ESTROGENS
• Estradiol - 17 β-estradiol
• Estrone
• primary circulating estrogen after
menopause
• Estriol
• principal estrogen produced by the
placenta
• Conjugated estrogens – equine or plant-derived
• oral preparation for hormone
replacement therapy
• Synthetic estrogens - ethinyl estradiol
• undergo less first-pass metabolism -
effective orally at lower doses
• Selective estrogen-receptor modulators
• Tamoxifen and raloxifene
Mechanism of action
• Activated steroidreceptor complex interacts
with nuclear chromatin to initiate hormone-
specific RNA synthesis
• Synthesis of specific proteins that mediate
physiologic functions
Therapeutic uses
• Contraception
• Combination of estrogen and
progestogen via oral or transdermal route
• Prevention of osteoporosis
• Alendronate
• Replacement therapy in premenopausal
patients
• Hypogonadism, premature menopause or
surgical menopause
 Postmenopausal hormone therapy (HT)
• Lowest effective dose for shortest possible
time
• Extended use of HT
• Women with intact uterus - progestogen +
estrogen therapy
• reduces the risk of endometrial
carcinoma
• Women who have undergone a hysterectomy -
estrogen therapy
• progestins alter beneficial effects of
estrogen on lipid parameters
Pharmacokinetics
1. Naturally occurring estrogens
• Absorbed through GIT, skin and mucous
membranes
• Taken orally, estradiol - rapidly metabolized and
partially inactivated
• Micronized estradiol - better bioavailability
2. Synthetic estrogen analogs: ethinyl estradiol
and mestranol
• Well absorbed after oral administration
• Mestranol - demethylated to ethinyl estradiol
• Metabolized more slowly
• Stored in adipose tissue
• Prolonged action and higher potency
 Metabolism
• Serum albumin or sex hormone–binding
globulin
• Bioavailability if taken orally - low due to first-
pass metabolism in liver
• Transdermal route (patch, topical gel,
topical emulsion, or spray), intravaginally
(tablet, cream, or ring) or by injection
• Hydroxylated in liver to derivatives  glucuronidated
or sulfated
• Parent drug, metabolites - excretion to bile  reabsorbed
through enterohepatic circulation
• Inactive products - excreted in urine
Adverse effects
• Nausea and breast tenderness
• Postmenopausal uterine bleeding
• Risk of thromboembolic events, myocardial
infarction, and breast and endometrial cancer
• risk of endometrial endometrial cancer –
addition of progestogen
• Hypertension
• Headache
• Peripheral edema
 SELECTIVE ESTROGEN-RECEPTOR MODULATORS (SERMs)
• Class of estrogen-related compounds that interact at estrogen receptors but have different effects
depending on the tissues
• Tamoxifen, raloxifene, toremifene (orphan drug) and clomiphene
Tamoxifen Clomiphene Raloxifene
Mechanism of action competes with estrogen • partial estrogen • exhibits antagonism
for binding to receptor agonist; interferes with of estrogen receptors in
in breast tissue negative feedback of breast tissue
estrogens • decreases bone
• increases secretion of resorption and overall
GnRH and bone turnover
gonadotropins, • little to no effect on
stimulating ovulation the endometrium
• lowers total
cholesterol, LDL but no
effect on HDL or
triglyceride
Therapeutic uses • Metastatic breast • prophylaxis of breast Infertility associated
cancer in cancer in high-risk with anovulatory cycles
postmenopausal women
women • prevention and
• Adjuvant therapy treatment of
following mastectomy osteoporosis in
or radiation in breast postmenopausal
cancer women
• Prophylactic therapy -
breast cancer in high-
risk patients
Adverse effects • Most common: hot • Hot flashes and leg • Dose related
flashes and nausea cramps • Headache, nausea,
• Menstrual • Increased risk of deep- vasomotor flushes,
irregularities and vein thrombosis, visual disturbances,
vaginal bleeding pulmonary embolism, and
• Endometrial and ovarian enlargement
hyperplasia and retinal-vein thrombosis • Risk of multiple births
malignancies • Avoided in women who (twins or triplets) - 3 to
- Limit length of time are or may become 5%
• Drug interactions with pregnant
CYP450 inhibitors: • Drug Interaction with
amiodarone, cholestyramine
haloperidol, risperidone - reduce absorption of
– reduced efficacy raloxifene by 60%

Pharmacokinetics
• Absorbed after oral administration
• Tamoxifen - extensively metabolized by CYP450 enzymes
• Raloxifene - converted to glucuronide conjugates through firstpass metabolism; bound to plasma proteins
• Enterohepatic cycling; primary route of excretion - through bile into feces
 Progesterone
• Secretory endometrium – implantation embryo
• Luteal phase - inhibit gonadotropin and
ovulation
• (+) Conception: Progesterone continues to be
secreted
• If conception does not take place, the release of
progesterone from the corpus luteum ceases
abruptly  menstruation
Therapeutic uses
• Treatment of hormonal deficiency and
contraception
• Generally used with estrogens
• Synthetic progestogens – progestins, stable to
first-pass metabolism
• Norethindrone, norethindrone acetate,
norgestrel, levonorgestrel, desogestrel,
norgestimate, and drospirenone
• Progestins in oral contraceptives (for example,
norethindrone,
norethindrone acetate, norgestrel, levonorgestrel)
• 19-nortestosterone and possess some
androgenic activity
• Medroxyprogesterone acetate
• Injectable contraceptive
• Oral form - progestin component of
postmenopausal HT
• Control of dysfunctional uterine bleeding,
treatment of dysmenorrhea, and management of
endometriosis and infertility
Adverse effects
• Headache, depression, weight gain, and changes
in libido
• Androgenic activity (acne and hirsutism) and
increase LDL /HDL
• Less androgenic progestins, such as
norgestimate and drospirenone, preferred in
women with acne
• Injectable medroxyprogesterone acetate
• increased risk of osteoporosis
Antiprogestin: Mifepristone (RU-486)
• Progesterone antagonist with partial agonist
activity
• Early in pregnancy - abortion of fetus
• Combined with misoprostol (administered orally • Oral contraceptive and emergency contraceptive
or intravaginally) to induce uterine contractions agent
• Major adverse effects - significant uterine
bleeding and the possibility of incomplete
abortion
CONTRACEPTIVES
• Drugs that decrease fertility by number of different
mechanisms
• Preventing ovulation
• Impairing gametogenesis or gamete maturation
• Interfering with gestation
• Currently, interference with ovulation
• most common pharmacologic intervention for
preventing pregnancy

Oral Contraceptive
Combination OCPs Progestin-only pills
• Combination oral contraceptives: estrogen and • Contains progestin only - norethindrone
progestin • Low, continuous dosage of drug
• Monophasic combination pills vs Triphasic oral • Less effective than combination pill
contraceptives • May produce irregular menstrual cycles
• Pills taken for 21 days followed by 7 days of • Indicated for patients:
placebo • Breastfeeding
• Withdrawal bleeding • Intolerant to estrogen
• Most common estrogen - ethinyl estradiol • Smokers
• Most common progestins - norethindrone, • Other contraindications to estrogen-
norethindrone acetate, norgestrel, levonorgestrel, containing products
desogestrel, norgestimate, and drospirenone
 Transdermal Patch
• Alternative to combination OCPs
• ethinyl estradiol and the progestin Injectable Progestin
norelgestromin
• One contraceptive patch - applied each week
• Medroxyprogesterone acetate
for 3 weeks to the abdomen, upper • administered every 3 months
torso, or buttock • Intramuscular and subcutaneous injection
• Week 4 is patch free and withdrawal formulations
bleeding occurs • Weight gain
• Pharmacokinetic studies • Amenorrhea
• Total estrogen exposure - 60 percent greater • Return to fertility
than that seen with a 35-μg estrogen • Bone loss, osteoporosis and fractures
oral contraceptive
• May increase the risk of adverse events

Progestin Implants
• Subdermal implant
containing etonogestrel (4-
cm capsule)
• Contraception for 3 years
• Sterilization
• Totally reversible
• Low failure rate
• Principal side effects -
irregular menstrual
bleeding and headaches
Major classes
Progestin Post-coital Contraception
Intrauterine Device
• Levonorgestrel- • Reduces probability of pregnancy after sexual
releasing intercourse
intrauterine system • Emergency contraception uses high doses of
• Contraception for progestin or high
up to 5 years doses of estrogen plus progestin administered
• Suitable method for within 72 hours
women with at least • Newer progestin-only regimen - one-time dose of
one child and no 1.5 mg levonorgestrel
history • Emergency contraception - within 72 hours
of PID or ectopic • Progestin-only emergency contraceptive regimens
pregnancy better tolerated
• Single dose of mifepristone

Mechanism of action
• Combination of estrogen and progestin inhibits ovulation
• Estrogen - negative feedback on the release of LH and follicle-stimulating hormone (FSH) by the
pituitary gland
• Progestin - inhibits LH release and thickens the cervical mucus
• Withdrawal of progestin stimulates menstrual bleeding during placebo week

Adverse effects
• Estrogen component
• Cardiovascular effects - both estrogen and progestin
• Incidence of adverse effects - relatively low
• Major adverse effects: breast fullness, depression, fluid retention, headache, nausea and vomiting
• Carcinogenicity
• Metabolic – abnormal glucose tolerance, weight gain
• Serum lipids
 ANDROGENS
• Steroids with anabolic and/or masculinizing
effects
• Testosterone
• Leydig cells (testes), thecal cells (ovary)
and adrenal gland
• 5α-dihydrotestosterone (DHT), androstenedione
and dehydroepiandrosterone (DHEA)
• Functions:
1) normal maturation in the male
2) sperm production
3) increased synthesis of muscle proteins and
hemoglobin
4) decreased bone resorption
• Synthetic modifications

Mechanism of action
• Bind to specific nuclear receptor in target cell
• Active ligand in muscle and liver – testosterone;
in other tissues
metabolized to derivatives
• Prostate, seminal vesicles, epididymis,
and skin - testosterone converted by 5α-
reductase to DHT
• Brain, liver and adipose tissue, bio-
Therapeutic uses
transformed to estradiol by CYP450
aromatase 1. Androgenic effects
• Complex binds to DNA  stimulates synthesis 2. Anabolic effects
of RNAs and proteins 3. Endometriosis
• Testosterone analogs cannot be converted to • Danazol - treatment of endometriosis and
DHT fibrocystic breast disease
• less effect on the reproductive system than • Antiestrogenic activity; Inhibits release of
skeletal musculature FSH and LH
4. Unapproved use
• increase lean body mass, muscle
strength and endurance in athletes
• DHEA (a precursor of testosterone and
estrogen) - anti-aging hormone as well as
a “performance enhancer”

Pharmacokinetics
 Testosterone
• Ineffective orally - first-pass inactivation
• Rapidly absorbed and metabolized to inactive
compounds excreted primarily in urine
• C17-esters of testosterone - administered
intramuscularly
• Addition of esterified lipid makes
hormone more lipid soluble, increasing
duration of action
• Transdermal patches, topical gels, and buccal
tablets of testosterone
• Testosterone and its esters demonstrate a 1:1
relative ratio of androgenic to anabolic activity
 Testosterone derivatives
• Alkylation of 17α position of testosterone
• allows oral administration
• Longer half-life than naturally occurring
androgen
• Fluoxymesterone - effective orally, has 1:2
androgenic to anabolic ratio
• Oxandrolone - orally active, anabolic
activity 3 to 13 times
• Hepatic adverse effects
Antiandrogens
• Interferes with synthesis of androgens or block
receptors
• At high doses, the antifungal drug
ketoconazole inhibits several of the
CYP450 enzymes involved in steroid synthesis
• Flutamide
• act as competitive inhibitors of
androgens at target cell
• Treatment of prostatic carcinoma in
males
• Nicalutamide and nilutamide
• effective orally for prostate cancer
• Finasteride and dutasteride
• Treatment of BPH
• Inhibit 5α-reductase
• Decrease formation of
dihydrotestosterone in prostate leads to
reduction in prostate size

Adverse effects
1. In females
• Masculinization, acne, facial hair, deepening of
voice, male pattern baldness and excessive
muscle development
• Menstrual irregularities
2. In males
• Priapism, impotence, decreased
spermatogenesis and gynecomastia
• Androgens stimulate growth of prostate
3. In children
• Abnormal sexual maturation and growth
disturbances resulting from premature closing of
the epiphyseal plates
4. General effects
• Increase the LDL:HDL
• Increase risk for premature coronary heart
disease
• Fluid retention and edema
5. In athletes
• Premature closing of epiphysis of long bones
• Stunts growth and interrupts development
• Reduction of testicular size, hepatic
abnormalities, increased aggression (“roid rage”),
major mood disorders