogonadism.This can be prevented by carefully adjusting the
dose of estrogen.
2---Endometrial cancer risk increment when used as HRT.This can be
prevented by combining estrogen with a progestin.
3---Breast cancer risk small increment association when used by
post-menopausal women. This can not be prevented by combining
estrogen with a progestin.
4---Stroke risk small increment association when used by post-menopausal
women.
5---Nausea.
6---Migrain headache.
7---Thromboembolic events (eg DVT).
8---Gallbladder disease
9---Hyprtriglyceridemia.
10---Hypertension.
11---Breast tendeness.
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Antiestrogens
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1-Inhibitors of steroid synthesis
---Aminoglutethamide
---Ketoconazol
2-Gonadotropin-releasing hormone analogs
---Leuprolide,goseriline,Nafareline.
3-Aromatase inhibitors
---Astranazole & related compounds as letrozole ,nonstroidal
compounds,which inhibit aromatase which catalyzes conversion of
testosterone to estradiol.
---Exemastane, a steroidal compound which inhibits aromatase.
4-Estrogen receptor blockers (some of them are partial agonists)
1.Clomiphene
2.Tamoxifene
3-Toremifene
4.Raloxifene
5-Fulvestrant
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Progestins
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Progeterone is the major progestin in humans.
Available forms
-Oral micronized progesterone.
-Progesterone containing vaginal cream.
-Medroxyprogesterone ,a synthetic progestin.
-The 19-nortestosterone compounds include
1-old ones as norethindrone & L-norgestryl are more androgenic than
the newer progestins.
2-The newer ones as norgestimate & desogestrel.
Effects
-Progestrone induces secretory changes in the endometrium .
-Progestrone is required for the maintinance of pregnancy.The other
progestins do not support pregnancy.
-High doses suppress gonadotropin secretion & cause anovulation in
women.
Clinical uses
1-Progstins are used as contraceptives alone
2-Progstins are used as contraceptives in combbination with an estogen.
3-Progestins are used in combinaation with an estrogen in HRT to prevent
estrogen-induced endometrial cancer.
4-P r o g e s t r o n e is used in assisted reproductive technology
programs to promote & maintain pregnancy.
Adverse effects
1-They may increase blood pressure.
2-They may decrese high-density lipoproteins level ( HDL ).
3-Long-term use of high doses in premnopausal women is associated with
-A delayed resumption of ovulation after termination of treatment.
-A reversible decrease in bone density.
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Antiprogestins
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1-Mifepristone
2-Danazol
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Hormonal contraceptives
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Components
Hormonal contraceptives contain either a combination of an estrogen & a
progestin or a progestin alone.
Available forms
1-Oral pills.
2-Long-acting injections.
3-Transdemal patches.
4-Vaginal rings.
5-Intr-uterine devices (IUDs).
6-Postcital pills,called also``emergency pills``.They prevent pregnancy if
given within 72 hours of intercourse.
Mechanism of action of hormonal contraceptives
1-Inhibition of ovulation.
2-Effects on cervical mucus glands.
3-Effects on uterine tubes & endometrium.
Clinical uses of hormonal contrceptives
1-Contraception.
2-Other usese as to treat acne,hirsutism,dysmenorrhea & endometriosis.
Advrese effects
1-Thromboembolism
Thromboembolism relates to the action of the estrogenic component on
blood coagulation.
There is a well documented increase in the risk of thromboembolic events (
myocardial infarction , strock ,,, deep vein thromosis & pulmonary
embolism ) in:
1-Older women.2-Smockers.3-Women with a personal history of
such problms.4.Women with a family history of such problems.However
the risk of thromboembloism incurred by the use of these drugs is usually
less than that imposed by pregnancy.
2-Breakthrough bleeding
3-Nausea
4-Headache
5-Skin pigmentation
6-Depression
7-Breast tenderness
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Done by
Ali Kareem