ESTROGENS&PROGESTERONE ESTROGENS&PROGESTERONE

ESTROGENS: Three ovarian estrogens form are secreted 1-Estradiol: is the major estrogen produced by the ovary& the most potent 2-estriol: is the main form of hormone secreted During pregnancy by the placenta.

3-Estrone: is the primary circulating Estrogen after menopause. The estrogenic potency of Estradiol is 12 times that of estrone and 80 times that of estriol. the level of estrogen in male 20–80 pg/ml while in female 1-30-49 pg/ml(early follicular). 2-150-449 pg/ml(mid-cycle). 3-101-209 pg/ml(luteal), 4-< 41 pg/ml(postmenopausal).

the ovary is the major site of estrogen synthesis in nonpregnant women. in pregnant women the fetoplacental unit is the major site.

Peripheral site of estrogen synthesis include liver, kidney, adipose tissue& skeletal muscle &this account for about 10% of total estrogen production in premenopausal women. After menopause estrogen synthesis decline greatly& Peripheral production account for most estrogen synthesis

during the first part of the menstrual cycle estrogens are produced in the ovarian follicle by the theca interna and granulosa cells.

After ovulation, the estrogens as well as progesterone are synthesized by granulosa and theca cells of the corpus luteum

Mechanisms of Action There are two form of estrogen receptor ERα &

ERβ. ERα found primarily in the uterus, kidneys, liver, and heart, ERβ is found primarily in the ovaries, prostate, lungs, gastrointestinal tract, hemopoietic system,and CNS.

17-beta-estradiol binds equally well to both receptors.

estrone bind preferentially to the alpha receptor.

estriol to the beta receptor. Estrogens circulate in the bloodstream bound

to sex hormone binding globulin(SHBG)or albumin

Then estrogen diffuse through target cell membrane. binding of estrogen to these nuclear-receptor proteins which found in cell form estrogen–receptor complex which is then transported to the cell nucleus where it interacts with deoxyribonucleic acid (DNA) to produce ribonucleic acid (RNA). These substances stimulate cell reproduction and production of various proteins that stimulate a number of physiological function of estrogen.

Physiological action of the estrogen

1-Breast:Stimulate growth at puberty by causing deposition of fat, formation of connective tissue and construction of ducts.

2- Sexual Organs: Cause the endometrial lining of the uterus to proliferate, Enlarge the uterus, vagina, and external genitalia at puberty,

3-Anterior Pituitary Gland: Decrease pituitary secretion of follicle-stimulating hormone.they increase LH secretion (positive feedback) in other circumstances,they inhibit LH secretion (negative feedback).

4-Metabolism: Increase protein anabolism, bone growth, and epiphyseal closure in young person.

sodium and water retention serum triglycerides, and high-density lipoproteins (HDL).

low-density lipoproteins (LDL). Increase the amount of cholesterol in bile

and thereby increase gallstone formation5-Blood Coagulation: enhance coagulation

by increasing blood levels of several clotting factors and increase platelet aggregation.

Route of administration of estrogen&progesterone

1-orally: ethinyl estradiol

2- Transdermal preparation: Estradiol transdermal system which provides constant serum levels similar to ovarian estradiol secretion

3- Cream : such as natural progesterone cream

4-Injection: medroxyprogesterone acetate5- Vaginal ointment: Premarin ointment6- Conjugated estrogen preparations: Premarin

PHARMACOKINETIC: Estrogen has more than 90% protein

binding to(SHBG) or albumin which is biologically inactive. so only the free form can enter cell & therefore biologically active

estrogens are deactivated in the liver, mainly by cytochrome P450 3A4 enzymes.

The estrogens then conjugated with glucuronic acid or sulfuric acid, which makes them water soluble and readily excreted through the kidneys.

Metabolites are also formed in the GIT tract, brain, skin, and other steroid target tissues. Most of the conjugates are excreted in urine; some are excreted in bile.

PREPARATION OF ESTROGEN:

they produce the same effects as endogenous hormones. they divide into four group

1-Naturally occurring estrogens:(estradiol, estrone) they given by injection because they are rapidly metabolized if administered orally. Some crystalline suspensions of estrogens and oil solutions of estrogens prolong drug action by slowing absorption.

2-Conjugated estrogens eg: Premarin, which given orally 0.3–1.25 mg daily for 21d in the therapy of menopause complaint.

3-synthetic steroidal derivatives of natural estrogens which include

1-Estradiol (ethinyl estradiol, Mestranol,polyestradiol phosphate 2-Estrone (estrone sulfate) 3-Estriol(Promestriene) 4-Other synthetic derivatives such as, Equilenin, Equilin

some of these derivatives are effective with oral administration.

ethinyl estradiol: it is The most widely used synthetic steroidal estrogen& also consider the prototype for this group

Uses: 1-Menopausal Symptoms:(0.02–0.05) mg orally 2- Female Hypogonadism: 0.05 mg orally by Sequential therapy (one to three times daily for 2 wk with addition of progestin for last 2 wk of month).

is well absorbed with oral administration and reaches peak plasma level within 2 hours.

It is 98% bound to plasma proteins and its half-life varies from 6 to 20 hours.

Ethinyl estradiol undergoes extensive first-pass hepatic metabolism and is further metabolized and conjugated in the liver the conjugates are then excreted in bile and urine.

4-Nonsteroidal synthetic preparations: are usually administered orally or topically. These include dienestrol, benzestrol, hexestrol, methestrol, methallenestril, and diethylstilbestrol. They are chemically altered to slow their metabolism in the liver. They are also less bound to serum proteins than naturally occurring hormones.

THERAPEUTIC USE OF ESTROGEN

1-replacement therapy in deficiency states. As in hypofunction of the pituitary gland or the ovaries. initiated with small doses of estrogen (0.3 mg conjugated estrogens or 5-10 mcg ethinyl estradiol) on days 1-21 each month and is slowly increased to adult doses maintained until the age of menopause (approximately 51 years).

2-Menopause:to relieve symptoms of estrogen deficiency as atrophic vaginitis and vasomotor instability, which produces hot flashes. When estrogen is prescribed for women with a uterus, a progestin added to prevent endometrial cancer this called ERT or HRT.

3-osteoporosis:The amount of bone is maximal in the young active adult in the third decade of life and begins to decline more rapidly in middle age in both men and women. Conjugated estrogens

(Premarin) PO 0.625 mg daily for 21 d,4- component in birth control pills and other

contraceptive preparations. contraceptives act by several mechanisms A-they inhibit hypothalamic secretion of gonadotropin-releasing hormone, which inhibits pituitary secretion of FSH and LH.

B-the drugs produce cervical mucus that resists penetration of spermatozoa into the upper reproductive tract.

C- the drugs interfere with endometrial maturation and reception of ova that are released and fertilized.

An estrogen, when combined with a progestin is used widely in the 12-45 year age group to control fertility If pregnancy does occur, estrogens are contraindicated because their use during pregnancy has been associated with the occurrence of vaginal cancer in female offspring and possible harmful effects on male offspring.

Adverse effects: estrogen excess cause widespread of effect but the most prominent effect include:

1-Uterine bleeding: Estrogen therapy is a major cause of postmenopausal uterine bleeding. also there is a risk of thromboembplic formation.

2- Melasma: symmetrical hyperpigmented patches which seen on the lateral aspect of the forehead, upper part of the cheek, and mandibular area. This occur because the hormones cause excessive production of melanin and this corresponds to darkening of the skin

3-endometrial hyperplasia frequently develop in premenopausal &postmenopausal women receiving estrogen alone.

which regarded as premalignant condition & will develop high rate of incidence of endometrial carcinoma, this can be prevented by administration of a progestational agent with estrogen in each cycle

5- Nausea, weight gain and breast tenderness are common and can be minimized by using the smallest effective dose of estrogen ,Hyperpigmentation also occurs.

4- Estrogen therapy is associated with an increase incidence of cholestasis, gallbladder disease, and hypertension.

CONTRAINDICATIONS:1- Estrogens should not be used in patients with

estrogen-dependent neoplasms such as carcinoma of the endometrium.

2- Estrogens Contraindications in individualds who are at high risk for carcinoma of the breast.

3- Estrogens should be avoided in patients with undiagnosed genital bleeding, liver disease, or a history of thromboembolic disorder.

4- the use of estrogens should be avoided by heavy smokers.

5- Estrogens dose should be minimized in patients with hypertension.

SELECTIVE ESTROGEN RECEPTOR MODULATORS(SERMS):

SERMs: are nonhormonal pharmacological agent that bind to ERs. Characteristic feature of SERMs is that a given agent will act as an estrogen agonist in one or more tissue and as an estrogen antagonist in one or more other estrogen target organ .Tamoxifen ,Raloxifene ,Clomiphene ,Toremifene, Afimoxifene, Cyclofenil , Arzoxifene , are examples of nonsteroidal SERMs.

Tamoxifen: competitive partial agonist inhibitor of estradiol at the estrogen receptor

.

Uses: 1-it is partial agonist in breast& therefore used in the palliative treatment of breast cancer in postmenopausal women 2-approved for chemoprevention of breast cancer in high-risk women.

Pharmacokinetic: It is a nonsteroidal agent that is given orally. Tamoxifen half-life 7-14 h and is predominantly excreted by the liver. It is used in doses of 10-20 mg twice daily.

Adverse effect: : 1- nausea and vomiting occur in 25% of patients. 2-Tamoxifen is full agonist in endometrium &prolonged use lead to a fourfold to fivefold increase in the incidence of endometrial cancer.

Raloxifene:A new SERM partial estrogen agonist

Uses: use in treatment & prevention of postmenopausal osteoporosis .Raloxifene is an estrogenic antagonist in both breast& endometrial tissue. the estrogenlike properties of raloxifene result in maintenance of lipid serum profile( LDL with no change in either HDL or triglyceride),

Pharmacokinetic: Raloxifene is 95% bound to plasma protein and it subject to a high first-pass effect, has a very large vd and a long half-life (> 24 hours), so it can be taken once a day. absorption of Raloxifene is impaired by cholestyramine.

Toremifene: A SERM drug with properties similar to that of Tamoxifen it uses in treatment of Metastatic breast cancer in postmenopausal women Adverse effect: Hot flashes, nausea, hypercalcemia,

Fulvestrant : 500mg imis a SERM .it is administered as monthly injection. it used against advanced breast CA in postmenopausal women.

Tamoxifen, Raloxifene, Clomiphene, are orally active. the primary route of excretion of all three drugs in the feces. the most common unwanted effect associated with these drugs is 1-increased risk of thromboembolism 2-increase frequency of hot flashes both effect are attributed to their estrogenic activity.

OTHER INHIBITORS :Anastrozole: a selective nonsteroidal inhibitor of aromatase

(the enzyme required for estrogen synthesis) is effective breast tumors have become resistant to tamoxife.

Letrozole : is similar AnastrozoleExemestane: a steroid molecule, is an irreversible

inhibitor of aromatase. Like anastrazole and letrozole, it is approved for use in women with advanced breast cancer.

Fadrozole: is a newer oral nonsteroidal inhibitor of aromatase activity. These compounds appear to be as effective as tamoxifen.

Uses: 1-use in breast cancer. 2-aromatase inhibitors have employed as adjuncts to androgen antagonists in the treatment of precocious puberty and as primary treatment in the excessive aromatase syndrome.

OVULATION-INDUCING AGENTS

CLOMIPHENE:: Clomiphene a partial estrogen agonist,

kinetic: This compound is active when taken orally. About half of the compound is excreted in the feces within 5 days after administration.

Mechanism of action: Clomiphene has been shown to effectively Cause an increase in the secretion of gonadotropins and estrogens by blocking the feedback inhibitory influence of estrogens on the hypothalamus, causing a surge of gonadotropins, which leads to ovulation.

Clinical Use: used in the treatment of disorders of ovulation in patients who wish to become pregnant. a single ovulation is induced by single course of therapy, patient must be treated repeatedly until pregnancy is achieved .

When clomiphene is administered in doses of 100 mg/d for 5 days,a rise in plasma LH and FSH is observed after several days. In patients who ovulate, the initial rise is followed by a second rise of gonadotropin levels just prior to ovulation.

Adverse effect: 1-ovarian enlargement: this consider is the most common

adverse effects. the degree of enlargement tends to be greater and its incidence higher in patients who have enlarged ovaries at the beginning of therapy

2- hot flushes which resemble those experienced by menopausal patients. also reports of eye symptoms due to intensification and prolongation of afterimages. These are generally of short duration. Headache, constipation, allergic skin reactions.

3-nausea and vomiting, increased nervous tension, depression, breast soreness, weight gain, and heavy menses have also been reported. The incidence of multiple pregnancy is approximately 10%. Clomiphene has not been shown to have an adverse effect when inadvertently given to women who are already pregnant.

Contraindications:1-women with enlarged ovaries are thought to

be more sensitive to this drug and should receive small doses. Maximum ovarian enlargement occurs after the 5-day course has been completed, and many patients can be shown to have a palpable increase in ovarian size by the seventh to tenth days.

2- Treatment with clomiphene for more than a year may be associated with an increased risk for low-grade ovarian cancer.

3- Special precautions must also be taken in patients who have visual symptoms associated with clomiphene therapy, since these symptoms may make activities such as driving more hazardous.

PROGESTERONE: Progesterone is the most important progestin in

humans. it serves as a precursor to the estrogens,

androgens, and adrenocortical steroids. It is synthesized in the ovary, testis, and adrenal

from circulating cholesterol. Large amounts are also synthesized and released by the placenta during pregnancy

In the ovary, progesterone is produced primarily by the corpus luteum. in pregnant woman Plasma levels of progesterone are further elevated and reach their peak levels in the third trimester of pregnancy.

The corpus luteum produces progesterone during the first few weeks of gestation. Then the placenta produce the progesterone needed to maintain the endometrial lining of the uterus.

Normal males progesterone plasma levels < 0.63 ng/ml. while in female 1- < 0.63 ng/ml (follicular) 2-> 4.7 ng/ml (mid-luteal) 3-< 0.63 ng/ml (postmenopausal).

When fertilization does not take place, the progesterone level decrease and menstruation occurs.

Mechanism: There are two isoforms of progesterone receptor: α and

β. Progestins enter the cell and bind to progesterone

receptors that are distributed between the nucleus and the cytoplasm.

The ligand-receptor complex binds to a progesterone response element (PRE) to activate gene transcription.

The response element for progesterone appears to be similar to the corticosteroid response element, and the specificity of the response depends upon which receptor is present in the cell as well as upon other cell-specific receptor and interacting transcription factors.

The progesterone-receptor complex then bind to DNA which lead to production of various protein & growth factor which responsible for physiological function of it.

PHYSIOLOGICAL ACTION OF THE PROGESTERONE

1- progesterone continues the changes in the endometrial lining of the uterus begun by estrogens during the first half of the menstrual cycle. These changes provide for implantation and nourishment of a fertilized ovum.

2- In addition to its effects on the uterus, progesterone prepares the breasts for lactation by promoting development of milk-producing cells.

3- Progesterone also may help maintain pregnancy by decreasing uterine contractility.

4- Progesterone can compete with aldosterone for the mineralocorticoid receptor of the renal tubule, causing a decrease in Na+ reabsorption.

THERAPEUTIC USE OF PROGESTINS

1-Progestins are most often used in combination with an estrogen in contraceptive products.

2-They also are used to suppress ovarian function in dysmenorrhea , endometriosis, and uterine bleeding.

3-Progestins also used in combination with estrogen for long-term HRT in postmenopausal women with intact uteri. the purpose of a progestin is to prevent endometrial cancer, which can occur with unopposed estrogenic stimulation.

4-Diagnostic uses: Progesterone can be used as a test of estrogen secretion. The administration of progesterone or medroxyprogesterone, 150 mg/d for 5-7 days, is followed by withdrawal bleeding in amenorrheic patients only when the endometrium has been stimulated by estrogens.

ADVERSE EFFECT:

1- Progesterone decrease high-density lipoprotein (HDL) and increase low density lipoprotein (LDL) cholesterol, both of which increase risks of cardiovascular disease.

2- progesterone increases insulin levels but does not impair glucose tolerance, but long-term administration of progestins may decrease glucose tolerance and make diabetes mellitus more difficult to control.

3-combined progestin plus estrogen in replacement therapy in postmenopausal women may increase breast cancer risk significantly compared with the risk in women taking estrogen alone.

4-progestational compounds alone and with combination oral contraceptives may increase blood pressure in some patients

Contraindications: progestational compounds are commonly contraindicated in depression, preexisting cardiovascular disease, breast CA, vaginal bleeding of unknown cause.

Synthetic preparation of progestins Synthetic preparation of progestins have the same effect as endogenous progestins. Generally they divided into two chemical classes

first chemical class of synthetic progestins is derived from testosterone &is known as 19-nortestosterone,these compound have some androgenic activity.

There are three classes of these compound1-1st class: Norethindrone , Norethindrone acetate,

Ethynodiol diacetate2-2nd class: Levonorgestrel, Norgestrel,

Norelgestromin 3-3rd class: Desogestrel ,Gestodene Norgestimate

These new group of synthetic progestins has ,been introduced as components of oral contraceptives & they have lower androgenic activity than older synthetic progestins.

Second chemical class of synthetic progestins characterized by addition of Alkyl chain to C17 position which biological half-life of these compound and increase there progestational activity,

an examples of these compound include hydroxyprogesterone, medroxyprogesterone, megestrol, dimethisterone, Chlormadinone, these compound are the most closely related pharmacologically as well as chemically to progesterone. these compound metabolized in the same manner as progesterone & excreted in urine.

Norethindrone considered the prototype of progestins agonist it undergoes first-pass metabolism so that it is only 65% bioavailable. It reaches peak plasma levels in 0.5 to 4 hours and has a half-life of 5 to 14 hours. It is metabolized by conjugation & hydroxylation in the liver and excreted in urine and feces.

ADVERSE EFFECT:

1-administration of progestational compounds alone or with combination oral contraceptives indicate that the progestin in these agents may increase blood pressure in some patients. 2- The more androgenic progestins also reduce plasma HDL levels in women & increase the level of plasma LDL which increase liability to atherosclerosis. 3-nausea, vomiting ,weight gain & increase risk of thromboembolic formation.

Contraindications: progestational compounds are commonly contraindicated in pregnancy ,depression, preexisting cardiovascular disease, breast CA, vaginal bleeding of unknown cause.

PROGESTERONE INHIBITOR:

Mifepristone: is progesterone antagonist that binds strongly to the progesterone receptor and inhibits the activity of progesterone.

The drug has luteolytic properties in 80% of women when given in the mid-luteal period.

also because the compound has a long half-life, large doses may prolong the follicular phase of the subsequent cycle and so make it difficult to use continuously for this purpose.

the drug use as an emergency postcoital contraceptive, though it may result in delayed ovulation in the following cycle.

the drug also binds to and acts as an antagonist at the glucocorticoid receptor.

Therapeutic Use:1-Mifepristone major use to terminate early

pregnancies (during first trimester). Doses of 400-600 mg/d for 4 days or 800 mg/d for 2 days successfully terminated pregnancy in over 85% of the women.

2-it also useful in the treatment of endometriosis, Cushing's syndrome, breast cancer, and possibly other neoplasms such as meningiomas that contain glucocorticoid or progesterone receptors.

Adverse effect: 1- prolonged bleeding that on most occasions did not require treatment. As many as 5% of patients have vaginal bleeding requiring intervention. 2-vomiting, diarrhea, and abdominal or pelvic pain.

Danazol: Danazol has weak progestational, androgenic, and glucocorticoid activities. is used to suppress ovarian function.

mechanism: Danazol inhibits the mid-cycle surge of LH and

FSH and can prevent the compensatory increase in LH and FSH following castration, but it does not significantly lower or suppress basal LH or FSH levels in normal women.

it does bind to sex hormone-binding globulin and corticosteroid-binding globulin.

it does not inhibit aromatase, the enzyme required for estrogen synthesis. it increases the mean clearance of progesterone, probably by competing with the hormone for binding proteins, and may have similar effects on other active steroid hormones.

Pharmacokinetic: Danazol is slowly metabolized, having a half-life of over 15 hours. This results in stable circulating levels when the drug is administered twice daily. It is highly concentrated in the liver, adrenals, and kidneys and is excreted in both feces and urine. Ethisterone a major metabolite of danazol, has both progestational and mild androgenic effects.

Therapeutic use: 1-Danazol used as an inhibitor of gonadal function

therefore use in the treatment of endometriosis. it can be given in a dosage of 600 mg/d. The dosage is reduced to 400 mg/d after 1 month and to 200 mg/d in 2 months.

2-Danazol also used in the treatment of fibrocystic disease of the breast and hematologic or allergic disorders, including hemophilia, Christmas disease(Factor IX), idiopathic thrombocytopenic purpura, and angioneurotic(sudden accumulation of liquid under the skin, similar to nettle rash edema).

Adverse effect: 1-weight gain, edema, decreased breast size, 2-increased hair growth, deepening of the voice, headache. 3- changes in libido, and muscle cramps. Occasionally, because of its inherent glucocorticoid activity, danazol may cause adrenal suppression.

Contraindication: 1-Danazol should be used with great caution in

patients with hepatic dysfunction, because it produce mild to moderate hepatocellular damage in some patients, as evidenced by enzyme changes.

2-also contraindicated during pregnancy and breast feeding, as it may produce urogenital abnormalities in the offspring.

PRODUCED BY

Haider faroon