GONADAL HORMONES &

INHIBITORS

HIGH YIELD TERMS

5-Reductase  Converts testosterone to dihydrotestosterone
 Inhibited by Finasteride (Treat benign prostatic hyperplasia &
prevent male-pattern hair loss in men
Anabolic steroid  Androgen receptor agonists used for anabolic effects (eg, weight
gain, increased muscle mass)
Breakthrough bleeding  Vaginal bleeding that occurs outside of the period of regular
menstrual bleeding
Combined oral  Hormonal contraceptive administered orally that contains an
contraceptive estrogen and a progestin
(COC or OC)
Hirsutism  Male pattern of body hair growth (face, chest, abdomen) in
females
 Results from hyperandrogenism
Hormone replacement  Estrogen replacement for women who have lost ovarian
therapy; HRT function
 Combination therapy with estrogen and a progestin
Selective estrogen  eg, tamoxifen
receptor modulator;
SERM
  Surgical removal of the ovaries.
ESTROGEN ( HRT ameliorates hot flushes and atrophic changes in the urogenital tract )
 ESTRADIOL o Effective in preventing bone loss and osteoporosis.
o Major ovarian estrogen o Are components of hormonal contraceptives
o Low oral bioavailability but is available in a micronized form for oral use
o Administered via :
 Transdermal patch TOXICITY
 Vaginal cream o In hypogonadal girls, the dosage of estrogen must be adjusted carefully to prevent
 Intramuscular injection premature closure of the epiphyses of the long bones and short stature.
o Used as HRT; Increases the risk of endometrial cancer
 Long-acting esters of estradiol that are converted in the body to estradiol  Prevented by combining the estrogen with a progestin.
o Eg.Estradiol cypionate o In post menopausal women:
o Administered by intramuscular (IM) injection  Increase in the risk of breast cancer
 Cardiovascular events (myocardial infarction,stroke).
 Mixtures of conjugated estrogens from biologic sources o Dose-dependent toxicity includes:
o Eg,.Premarin  Nausea
o Used orally for hormone replacement therapy (HRT).  Breast tenderness
 Synthetic estrogens with high bioavailability  Increased risk of migraine headache
o Eg. Ethinyl estradiol, Mestranol  Thromboembolic events (eg, deep vein thrombosis)
o Used in hormonal contraceptive  Gallbladder disease
 Hypertriglyceridemia
 Hypertension.
o Diethylstilbestrol (DES)
 Nonsteroidal estrogenic compound
EFFECTS  Infertility
o Essential for normal female reproductive development.  Ectopic pregnancy
o Responsible for the growth of the genital structures (vagina, uterus, and uterine  Vaginal adenocarcinoma
tubes) during childhood o Continuous administration of estrogen, in combination with a progestin, inhibits the
o Responsible for appearance of secondary sexual characteristics and the secretion of gonadotropins from the anterior pituitary
o Responsible growth spurt associated with puberty
o Metabolic effects:
 Modifies serum protein levels
 Reduces bone resorption
o Enhances the coagulability of blood
o Increases plasma TAG levels
o Reducing (LDL) cholesterol
o Increasing high-density lipoprotein (HDL) cholesterol

CLINICAL USE
o Treatment of hypogonadism in young females
o HRT in women with estrogen deficiency resulting from:
 Premature ovarian failure
 Menopause
PROGESTINS
 Progesterone - major progestin in humans o Oral pills
 Administered via: o Long acting injections
o Orally ( micronized form for HRT) o Subcutaneous implants
o Vagina creams (progesterone-containing vaginal creams) o Transdermal patches
 Synthetic progestins o Vaginal ring
o Eg, Medroxyprogesterone o Intrauterine devices (IUDs)
o Improved oral bioavailability  Three types of oral contraceptives for women
 Older drugs o Monophasic preparations
o Eg, l-norgestrel , Norethindrone  Combination estrogen-progestin tablets that are taken in constant dosage
o More androgenic than the newer progestins (eg, Norgestimate,Desogestrel) throughout the menstrual cycle
o (Biphasic, Triphasic, and Quadriphasic)
EFFECTS  Combination preparations in which the progestin or estrogen dosage, or both,
o Induces secretory changes in the endometrium changes during the month (to more closely mimic hormonal changes in a
o Required for the maintenance of pregnancy menstrual cycle)
o Do not significantly affect plasma proteins o Progestin-only preparations (fewer side effects)
o Do affect carbohydrate metabolism
o Stimulate the deposition of fat  Postcoital contraceptives ( “emergency contraception”)
o Prevent pregnancy
CLINICAL USE o Administered within 72 h after unprotected intercourse.
o Used as contraceptives ( alone or in combination with an estrogen) o Oral preparations contains:
o In HRT it is combine with an estrogen to prevent estrogen-induced endometrial cancer.  A progestin (l-norgestrel) alone
o Assisted reproductive technology methods to promote and maintain pregnancy  Estrogen alone
 Combination of an estrogen and a progestin are effective.
TOXICITY
o Toxicity is low MECHANISM OF ACTION
o May increase blood pressure  Combination hormonal contraceptives have several actions:
o Decrease HDL. o Inhibition of ovulation (the primary action)
o Long-term use of high doses in premenopausal women  Decrease the likelihood of fertilization and implantation (cervical mucus glands,uterine
 Associated with a reversible decrease in bone density (a secondary effect of ovarian tubes, and endometrium )
suppres sion and decreased ovarian production of estrogen)  Progestin-only agents
o Delayed resumption of ovulation after termination of therapy o Do not always inhibit ovulation and instead act through the other mechanisms listed.
o High doses suppress gonadotropin secretion and often cause anovulation in women.  When administered before the LH surge, they inhibit ovulation.
 Affect cervical mucus,tubal function, and the endometrial lining.
 Synthetic progestin= Dec. GnRH release = decrease in FSH & LH levels
HORMONAL CONTRACEPTIVES  Dec. FSH results inhibition of Follicular development
 A combination of an estrogen and a progestin or a progestin alone.  Dec.LH levels results in absence of Ovulation
 Available in a variety of preparations
OTHER CLINICAL USES AND BENEFICIAL EFFECTS o Hirsutism
 Combination hormonal contraceptives  High dose of estrogen in estrogen-containing postcoital contraceptives
o Used in young women with primary hypogonadism o Associated with significant nausea.
o Prevent estrogen deficiency.
 Hormonal contraceptives + Progestins
o Used to treat the following:
 Acne
 Hirsutism
 Dysmenorrhea
 Endometriosis.
 Reduced risks of the following:
o Ovarian cysts
o Ovarian and endometrial cancer
o Benign breast disease
o Pelvic inflammatory disease (PID)
o Lower incidence of ectopic
o Iron deficiency anemia
o Rheumatoid arthritis.

TOXICITY
 Thromboembolism
o Increase in the risk of thromboembolic events
 (Myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism) in
older women, smokers
 Women with a personal or family history of such problems
 Women with genetic defects that affect the production or function of clotting
factors.
 Risk of thromboembolism is usually less than that imposed by pregnancy
 Breast cancer
 Low-dose combined oral + progestin-only contraceptives
o Bleeding especially during the first few months of therapy
 Nausea
 Breast tenderness
 Headache
 Skin pigmentation
 Depression
 Preparations containing older more androgenic progestins :
o Can ause weight gain
o Acne
ANTIESTROGENS
&
ANTIPROGESTIN
SELECTIVE ESTROGEN RECEPTOR MODULATORS
 tissue Increased risk of venous


thrombosis
Reduces the incidence of
Mixed estrogen agonists breast cancer in women
who are at very high risk
that have estrogen agonist effects in some tissues and act as partial agonists or antagonists of estrogen in
other tissues Clomiphene Selectively blocking Used to induce ovulation Hot flushes
estrogen receptors in the in anovulatory women Headache
Dosage: pituitary, clomiphene who wish to become Constipation
Mechanism of Action Clinical Uses Toxicity 100mg/d for 5 days reduces negative feedback pregnant Allergic Skin Reaction
and increases FSH and LH Reversible hair loss
Tamoxifen Acts as as a competitive Treatment of hormone- As an agonist of output. The increase in Ovarian Enlargement
estrogen-receptor responsive breast cancer endometrial gonadotropins stimulates Multiple pregnancy
Half Life: antagonist to prevent receptors,promotes: ovulation.
7-14 hrs receptor activation by Agonist:


endogenous estrogens

 Pure Estrogen Receptor Antagonists

Dosage:
10-20 mg twice daily

Mechanism of Action Clinical Uses Other Effects

hyperplasia
osteoporosis in post


menopausal women
NOTES: Toremifene is
structurally related to
Fulvestrant Pure estrogen receptor antagonist Treatment of women with
(in all tissues). breast cancer that has
developed resistance to
Inhibit dimerization of the occupied tamoxifen
estrogen receptor & interferes with
endometrial cancer its binding to DNA


tamoxifen and has similar
properties, indications, and
toxicity Synthesis Inhibitors
Mechanism of Action Clinical Uses Others
Antagonist effect :
Anastrozole Nonsteroidal competitive Treatment of breast Similar Drugs:


inhibitors of aromatase cancer Letrozole
Exemestane
Acts to inhibit aromatase
thereby results in decrease Side Effects:
Estradiol levels. Osteoporosis
Hyperlipidemia
Aromatase – Enzyme Increase incidence of
Raloxifene Partial estrogen agonist- Agonist: Drug Has No estrogenic
respomsible for converting cardiovascular events
antagonist Approved for prevention effects on endometrial
androgens to estrogens Hot Flashes
Half Life: and treatment of tissue
>24 hours Bazedoxifen- newer drug osteoporosis in
Danazol Inhibits several Treatment of Adverse Effect:
postmenopausal women Antagonist:
Dosage: cytochrome P450 enzymes endometriosis and Masculiization
Hot flushes
Once a day involved in gonadal steroid fibrocystic disease of the Hirsutism
Antagonist:
synthesis breast Acne
Effects in breast Agonist:

A weak partial agonist
of progestin, androgen,
and glucocorticoid
receptors thereby resulting
in decrease LH & FSH
secretion
Gonadotropin-Releasing Hormone Analogs and
Antagonists
Mechanism Of Action
Leuprolide GnRH analogue
Suppresses gonadotropin
secretion and thereby inhibits
ovarian production of estrogens
and progesterone
Used For :
Hereditary Angioedema
Menorraghia
Clinical Use
GnRH receptor antagonist:
Ganirelix and Cetrorelix -
used for controlled ovarian
hyperstimulation
Stimulation:
Female infertility
Male infertility
Diagnosis of LH responsivenss
Suppression of GOnadotropin
Production:
Controlled ovarian
hyperstimulation
Prostate cancer
Treatment of precocious
puberty in children and short-
term (<6 mo) treatment of
endometriosis and uterine
fibroids in women
GnRH agonists + other agents
used in ovarian
hyperstimulation
Weight gain
Edema
Elevation of hepatic
enzymes
Antiprogestins
Mechanism of Action Clinical Use Others
Mifepristone
(RU 486)
Orally active steroid Abortifacient in early pregnancy Common complication :
antagonist of (up to 49 days after the last Failure to induce a
Others progesterone and menstrual period). complete abortion
glucocorticoids
Adverse effect: Half life: Mifepristone + prostaglandin E Side effects( Misoprostol):
Treatment beyond 6 mo in 20 hrs analog misoprostol = Nausea
premenopausal women Achieves a complete abortion in Vomiting
result in decreased bone over 95% of early pregnancies Diarrhea plus the cramping
density and bleeding associated
with passing the pregnancy
Rarely Mifepristone +
misoprostol for medical
abortion have experienced
serious infection, sepsis,
and even death due to
unusual infection
 o Enlargement of muscle mass
o After puberty,it acts to maintain secondary sex characteristics, fertility, and
libido
o It also acts on hair cells to cause male-pattern baldness
 Rapidly absorbed orally

Mechanism of Clinical Use Toxicity

ANDROGENS Androgen
Action

Androgens enter cells Primary clinical use = Use of androgens by

 Testosterone and related androgens are produced in the testis,adrenal, and ovary. and bind to cytosolic Replacement therapy in hypogonadism females =virilization
receptors. The (hirsutism,enlarged
 Testosterone is synthesized from progesterone and dehydroepiandrosterone (DHEA). hormone-receptor Stimulate red blood cell production in certain clitoris, deepened voice)
 In the plasma complex enters the anemias and menstrual
nucleus and irregularity.
o Testosterone is partly bound to sex hormone-binding globulin (SHBG), a modulates the Promote weight gain in patients with wasting
transport protein. expression of target syndromes (eg, In pregnant with a
genes AIDS patients). female fetus, exogenous
o Hormone is converted in several organs (eg, prostate) to dihydrotestosterone androgens can cause
(DHT), which is the active hormone in those tissues. Anabolic effects have been exploited illicitly virilization of the fetus’s
by athletes to increase muscle bulk and external genitalia.
o Because of rapid hepatic metabolism, testosterone given orally has little effect.
strength and perhaps enhance athletic
o It may be given by injection in the form of long-acting esters or transdermal performance. Execessive doses in men
can result in feminization
patch. Osteoporosis (gynecomastia, testicular
o Oxandrolone and stanozolol are examples of drugs that, in laboratory testing, shrinkage, infertility) as a
result of feed
have an increased ratio of anabolic-androgenic action. back inhibition of the
 All the so-called anabolic steroids have full androgenic agonist effects pituitary and conversion
when used in humans. of the exogenous
androgens to estrogens.
 Testosterone is necessary for:
o Normal development of the male fetus and infant In both sexes, high doses
of anabolic steroids can
o Responsible for the major changes in the male at puberty (growth of penis, cause :
larynx, and skeleton Cholestatic jaundice
Elevation of liver enzyme
o Development of facial, pubic, and axillary hair Hepatocellular
o Darkening of skin carcinoma.
Edema
EFFECTS Major effect = an anabolic action that involves increased muscle size and strength
Increased red blood cell production.
Excretion of urea nitgen is reduced, and nitrogen balance becomes more positive.
Helps maintain normal bone density.
OTHERS

A. RECEPTOR INHIBITORS
 Flutamide
o Nonsteroidal competitive antagonists of androgen receptors.
5-Reductase Inhibitors
o Used to decrease the action of endogenous androgens in patients with
prostate carcinoma.  5aTestosterone is converted to DHT by the enzyme-reductase.
o Adverse effect:
 Mild gynecoastia
 Mild reversible hepatic toxicity Mechanism of Action Clinical Use Others
o Related drugs Finasteride Inhibit 5 a-reductase, the Treat Benign prostatic Side Effects:
 Bicalutamide enzyme responsible for the hyperplasia and @ lower Decrease libido
 Nilutamide Half life: conversion of testosterone dose Erectile dysfunction
8 hrs to dihydrotestosterone.
 Enzalutamide
Prevent hair loss in men
Dosage: In the prostate,
 Spironolactone 5 mg/d dihydrostestosterone acts
o Used principally as a potassium-sparing diuretic to stimulate growth to
stimulate growth of the
o Inhibits androgen receptors gland, so by decreasing the
o Usedin the treatment of hirsutism in women levels of
dihydrotestosterone,
prostate growth is
 Cryproterone & cyproterine acetate decreased
o Inhibit action of androgen Dutasteride A newer 5a-reductase
o The acetate form has a marked progestational effect that surppresses the inhibitor with a much
feedback enhancement of LH and FSH Dosage : longer half-life than that
0.5mg/d of finasteride
o Clinical Use:
 Treat hirsutism
 Treat men to decrease excessive sexual drive
o Dosage:
 2 mg/d + estrogen for hirsutism
Gonadotropin-Releasing Hormone Analogs and
Antagonists
 Suppression of gonadotropin secretion(LH),
 o Reduces the production of testosterone.
o Effectively accomplished with long-acting depot preparations of leuprolide or similar gonad otropin-
releasing hormone (GnRH) agonists
 Clinical Use:
o Used in prostatic carcinoma. During the first week of therapy, an androgen receptor antagonist (eg,
flutamide) is added to prevent the tumor flare that can result from the surge in testosterone
synthesis caused by the initial agonistic action of the GnRH agonist.
 Within several weeks, testosterone production falls to low levels.
 Abarelix & Degarelix
o GnRH receptor antagonists
o Approved for advanced prostate cancer

Combined Hormonal Contraceptives

 Used in women with androgen-induced hirsutism.
 The estrogen in the contraceptive acts in the liver to increase the production of sex hormone-
binding globulin, which in turn reduces the concentration of the free androgen in the blood that is causing
the male-pattern hair growth characteristic of hirsutism.

Inhibitors of Steroid Synthesis

 Ketoconazole
o An antifungal drug
o Inhibits gonadal and adrenal steroid synthesis.
o Used to suppress adrenal steroid synthesis in patients with steroid-responsive metastatic prostate
cancer.
ANTIANDROGENS