Therapeutic uses and adverse effects of estrogen and selective estrogen receptor modulators

Natural Sex hormones produced by the gonads are necessary for, used therapeutically in

Conception, embryonic maturation, and development of primary and

secondary sex chatacters at puberty

Their activity in target cells is modulated by receptors.

Used therapeutically in : Replacement therapy, contraception, manage menopausal symptom. estrogen antagonist effective in chemo

Estrogen (Prep)

Estrogen prep : Conjugated estrogens contain estrone sulfate esters and equilin (preg mares urine) oral prep for hormone replacement therapy,

Plant derived conjugated estrogen products ,

synthetics estrogen aka ethinly estradiol

Estrogen mech

1. Sex hormone binding globulin or albumin in plasma (After dissociating from binding sites) → bind with High affinity to specific nuclear receptor proteins (a and b)

2. Activated steroid receptor complex with nuclear chromatin → Hormone specific RNA synthesis → Protein synthesis

Therapeutic uses to estrogen

1. Contraception

2. Prevention of ostoporosis

3. Postmenopausal hormone therapy

4. Premenopausal replacement theray

In woman with deficient estrogen due to inadequate ovary function. premature menopause surgical menopaus

Therapeutic uses to estrogen (postmenopausal HT)

1. Postmenopausal HT: (treat menopausal symptoms)

Intact uterus → Progesterone + Estrogen as reduce risk of endome carcinoma

Women with uterus surgically removed → Estrogen only

Oral estradiol, transdermal patch

Vaginal atrophy = vaginal estrogen

2, Contraception

3. Other uses

• Primary hypogonadisms stimulate development of 2ry sex characteristics in young women (11-13)

• Premature menopause or premature ovarian follicle ( up till 50 average age of normal menopause)

• Dysmenorrhea and oligomenorrhoea

• Palliative treatment of prostate cancer (antiprolif action)

Naturally occuring estrogen

1. Naturally occuring estrogen (absorbed through GIT,skin, mucous memb, have some 1st pass metabolism

2. Synthetic estrogen analogs

• Ethinyl estradiol and mestranol (well absorved after oral administration

• Metab more slowly than natural by liver and peripheral tissue

• less 1st pass metabolism = prolonged action and higher potency

Stored in adipose tissue → slowly released into blood bound to serum albumin or sex hormone binding protein

Bioavailability of oral estrogen is low due to 1st pass metab → reduce 1st pass by transdermal route, intravaginal

Excretion in bile enterohepatic circ

Inactive product excreted in urine

Liver damage = feminine man and excess estrogen in woman

Adverse effects of estrogen

1. Nausea, Headache, peripheral edema, breast tenderness (Most common)

2. Thromboembolic events , Myocardial infarction breast and endometrial cancer (countered by having estrogen + progesterone)

Selective estrogen modulators

Tamoxifen -

Antagonist of estrogen in breast tissue treats breast cancer by fighting estrogen for its receptor

Oral administration → Metab by CYP450 enzymes

Effects: Hot flashes, nausea, irreg menses and vaginal bleeding, hyperplasia and malignancies, drug interactions

Raloxifene -

Antagonist of estrogen in bone treats osteoporosis by decreasing bone resorption and decreases cholesterol

Oral administration → Glucorinide conjugation 1st pass metab more than 95% plasma bound

Effects: Hot flashes, leg cramp, increase risk of deep vein thrombosis, pulmonary embolism and retinal vein thrombosis

Clomiphene -

Partial Agonist of estrogen in infertility associated with anovulatory cycle (PCOS)

interfere with - feedback of estrogen on hypothalmus

Oral administration

Effects: Headache, nausea, vasomotor flushes,

Visual disturbances
Ovarian enlargement.

All do Enterhepatic recycling bile → into feces excretion

Progesterone

Produced response to LH surge

Secreted by corpus luteum after ovulation

by placenta during preg

Promotes development secretory endomet allowing implantation

Therapeutic uses of progestogens + Pharmacokinetics

Therapeutical uses : Treat hormonal deficiency and contraception

Synthetic progestogens (progestins) used in contraception>stable to 1st pass allowing lower dose administered

Absorbed orally, short half life and metab by liver and excreted by kidney

Synthetic progestins

Less rapid metab

Medroxyprogesterone acetate

Oral have a half life of 30 days

IM or subcutaneously half life 40-50 days. and provide contraceptive activity for 3 months

Other progestins have ½ life 1-3 days. Once daily dosing

Adverse effects

1. Headache , depression and weight gain

2. Some progestins (19-nortestosterone derivatives have androgenic activity and can cause increase ratio of LDL to HDL cholesterol and cause acne and hirsutism

3. Less androgenic progestins - norgestimate and drospirenone may be preffered for acne woman

4. Injectable medroxyprogesterone acetate increease osteoporosis risk so say use to 2 yrs

Antiprogestin

Mifepristone

• Progesterone antagonist (partial agonist)

• Potent antiglucocorticoid activity

• Early in preg cause abortion

• Mifepristone with misoprostol (oral or intravaginal) to induce uterine contraction

• Adverse effect: Significant uterine bleeding, Abortion