The Gonadal Hormones&

Inhibitors

By

M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science

M.H.Farjoo

The Gonadal Hormones & Inhibitors

Introduction The Estrogens The Progestins Other Ovarian Hormones Hormonal Contraception Estrogen & Progesterone Agonists & Antagonists The Testis Androgens & Anabolic Steroids Androgen Suppression Antiandrogens Contraception in Men Drug Pictures

M.H.Farjoo

Introduction LH causes the outer theca and inner granulosa

cells of the follicle synthesize estrogens.

The estrogen secretion reaches a peak just before midcycle.

Corpus luteum produces estrogens and progesterone for the remainder of the cycle or in pregnancy.

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Introduction Cont’d

Common causes of ovulatory disturbances: Severe exercise eg: distance running and

swimming (anovulatory cycles )

Prolactinomas

Excessive androgen production

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The Estrogens General Consideratios for Estrogens Mechanism of Action of Estrogens Physiologic Effects of Estrogens Clinical Uses:

Primary Hypogonadism Postmenopausal Hormonal Therapy

Adverse Effects of Estrogens Estrogen Contraindications Preparations & Dosages of Estrogens

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General Consideratios

The major estrogens produced by women are estrone (E1), estradiol (E2), and estriol (E3).

Estradiol is the major secretory product of the ovary

Estrone & estriol are formed in the liver from estradiol.

During pregnancy, a large amount of estrogen is synthesized by the fetoplacental unit.

Repeated assay of maternal urinary estriol excretion has been used in the assessment of fetal well-being.

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Mechanism of Action of Estrogens

The estrogen receptors are found predominantly in the nucleus.

The receptor-hormone complex binds to nucleotides called: Estrogen Response Elements (EREs).

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Physiologic Effects of Estrogens Enterohepatic circulation causes oral estrogens

have a high ratio of hepatic to peripheral effects. Hepatic effect causes a higher level of CBG,

TBG, SHBG, transferrin, renin substrate, and fibrinogen.

This increases clotting factors, thyroxine, estrogen, testosterone, iron, copper, and other substances.

The hepatic effects of estrogen can be minimized by vaginal, transdermal, or parenteral routes.

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Physiologic Effects of Estrogens Cont’d

Estrogens maintain the normal structure of the skin and blood vessels in women.

Estrogens decrease resorption of bone by: Promoting the apoptosis of osteoclasts Antagonizing the effects of PTH and IL6.

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Physiologic Effects of Estrogens Cont’d

Exposure to estrogens for a long time causes endometrial hyperplasia and abnormal bleeding.

Estrogens enhance the coagulability of blood by: Increasing clotting factors Decreasing antithrombin III.

Estrogens increase HDL and triglyceride and reduce LDL and cholesterol levels.

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Primary Hypogonadism

Treatment is begun at 11-13 years of age. Estrogen is given on days 1-21 each month and

slowly increased to adult doses and maintained until menopause.

A progestin is added after the first uterine bleeding.

When growth is completed, chronic therapy consists of adult doses of both estrogens and progestins.

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Postmenopausal Hormonal Therapy

Hormonal "replacement" therapy is: HRT or HT. There is no cardiovascular benefit from estrogen

plus progestin in perimenopausal patients. There is even a small increase in cardiovascular

problems and breast cancer with HRT. Young women with premature menopause should

definitely receive HRT.

Estrogens should always be used in the smallest dosage possible.

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Postmenopausal Hormonal Therapy Cont’d

Osteoporosis depends on: The amount of bone present at menopause Vitamin D and calcium intake Degree of physical activity Depression

The risk is highest in thin inactive smokers with low calcium intake and family history of osteoporosis.

To prevent osteoporosis, therapy should begin as soon as possible after the menopause

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Postmenopausal Hormonal Therapy Cont’d

Non oral estrogens are completely absorbed into the circulation and should be given cyclically.

If risk of osteoporosis is low, mild atrophic vaginitis can be treated with topical estrogens.

The vaginal route is also useful for urinary tract symptoms.

If estrogen is contraindicated, for hot flushes clonidine may relieve symptoms.

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Adverse Effects of Estrogens

Estrogen therapy is a major cause of postmenopausal uterine bleeding.

Vaginal bleeding at this time may also be due to endometrial carcinoma which estrogen may cause it.

In order to avoid confusion: Patients should be treated with the smallest amount of

estrogen possible. It should be given cyclically so that bleeding will occur

during the withdrawal period.

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Adverse Effects of Estrogens Cont’d

A small increase in the incidence of breast cancer occurs with prolonged estrogen therapy.

Addition of progesterone does not confer a protective effect.

Actually in postmenopausal women progestin plus estrogen may increase the risk significantly compared with estrogen alone.

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Adverse Effects of Estrogens Cont’d

There is an increased risk of endometrial carcinoma in patients taking estrogens alone.

The risk is 15 times greater in patients taking large doses of estrogen for 5 or more years.

The risk is 2 to 4 times greater in patients receiving lower doses for short periods.

If estrogen is combined with a progestin the risk of endometrial carcinoma is half of that in women not receiving HRT: Estrogen is given for the first 25 days of the month. Medroxyprogesterone is added during the last 10-14 days.

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Adverse Effects of Estrogens Cont’d

Nausea & breast tenderness Increase in frequency of:

Migraine headaches Gallbladder disease Hypertension

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Estrogens Contraindications

Estrogen-dependent neoplasms: Carcinoma of the endometrium Carcinoma of the breast

Undiagnosed genital bleeding Liver disease History of thromboembolic disorder In heavy smokers

Commonly used estrogens.Average Replacement Dosage    

0.005-0.02 mg/d Ethinyl estradiol

1-2 mg/d Micronized estradiol

2-5 mg every 3-4 weeks Estradiol cypionate

2-20 mg every other week Estradiol valerate

1.25-2.5 mg/d Estropipate

Conjugated, esterified, or mixed estrogenic substances:

0.3-1.25 mg/d Oral  

0.2-2 mg/d Injectable  

Patch Transdermal  

0.1-0.2 mg/week Quinestrol

12-25 mg/d Chlorotrianisene

3-9 mg/d Methallenestril

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The Progestins

General Consideratios of Progestins

Mechanism of Action of Progestins

Physiologic Effects of Progestins

Clinical Uses of Progestins

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General Consideratios

Progesterone is the most important progestin in humans.

It is a precursor to the estrogens, androgens, and adrenocortical steroids.

It is synthesized in the ovary, testis & adrenal from circulating cholesterol.

Large amounts are also synthesized by the placenta during pregnancy.

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Mechanism of Action

Progesterone is completely metabolized in one passage through the liver (not effective orally).

Micronized oral progesterone preparations provide adequate progestational effect.

Progesterone receptors are distributed between the nucleus and the cytoplasm.

The ligand-receptor complex binds to a Progesterone Response Element (PRE).

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Physiologic Effects of Progesterone

Increases basal insulin levels and the insulin response to glucose.

Increases secretion of aldosterone. Increases body temperature. Increases the ventilatory response to CO2. Promotes ketogenesis. Has depressant & hypnotic effects on the brain. Develops secretory apparatus in the breast. Causes secretory changes in the endometrium.

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Clinical Uses of Progestins

The major uses are for hormone replacement therapy and hormonal contraception.

When used alone in large parenteral doses, prolonged anovulation and amenorrhea result.

This is used for contraception and treatment of dysmenorrhea, endometriosis and bleeding disorders when estrogens are contraindicated.

It should not be used for patients planning a pregnancy in the near future.

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Clinical Uses of Progestins Cont’d

Similar regimens may relieve hot flushes in menopausal women (if estrogen therapy is contraindicated).

Progesterone can be used as a test of estrogen secretion in amenorrheic patients.

The administration of progestins for 5-7 days, causes withdrawal bleeding if only estrogens are pre secreted.

A combination of estrogen and progestin tests the responsiveness of the endometrium in patients with amenorrhea.

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Other Ovarian Hormones

The ovary also produces Inhibin and Activin. These peptides consist of several combinations of α and β subunits.

The αβ dimer (inhibin) inhibits FSH secretion while the ββ dimer (activin) increases FSH secretion.

Relaxin is another ovarian peptide. It increases water uptake by the myometrium and

decreases uterine contractility. The physiologic roles of all these peptides are not

fully understood.

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Hormonal Contraception Classification Mechanism of Action Pharmacologic Effects Clinical Uses Adverse Effects: Mild, Moderate, Severe Contraindications Contraception With Progestins Alone Postcoital (Emergency) Contraceptives Beneficial Effects

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Classification

Two types of preparations are used for oral contraception: Combinations of estrogens and progestins

Monophasic LD: Low Dose HD: High Dose

Biphasic or Triphasic

Progestin therapy alone.

Constant dosage of both components during the cycle.

Dosage of one or both components is changed once or twice during the cycle.

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Mechanism of Action The combination pills selectively inhibit pituitary

function that results in inhibition of ovulation.

The combination agents also change the cervical mucus, the endometrium, and motility and secretion of the uterine tubes.

The continuous use of progestins alone does not always inhibit ovulation but inhibits pregnancy.

The other factors mentioned, therefore, play a major role in the prevention of pregnancy.

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Pharmacologic Effects Ovary & breast

Central Nervous System

Endocrine function

Blood Liver Lipid and carbohydrate metabolism

Skin

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Ovary & breast

75% of women will ovulate in the first post treatment cycle and 97% by the third post treatment cycle.

About 2% remain amenorrheic for up to several years after administration is stopped.

Estrogens alone or in combinations tend to suppress lactation.

When the doses are small, the effects on breast feeding are not appreciable.

Only small amounts of these compounds cross into the milk which is not important.

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Central Nervous System

Estrogens tend to increase excitability in the brain, whereas progesterone decreases it.

The thermogenic action of progesterone has central origin.

Estrogens can relieve premenstrual tension syndrome, postpartum depression, and climacteric depression.

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Endocrine Function

Estrogens given orally or at high doses increase the concentration of the cortisol.

Cortisol concentrations may be more than double the levels in untreated individuals.

Large amounts of estrogen may decrease androgens by gonadotropin suppression.

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Blood

OCPs do not alter bleeding or clotting times.

There is an increase in factors VII, VIII, IX, and X and a decrease in antithrombin III.

Increased amounts of coumarin may be required to prolong PT in patients taking OCPs.

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Liver

The proportion of cholic acid is increased while the proportion of chenodeoxycholic acid is decreased.

So cholelithiasis is increased with the use of these agents.

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Lipid and Carbohydrate Metabolism

Lipid metabolism: Estrogens increase serum triglycerides,

cholesterol, Phospholipids and HDL but decreas LDL.

Carbohydrate metabolism: Potent progestins such as norgestrel may reversibly

decrease carbohydrate tolerance over several years.

M.H.Farjoo

Skin

The OCPs increase pigmentation of the skin (chloasma).

This effect is enhanced in women with dark complexions and by exposure to UV light.

Sebum production, acne, and terminal hair growth is decreased in many patients.

M.H.Farjoo

Clinical Uses The most important use of combined estrogens

and progestins is for oral contraception. The pregnancy rate with combination agents is

0.5–1 per 100 woman years Contraceptive failure occurs when:

One or more doses are missed. Antibiotics (especially broad spectrum) are taken. Use of enzyme inducing drugs (Phenytoin,

rifampin).Normal gastrointestinal flora increases the bioavailability of estrogens.

A poster printed in 1975 to encourage male participation in family planning programs.

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Clinical Uses Cont’d

Progestins and estrogens are also useful in the treatment of endometriosis.

In severe dysmenorrhea the suppression of ovulation with estrogen alone may be followed by painless periods.

The long-term use of large doses of progestins (single or with estrogens) prevents the periodic breakdown of the endometrium.

This may lead to endometrial fibrosis and prevent the reactivation of implants for prolonged periods.

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Mild Adverse Effects Nausea, mastalgia Headache which is mild and often transient Migraine is often made worse and has been

associated with an increased frequency of CVAs.

failure of Withdrawal bleeding, most often with combination preparations.

If disturbing, a different preparation may be tried or other methods of contraception used.Confusion with pregnancy

In this case or when migraine begins during therapy, treatment should be discontinued

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Moderate Adverse Effects Weight gain. Breakthrough bleeding: is the most common

problem in using progestational agents alone. It occurs in up to 25% of patients It is more frequent in low-dose preparations

than high levels of progestin and estrogen. The biphasic and triphasic pills decrease

breakthrough bleeding without increasing the total hormone content.

Any of them may require stopping the drug!

M.H.Farjoo

Moderate Adverse Effects Cont’d

Increased skin pigmentation especially in dark-skinned women.

The incidence being about 5% at the end of the first year and about 40% after 8 years.

It is exacerbated by vitamin B deficiency and is often reversible (though may be very slowly) upon discontinuance of drug.

Acne is exacerbated by androgen-like progestins whereas agents containing large amounts of estrogen improve it.

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Moderate Adverse Effects Cont’d

Hirsutism.

Ureteral dilation & more frequent bacteriuria.

Vaginal infections are more common.

Amenorrhea especially in patients who have had menstrual irregularities before.

Many of these patients have prolactinomas and galactorrhea so prolactin should be measured.

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Severe Adverse Effects The incidence of thromboembolic disease in patients

taking low-dose OCPs is threefold higher.

Its incidence is related to the estrogen.

Antithrombin III, is substantially decreased during OCP use.

The risk is increased in stasis, increased levels of homocysteine, diminished antithrombin III, or injury.

It is not related to age, parity, mild obesity or cigarette smoking.

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Severe Adverse Effects Cont’d

Myocardial infarction: Women 30–40 years who do not smoke, 4 / 100,000

per year. Women 40–44 years who smoke heavily, 185 / 100,000

per year.

CVA: prevalent in women > 35 years old. Risk of MI and CVA is not increased in past users. Subarachnoid hemorrhages is increased among

both current and past users and may increase with time.

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Severe Adverse Effects Cont’d

In general, OCPs increase cardiovascular disorders at all ages and among both smokers and non smokers.

This risk is concentrated in women 35 years or older who are heavy smokers.

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Severe Adverse Effects Cont,d

Cholestatic jaundice which disappears 1-8 weeks after the drug is discontinued.

The incidence of cholangitis and cholecystitis is increased.

Increased incidence of hepatic adenomas.

Depression in 6% of patients.

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Contraindications Thrombophlebitis, thromboemboli. Cardiovascular and cerebrovascular disorders or a

past history of these conditions. Vaginal bleeding with unknown cause. Breast tumor or estrogen-dependent neoplasm. Liver disease, asthma, eczema, migraine, diabetes,

hypertension, or convulsion. Heart failure or when edema is dangerous. In adolescents in whom epiphysial closure has not yet

been completed.

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Contraception with Progestins Alone

Injecting depot medroxyprogesterone acetate (DMPA, Depo-provera) every 3 months achieves effective contraception.

After a 150 mg dose, ovulation is inhibited for at least 14 weeks.

All users have unpredictable spotting and bleeding.

Ovulation suppression can persist for 18 months after the last injection.

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Contraception with Progestins Alone Cont,d

Norgestrel, also used in combined OCPs and minipill, is available in the SC implant form (in USA).

Progestins alone are about as effective as IUDs or LD combination pills.

Norgestrel is used in nursing mothers as “minipill”.

Minipill has also used in women over 40, in whom fertility may be decreased.

Progestins alone reduce the risk of endometrial cancer but increase the risk of atherosclerosis.

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Contraception with Progestins Alone Cont,d

The progestin implant method (Norplant) lasts 5 – 6 years.

Patients with headache or visual disturbances should be checked for papilledema.

Useful in patients with: Hepatic disease Hypertension Psychosis or mental retardation Prior thromboembolism.

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Postcoital (Emergency) Contraceptives

Estrogens alone or in combination with progestins are used (morning after pills).

When treatment is begun within 72 hours, it is effective 99% of the time.

Antiemetics are often administered, since 40% of the patients have nausea or vomiting.

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Postcoital (Emergency) Contraceptives Cont,d

Other adverse effects include headache, dizziness, breast tenderness, and abdominal and leg cramps.

Mifepristone (RU 486), has a luteolytic effect and is effective as a postcoital contraceptive.

When combined with a prostaglandin it is also an effective abortifacient.

Conjugated estrogens: 10 mg three times daily for 5 days

Ethinyl estradiol: 2.5 mg twice daily for 5 days

Diethylstilbestrol: 50 mg daily for 5 days

Mifepristone, 600 mg once with misoprostol, 400 mcg once1

L-Norgestrel: 0.75 mg twice daily for 1 day (eg, Plan B2)

Norgestrel, 0.5 mg, with ethinyl estradiol, 0.05 mg (HD OCP) Two tablets and then two in 12 hours

1Mifepristone given on day 1, misoprostol on day 3.

Postcoital Contraceptives

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Beneficial Effects of OCPs

Reduces the risk of: Ovarian cysts, ovarian and endometrial

cancer, and benign breast disease.

Ectopic pregnancy, iron deficiency and rheumatoid arthritis.

Premenstrual symptoms, dysmenorrhea, endometriosis.

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Estrogen & Progesterone Agonists & Antagonists

Tamoxifen

Mifepristone (RU 486)

Danazol

Clomiphene

Miscellaneous

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Tamoxifen

A competitive partial agonist inhibitor of estradiol at the estrogen receptor.

It was the first selective estrogen receptor modulator (SERM) to be introduced.

Extensively used in the palliative treatment of advanced breast cancer in postmenopausal women.

It is approved for chemoprevention of breast cancer in high-risk women.

Causes 35% decrease in contralateral breast cancer.

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Mifepristone (RU 486)

It is an antagonist of progesterone. Mifepristone's major use is to terminate pregnancies.

It terminates pregnancy in > 85% of cases during the first 7 weeks of conception.

The major adverse effect was prolonged bleeding that on most occasions did not require treatment.

Mifepristone with a vaginal PGE1 or its oral type (misoprostol) terminates pregnancy in > 95% of patients.

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Danazol

Danazol is an antagonist of progestational, androgenic, and glucocorticoids.

It inhibits the midcycle surge of LH and FSH.

Its major use is the treatment of endometriosis.

Danazol requires great caution in hepatic dysfunction.

Contraindicated during pregnancy & breast feeding (produces urogenital abnormalities in the offspring).

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Clomiphene

Is a partial estrogen agonist and ovulation-Inducing agents.

Increases secretion of gonadotropins (and stimulates ovulation) by inhibiting estradiol's negative feedback.

It is used in women with oligomenorrhea or amenorrhea and ovulatory dysfunction.

The patient must be treated repeatedly until pregnancy is achieved.

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Clomiphene (Cont,d)

The most common adverse effect is hot flushes

Eye symptoms due to prolongation of afterimages occasionally occurs.

The incidence of multiple pregnancy is 10%

Does not have an adverse effect when given to women who are pregnant.

80% of anovulatory patients will have ovulation, half of them become pregnant.

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Clomiphene (Cont,d)

Special precautions should be observed in patients with enlarged ovaries.

These women are more sensitive to this drug and should receive small doses.

Any patient who complains of abdominal symptoms should be examined carefully.

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Miscellaneous

Anastrozole, an inhibitor of aromatase is effective in some breast tumors resistant to tamoxifen.

Letrozol and Fadrozole are inhibitors of aromatase and are as effective as tamoxifen.

Fulvestrant, an estrogen receptor antagonist is more effective than partial agonists in tamoxifen resistant breast cancers.

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The Testis

Gametogenesis of the testes is controlled by FSH.

With LH stimulation, testosterone is produced by the interstitial or Leydig cells.

Testosterone acts intracellularly in target cells. Dihydrotestosterone is the major active

androgen.

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Androgens & Anabolic Steroids

The anabolic effects of androgens may be dissociated from androgenic effects.

This is less marked in humans and all agents are potent androgens.

DHEA and DHEAS may prolong life in rabbits.

In men they improve the sense of well-being and inhibit atherosclerosis.

Androgen Preparations available and relative androgenic: anabolic activity in animals.

Androgenic to Anabolic Activity  

1:1 Testosterone

1:1 Testosterone cypionate

1:1 Testosterone enanthate

1:1 Methyltestosterone

1:2 Fluoxymesterone

1:3 Oxymetholone

1:3- 1:13 Oxandrolone

1:2.5- 1:4 Nandrolone decanoate

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Androgens & Anabolic Steroids (Cont,d)

Physiologic effects:

Stimulate erythrocyte production.

Increase protein synthesis or decrease in protein breakdown within the body.

This effect is much more pronounced in women and children than in men.

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Androgens & Anabolic Steroids (Cont,d)

Androgens are used in hypogonadal men. Even in the presence of pituitary deficiency,

androgens (not gonadotropin) are used except when normal spermatogenesis is desired.

Oral testosterone may cause liver tumors so skin patches or gels are used for scrotal or other skin area application.

The development of polycythemia or hypertension requires reduction in dose.

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Androgens & Anabolic Steroids (Cont,d)

Many athletes believe that anabolic steroids (10-200 times larger than the daily production) increase strength.

Such effects have been demonstrated only in women.

the adverse effects of these drugs clearly make their use inadvisable.

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Androgens & Anabolic Steroids (Cont,d)

Adverse effects: In pregnant women leads to causes abnormality in

external genitalia of the fetus.

Supraphysiologic doses produce azoospermia and decrease in testicular size

Induce psychologic dependence, increased aggressiveness and psychotic symptoms

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Contraindications of Androgens

Pregnant women or women who may become pregnant during therapy.

Carcinoma of the prostate or breast. Infants and young children. Renal or cardiac disease predisposed to edema. For aplastic anemia (Colony stimulating factors

should be used).

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Androgen Suppression

The treatment of advanced prostatic carcinoma requires orchiectomy or high dose estrogen.

The former has psychologic effects and the latter causes gynecomastia.

The GnRH analogs (goserelin, nafarelin, buserelin, leuprolide acetate) are useful in this regard.

They produce gonadal suppression if given continuously.

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Androgen Suppression (Cont,d)

At first they increase testosterone.

This increase is associated with a flare of tumor activity and symptoms.

The combination of a GnRH agonist and flutamide prevents the initial stimulation.

After a month, testosterone falls to 10% of its initial values with a GnRH agonist.

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Antiandrogens

Since dihydrotestosterone (not testosterone) is the essential androgen in the prostate, androgen effects is reduced by an inhibitor of 5a-reductase.

Finasteride is an inhibitor of this enzyme and reduces dihydrotestosterone.

Finasteride also reduces prostate size in BPH.

The dosage in prostatic carcinoma is 5 mg/d.

It is used in the treatment of hirsutism in women and early male pattern baldness in men (1 mg/d).

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Antiandrogens (Cont,d)

Cyproterone & cyproterone acetate inhibit the action of androgens at the target organ.

The acetate form has progestational effect that suppresses the feedback enhancement of LH and FSH, leading to more antiandrogenic effect.

They are used for hirsutism and in men to decrease excessive sexual drive.

Flutamide is a competitive antagonist and has been used in prostatic carcinoma.

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Antiandrogens (Cont,d)

Bicalutamide and nilutamide are antiandrogens given as a single daily dose and are used in patients with metastatic carcinoma of the prostate.

Bicalutamide is used in combination with a GnRH analog (to reduce tumor flare) and has fewer GI side effects.

Spironolactone, a competitive inhibitor of aldosterone, also competes with dihydrotestosterone for the androgen receptors.

It also reduces 17a-hydroxylase activity, lowering plasma levels of testosterone and androstenedione.

It is used in the treatment of hirsutism in women and is as effective as finasteride, flutamide, or cyproterone in this condition.

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Contraception in Men

Gossypol Destroys seminiferous epithelium but does not

alter the endocrine function of the testis.

Hypokalemia is the major adverse effect and may lead to transient paralysis.

Gonadorelin

Triptorelin

Triptorelin vial

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