Female sex hormones

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Gonadotropin releasing hormone (GnRH)

Released in “pulsalite manner” from the hypothalamus and acts on Pituitary to

stimulate the secretion of gonadotropins-FSH & LH

A. Short-acting analogs• Gonadorelin (t 1/2 = 4 min.)• It can be used in “Pulsatile” manner to stimulate

pituitary to secrete FSH and LH.Uses: • Diagnostic purpose• In infertility: Hypothalamic amenorrhea

1. GnRH analogs

B. Long-acting analogs• Goserelin, Nafarelin, Leuprolide• After initial stimulation, they will cause suppression of

gonadotropin (FSH, LH) secretion. (down-regulation)Therapeutic Uses: For Medical castration:• In precocious puberty• Breast Ca• Prostate Ca• Leiomyoma• EndometriosisAdverse effects:• Gonadal steroidal inhibition in females can cause: Hot

flashes, Vaginal atrophy, Decreased bone density

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2. GnRH antagonist

• Ganirelix• Cetrorelix• These are pure GnRH antagonists and do not

cause initial increase in gonadotropin secretion.

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3. Gonadotropins: FSH & LH

• Gonadotropin preparations:– Menotropins (LH + FSH)– Recombinant FSH and LH– hCG (Human chorionic gonadotropin)

Follicle-Stimulating Hormone (FSH)

Therapeutic uses:1. Treatment of infertility caused by hypogonadism in

both sexes.2. To stimulate ovulation as a part of in-vitro

fertilization (IVF) programs.Side effects:3. Hyperstimulation syndrome (enlarged ovaries,

ascites, fever, embolism, etc.).4. Multiple births.5. Gynecomastia in men.

Human chorionic gonadotropin (hCG) It is glycoprotein produced by the placenta hCG can be used as LH substitute.Therapeutic uses:1. Treatment of infertility both sexes.

A. In females hCG is used as a part of invitro fertilization (IVF) programs to induce ovulation when mature follicles are present (ovulation occurs 36-40hrs from injection).

B. HCG injections are used to stimulate the Leydig cells to synthesize testosterone.

2. Treatment hypogonadism3. Treatment of undescended testes (cryptorchidism)

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4. EstrogensPhysiological Role:1. Development of genital tract and breast.2. Secondary sex characters. Menstrual cycle3. During follicular phase it cause endometrium to grow4. Metabolic effects:• Increase bone mass and prevent bone resorption.• Increase blood glucose.• Increase serum TGs and decrease cholesterol. • Salt and water retention.

5. Increase blood coagulation and platelet adhesiveness.

Types of estrogen 1. Natural estrogens– Estradiol– Estriol– Estrone

2. Synthetic estrogens– Ethinyl estradiol

Routes of adminstration – Oral– IM– Transdermal

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Uses of Estrogens:

1. Hormone Replacement therapy:– Primary hypogonadism– Premature ovarian failure; surgical removal of

ovaries –Menopause

2. Oral contraception3. Osteoporosis4. Atrophic vaginitis

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Adverse effects• Nausea, vomiting• Thromboembolic problems• Myocardial infarction• Breast Ca• Endometrial Ca• Postmenopausal uterine bleeding• Diethylstilbestrol: Clear cell Ca (cervical & vagina)

• Prolonged administrations of estrogen abnormal endometrial hyperplasia, abnormal bleeding patterns, associated with high incidence of endometrial cancer.

• This can be prevented by administration of progesterone accompanies the estrogen.

• Thus, women taking HRT must also take a progesterone unless they have had a hysterectomy.

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5. Selective estrogen receptor modulators (SERMs)

• Tamoxifen, Raloxifene• These are drugs that interact with estrogen

receptors but have different effects on different tissues.

• They can show agonism or antagonism depending upon the tissue type.

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A. Tamoxifen• Antiestrogenic effect: on Breast– Effective in the treatment of breast Ca in patients

with tumor cells that are estrogen receptor- positive.– can be given after surgery to eradicate

micrometastases• Estrogenic effect: on Endometrium– Can cause endometrial Ca– Not prescribed to treat breast Ca for longer than 3-5

years in non-hysterectomized women

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Adverse effects: – Nausea/Vomiting– Hot flashes– Vaginal bleeding– Risk of Endometrial Ca– Thromboembolic disorders

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B. Raloxifene

• Antiestrogenic effect: Breast, Endometrium• Estrogenic effect: Bones, lipid metabolism

• Unlike Tamoxifen, it does not increase the risk of endometrial Ca.

• Approved to be used for the prevention of osteoporosis in postmenopausal women

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6. Estrogen antagonists• Clomiphene (Ovulation inducer):– It blocks estrogen receptors in the hypothalamus and

anterior pituitary so reduces negative feedback

– ↑ FSH and LH secretion leads to ovarian follicle development and ovulation

– Side effects include; Multiple pregnancies, Enlarged cystic ovaries.

– Used for Inadequate ovulation or low sperm count in males

7. Aromatase inhibitors• Anastrozole : non-steroidal agents; competitive inhibitors• Exemestane : steroidal agent; irreversible inhibitor

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Estradiol

Estrone

Estriol

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Mechanism of action: • Aromatase inhibitors block the synthesis of

estrogens from androgen precursors by inhibiting aromatase enzyme.

Uses: • it can be used to inhibit the growth of estrogen-

dependent tumors e.g., breast cancer.• Used in postmenopausal women with advanced

breast cancer. Unlike tamoxifen, they DO NOT increase the risk of endometrial carcinoma or venous thromboembolism.

• Endometriosis

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8. Progestins

• The physiological role of progesterone is maintenance of pregnancy

• Progestins are often combined with estrogen in various formulations to counteract the harmful effects of estrogens (Estrogen can cause endometrial carcinoma)

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Types Progestins:

1. Natural progestins: – Progesterone, 17-alpha hydroxyprogesterone

2. Synthetic progestins:– Medroxyprogesterone (Oral-daily, IM every 1-3 month)– Norgestrel, Levonorgestrel– Norgestimate (less androgenic)– Desogestrel (less androgenic)

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Uses: 1. As contraceptive and menopausal hormone therapy– Combined with estrogen (in COCPs & menopausal

hormonal therapy) – Progestin only contraceptive preparations– As post coital contraception

2. Dysmenorrhea3. Dysfunctional uterine bleeding 4. Endometriosis

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Adverse effects: – Edema– Depression– Breakthrough bleeding

ADRs of progestins having Androgen-like activity:– Increase the ratio of LDL to HDL cholesterol– Thrombophlebitis– Pulmonary embolism– Acne– Hirsutism– Weight gain– Liver dysfunction

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9. Progesterone antagonist

• Mifepristone: – Progesterone receptor antagonist– Glucocorticoid receptor antagonist

• Therapeutic uses:– Medical termination of pregnancy

(Mifepristone followed 48 hrs later by Misoprostol)

Infertility1. Clomifene– Safest & cheapest , Antiestrogens2. Gonadotropins– Used in women with hypopituitarism or do not respond to

clomifene therapy. – Treatment starts with daily injection of menotrophin (LH =

FSH ) or (FSH), followed by 1-2 large doses of chorionic gonadotropin (mostly LH) to induce ovulation.

– Adverse Effects: Multiple births, Ovarian hyperstimulation syndrome (OHSS), Bleeding, Low birth weight, Birth defects

– In men with hypogonadism, both LH and FSH are given to stimulate spermatogenesis and androgen release.

3. Bromocriptine– Dopamine agonist that inhibits prolactin

release4. GnRH releasing hormone (Gn-RH) analogs5. Aromatase inhibitors6. Metformin (Polycystic ovary syndrome)

Drugs affecting uterine smooth muscle

1.Stimulatants of uterus• Include Oxytocin, Ergot alkaloid, Prostaglandins A. Oxytocin• Enhances uterine contraction • Adverse Effects: Uterine rupture, fetal hypoxia or

trauma, hypertension, CVA.• Uses: Post-partum hemorrhage, induce and maintain

labor.

B. Ergot alkaloid :• Ergometrine, Methylergometrine • Effects: – Contract uterus– Vasoconstriction: Damage vascular endothelial cells

at high dose can lead to dry gangrene of the extremities after long term use.

• Uses: – Postpartum hemorrhage – To enhance the delivery of the placenta.– Migraine

• Adverse effects– GI disturbances: diarrhea, nausea, and vomiting

prolonged vasospasm• Contraindications– Cerebrovascular diseases; pregnancy

C. Prostaglandins • Dinoprostone， (PGE2）• Dinoprost and carboprost (PGF2）Used in• Medical abortion: combined with mifepristone• Induction of laborAdverse effects• GI disturbances: nausea, vomiting and abdominal painContraindications • Bronchial asthma; glaucoma

2. Relaxants of uterus (tocolytics):• Ritodrine, Terbutaline, Salbuterol, Magnesium sulfate,

nifedipine• Used to delay Premature birth or preterm labor • Ritodrine– Selective β2 adrenergic receptor agonist that relaxes

uterus – Used in preterm labor – Adverse Effects: palpitations, tachycardia

Good luck