Estrogen receptors (ERs) act by regulating

transcriptional processes. The classical

mechanism of ER action involves estrogen
binding to receptors in the nucleus, after
Estrogens and Androgens which the receptors dimerize and bind to
specific response elements known as
Dr.Raghad abdulsalam estrogen response elements (EREs)
located in the promoters of target genes.

Physiology Uses : HRT – Effects of Treatment

Reproductive Tissues
Growth of
Ovarian
Estrogen, or oestrogen, is the primary female sex hormone. Vaginal Mammary
Epithelium follilcle Gland
It is responsible for the development and regulation of the Growth of
female reproductive system. There are three major endometrium Sperm
transport
endogenous estrogens in females that have estrogenic
hormonal activity: estrone, estradiol, and estriol. The estrane Lowers
steroid estradiol is the most potent and prevalent of these. Plasma cholesterol Decreases
rate of bone (Increased risk of MI and stroke, especially in the
ESTROGENS resorption first year)

Behavioral effects Reduces

Bowel motility

Liver synthesis of
Transport Proteins Maintains normal
Increases blood coagulability
skin structure

Non-reproductive Tissues

Overview: Endocrine Physiology

Hypothalamus (GnRH)
& Pitutary

Luteinizing Hormone &

Follicle Stimulating Hormone

Ovaries & Testes

Reproduction

SERMs: Other

Raloxifene (EVISTA):
- High affinity for both ER-α and ER-β
-Treatment of osteoporosis in post-menopausal women.
-Does not cause proliferation of the endometrium or breast tumor cells
Selective estrogen receptor Side effects: 2-3 fold ↑ risk of deep vein thrombosis and pulmonary embolism

modulators, called SERMs Interactions: Ampicillin ↓ absorption

Raloxifene ↓ warfarin efficacy

SERMs (Selective Estrogen Receptor Modulators)

There are three SERMs:

tamoxifen in pill form (also called tamoxifen citrate; brand name:
Nolvadex) and in liquid form (brand name: Soltamox)
Evista (chemical name: raloxifene)
Fareston (chemical name: toremifene)
Each is a pill, usually taken once a day, except for tamoxifen in liquid
form. Tamoxifen is the oldest, most well-known, and most-prescribed
SERM.
SERMs can be used to treat women both before and after menopause.

• Selectivity is possible because

• ER-α and/or ER-β show differential tissue expression.
• Conformation dependent binding to DNA and transcription factors
• Tissue dependent responses ranging between pro-estrogenic, partially
estrogenic and anti-estrogenic effects

SERMs: Tamoxifen continued Anti-Estrogens

- Most effective in treatment of tumors that are ER-positive (50% response) or ER • Clomiphene Weak agonist and strong antagonist for
+ PR positive (70-80% response rates). Responses of ER-negative tumors is < ER-α or ER-β.
10%. -Oppose the negative feedback effects of endogenous
estrogen. ↑amplitude of the LH and FSH pulses
- Adjuvant therapy with chemo or radiation in treatment
- Major use: induction of ovulation in women with an
- Preventative agent for women at high risk for breast cancer. intact hypothalamic-pituitary-ovarian axis

-Adverse effects: multiple births, ovarian cysts

-Resistance is usually developed in 5 years, which may, in part, reflect alterations
in the ER receptors in the tumors.

• ICI 182,870 Fulvestrant (FASLODEX)

- pure estrogen antogonist
- effective in treating tamoxifen-resistant tumors

Progestins: anti-Progesterones

Mifepristone (RU 486) (mifeprex): PR antagonist

Used in first trimester to terminate pregnancy (along with prostaglandins to increase

uterine contractions)

Post-coital contraceptive (prevent implantation)

Investigational: induction of labor after fetal death and treatment of endometriosis.

Adverse Effects: vaginal bleeding, abdominal pain and cramping

Contraindicated in patients with vaginal bleeding, adrenal dysfunction or asthma

(due to anti-glucocorticoid actions)

Interactions:
Decreases efficacy of anticoagulants.
Inhibits hepatic metabolism by CYP3A4 (eg.anti-retroviral protease inhibitors,
calcium-channel blockers, carbamazepine)

Progestins – Therapeutic Progesterone Outline

• Naturally occurring progesterone (low oral bioavailability)

- Micronized particles suspended in oil and packaged in gelatin capsules • Contraception

(PROMETRIUM)
- Vaginal gel (CRINONE) • Therapeutic Estrogens & Progesterones
- Slow-release intrauterine device (PROGESTASERT)
• Oral Contraceptive Formulations
• 17-α-hydroxy-progesterone derivatives have substitutions at C17 that slow hepatic
metabolism : medroxyprogesterone (MPA) (PROVERA) • Emergency Contraception
• 19-nor testosterone derivatives display primarily progestational rather than • Extended-Regimen Contraception
androgenic activity : norethindrone

• Replacement of the 13-methyl group of norethindrone with a 13-ethyl substituent are • Mechanism of Action
more potent progestins and less androgenic: norgestrel, nomegestrol
• Effects

Progestins continued Contraception

Hypothalamus
Mechanism of Action: Interacts with PR to mimic the stimulatory affects of
progesterone GnRH
Oral Contraceptives
GnRH analogs Pituitary
Physiological Target: Reproductive Tract
- Decreases estrogen-driven endometrial proliferation LH FSH
- Establishment and maintenance of pregnancy
Ovary
Common Uses:
ovum Estradiol
- Oral contraceptives Progesterone
- HRT to limit estrogen’s effects on the endometrium Fallopian Tube
Tubal Ligation
- Uterine Bleeding disorders
Ovum transport
- Premature labor (decrease uterine contractions) IUD Uterus
Progestin only contraceptive
- Stimulate Appetite in AIDS or cancer patients Implantation
Barrier Methods Sperm transport
Natural family planning Cervix and Vagina
 Effects: Drug Interactions

Drugs that disrupt liver metabolism and increase oral contraceptive

metabolism

- anti-seizure medications, St. John’s wort

- antibiotics tetracycline and ampicillin
- HIV protease inhibitors
- Anti-tuberculosis drugs such as rifampin

Oral contraceptives effect the activity of other drugs

a. anticoagulants
b. benzodiazepines,
c. beta-blockers
d. corticosteroids, and tricyclic antidepressants

Emergency Contraceptives
• Drugs used for the prevention of pregnancy following unprotected
intercourse or a known or suspected contraceptive failure.

• Emergency hormone contraceptive regimens are highly effective and

decrease the risk of pregnancy by 75 percent

• To be effective these must be taken within 72 hours of intercourse

• May also inhibit ovulation or fertilization depending on timing of

administration Alteration of the endometrium, sperm penetration, and
tubal motility are also affected . ESTABLISHED PREGNANCIES ARE NOT
HARMED.

• Two products are available:

– Plan B: 0.75 mg levonorgestrel
– Preven: 0.25 mg levonorgestrel and 0.05 mg ethinyl estradiol (this
product includes a pregnancy test kit)

Contraceptives: MOA

↓LH/FSH release

An androgen (from Greek andr-, the stem of the word meaning Androgens are used for several reasons, such as:
↓ Follicular "man") is any natural or synthetic steroid hormone that regulates the To replace the hormone when the body is unable to
development & development and maintenance of male characteristics in vertebrates produce enough on its own.

ovulation by binding to androgen receptors. This includes the embryological To stimulate the beginning of puberty in certain boys
development of the primary male sex organs, and the development who are late starting puberty naturally.

of male secondary sex characteristics at puberty. Androgens are

synthesized in the testes, the ovaries, and the adrenal glands. To treat certain types of breast cancer in females.

Thank you