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Dr. Kaukab Azim. MBBS, PhD

Gonadal Hormones &

Inhibitors

• Hypogonadism in males and females• Precocious puberty, leiomyoma, endometriosis,

dysmenorhea• Hormonal contraceptives• Menopausal replacement therapy• Infertility• SERMs• Medical abortion• Gonadal hormones agonist and antagonists• Hormonal drugs for some cancers

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Hypothalamic and

ant. pituitary hormones

Estrogens&

Inhibitors

Progestins&

Inhibitors

Androgens&

Inhibitors

GnRH analogs Natural & Synthetic

Natural and synthetic

Natural and synthetic

GnRH antagonists

SERMs Anabolic steroids

Gonadotropins: FSH LH

Partial agonists &antagonists

Antagonist Antiandrogens-Gn release inhibitors-Receptors inhibitors-5-a reductase inhibitor-Synthesis inhibitor

Aromatase inhibitors

Gonadal Hormones and Inhibitors

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Key concepts of Pharmacology of Gonadal Hormones:

• Effects of GnRH release frequency on gonadotropin release.

• Interaction between estrogen and the pituitary gland.

• Tissue selectivity of estrogen agonists and antagonists.

• Various strategies to antagonize the effect of endogenous sex hormones.

Hypothalamus-Pituitary-Gonadal Axis

(Ovulation inducer)

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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

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GnRH analogsShort-acting analogs

• Gonadorelin (t1/2 = 4 min.)

It can be used in “Pulsatile” manner to stimulate pituitary to secrete FSH and LH.

Uses: • Diagnostic purpose• In infertility: Hypothalamic

amenorrhea

Long-acting analogs

• Goserelin• Nafarelin- nasal spray• Leuprolide

After initial stimulation, they will cause suppression of gonadotropin (FSH, LH) secretion. (down-regulation)

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GnRH analogs

Long-acting GnRH analogs

• Goserelin• Nafarelin• Leuprolide

After initial stimulation, they will cause suppression of gonadotropin (FSH, LH) secretion.

Therapeutic Uses:For Medical castration:

• In precocious puberty• Breast Ca• Prostate Ca• Leiomyoma• Endometriosis

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GnRH analogs: Adverse effects

Adverse effects of long-acting analogs:• Gonadal steroidal inhibition in females can

cause:– Hot flashes– Vaginal atrophy– Decreased bone density

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GnRH antagonist

– Ganirelix– Cetrorelix

These are pure GnRH antagonists and do not cause initial increase in gonadotropin secretion.

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Gonadotropins: FSH & LH

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

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Estrogens

Physiological Role:• Secondary sexual characteristics• Menstrual cycle

– During follicular phase it cause endometrium to grow

• For normal mineralization and osteoid formation– Deficiency of estrogens cause osteoporosis

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Estrogens

Natural estrogens• Estradiol• Estriol• Estrone

Synthetic estrogens• Ethinyl estradiol• Mestranol

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Estrogens

• Oral:– Estradiol: micronized form– Conjugated estrogens: conjugated equine estrogens– Ethinyl estradiol & Mestranol (synthetic estrogens)

• IM: aqueous or oil based esters of estradiol and estrione

• Transdermal preparations: estradiol

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Uses of Estrogens• Hormone Replacement therapy:

– Primary hypogonadism– Premature ovarian failure; surgical removal of ovaries – Menopause

• Oral contraception

• Osteoporosis

• Atrophic vaginitis

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Estrogens: Adverse effects

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

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Progestins

• Physiological role: – helps maintaining pregnancy

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

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ProgestinsNatural progestins:

– Progesterone, 17-alpha hydroxyprogesterone

Synthetic progestins:– Hydroxyprogesterone (IM, every 1-2 weeks)– Medroxyprogesterone (Oral-daily, IM every 1-3 months)– Norethindrone: belongs to 19-nortestoserone analogs– Norgestrel, Levonorgestrel– Norgestimate (less androgenic)– Desogestrel (less androgenic)

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Progestins: Uses

• As contraceptive and menopausal hormone therapy– Combined with estrogen (in COCPs & menopausal hormonal

therapy) – Progestin only contraceptive preparations– As postcoital contraception

• Dysmenorrhea• Dysfunctional uterine bleeding • Endometriosis

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Progestines: Adverse effects– Edema– Depression

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

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Hormonal Contraceptives

• Combined Oral Contraceptive Pills (COCPs)– contain both estrogen and progesterone– Monophasic, Biphasic, Triphasic forms

• Progestin only preparations– Progestin-only pills (“mini-pill”)– Progestin implants/depot (Levonorgestrel, medroxyprogesterone)

– Progestin containing Intrauterine device

• Postcoital contraception (emergency contraception)

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COCPs: Mechanism of action

1. Estrogen and progesterone causes feedback inhibition of FSH and LH secretion from the pituitary gland to inhibit ovulation. (main mechanism)

2. Progestins thicken the cervical mucous and prevent the entry of sperm.

3. Effects on uterine tubes and endometrium decrease the likelihood of fertilization and implantation

Feedback inhibition

↓ LH surge

No Ovulation

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COCPs: Adverse effects

• Nausea, vomiting, mastalgia• Headache• Breakthrough bleeding• Wt. gain• Acne and Hirsutism (19-nortestosterone derivatives)

• Chloasma (skin pigmentation)

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COCPs: Serious complications

• Leg vein and pulmonary thrombosis• Coronary and cerebral thrombosis• Rise in BP

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COCPs: Contraindications

COCPs are absolutely contraindicated in • Thromboembolic, coronary, cerebrovascular disease.

Greater risk for :– Women > 35 years of age– Heavy smokers– Obese

• Active liver disease• Suspected or overt malignancy of genitals/breast• Undiagnosed vaginal bleeding

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COCPs: Relative contraindications

• Hypertension• Migraine• Diabetes mellitus• Uterine leiomyoma• Mental illness• Gall bladder disease

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COCPs: Drug Interactions

• Enzyme inducers (Phenytoin, barbiturates, carbamazapine, Rifampin) cause contraceptive failure

• Antibiotics (Tetracyclines, ampicillin, etc.) cause contraceptive failure by suppressing intestinal microflora:

– Decreased deconjugation of estrogens excreted in bile – Decreased enterohepatic circulation of estrogens – Blood levels of estrogens fall contraceptive failure

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Progestin-only preparations• Progestin-only pill (“Mini-pill”)

– norethindrone or levonorgestrel

• Progestin implants/depot– Levonorgestrel: subcutaneous implant, 5 years– Medroxyprogesterone acetate (DMPA): IM, every 3

months.

• Progestin containing Intrauterine devices– Progestasert contains progesterone & mirena contains levonorgestrel

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Progestin-only preparations

Progestin-only preparations are suitable for women when estrogens are contraindicated :

• Smokers• Age > 35 years• h/o cardiovascular disease• Migraine• Liver impairment

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Progestin-only preparations

Disadvantages of progestins:

• Frequent spotting• Irregular and unpredictable menstrual cycles• Failure rate is higher as compared to combined

COCPs• Unfavorable effect on lipid profile

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Emergency contraception• Postcoital or “morning after” contraception

1. Combined oral contraceptive pills: 2 pills within 72 hours of unprotected sexual intercourse and 2 exactly 12 hours later.

2. Progestin-only pills (Levonorgestrel): one tablet within 72 hours of unprotected sexual intercourse followed by second dose exactly 12 hrs later.

3. Ulipristal: a selective progesterone receptor modulator; taken within 120 hrs of unprotected sexual intercourse

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Menopausal hormone therapy(HRT)

• Estrogen deficiency symptoms:– Hot flashes, chills, night sweats, mood swings, insomnia,

headache, palpitation– Vaginal and urethral atrophy– Osteoporosis (others drugs are preferred)

• Lowest effective dose of estrogen for the shortest duration to relieve estrogen deficiency symptoms in postmenopausal period.

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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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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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Tamoxifen: Adverse effects

• Nausea/Vomiting• Hot flashes• Vaginal bleeding• Risk of Endometrial Ca• Thromboembolic disorders

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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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Estrogen antagonists

• Clomiphene (Ovulation inducer):blocks estrogen receptors in the hypothalamus and anterior

pituitary reduces negative feedback

↑ FSH and LH secretionovarian follicle development and ovulation

• Fulvestrant

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Progesterone antagonist

• Mifepristone (RU 486)– Progesterone receptor antagonist– Glucocorticoid receptor antagonist

Therapeutic uses:– Medical termination of pregnancy

(Mifepristone followed 48 hrs later by Misoprostol)

Aromatase inhibitors• Anastrozole, Letrozole : non-steroidal agents;

competitive inhibitors• Exemestane : steroidal agent; irreversible inhibitor

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Estradiol

Estrone

Estriol

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Aromatase inhibitors• Aromatase inhibitors block the synthesis of estrogens

from androgen precursors by inhibiting aromatase enzyme.

• This approach 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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AndrogensTestosterone esters:• Testosterone propionate• Testosterone enanthate• Testosterone cypionate

17-alpha alkylated androgens:• Methyltestosterone• Fluoxymesterone• Oxandrolone (anabolic steroid)• Danazol (Danocrine)

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Androgens: Therapeutic Uses

• Hypogonadism: as hormonal replacement therapy.

• For Anabolic effects: – Osteoporosis– severe burns – to increase lean body mass, muscle strength

• Endometriosis

• Hereditary angioedema

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Danazolsynthetic derivative of 17-ethinyltestosterone

• It has weak androgenic, progestational and glucocorticoid activity

• Inhibits CYP450 enzymes involved in gonadal hormone synthesis

Uses:– Endometriosis– Fibrocystic breast disease– Hereditary angioedema (It occurs due to deficiency of C1-

esterase inhibitor)

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Danazol: Adverse effects

• Acne• Hirsutism• Menstrual irregularities• Hepatotoxicity• Thromboembolism• Teratogenic

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Anabolic steroids• Greater anabolic:androgenic activity• Oxandrolone (anabolic: androgenic=3:1-13-1)

Adverse drug reactions:• Infertility: due to suppressed FSH and LH

– Decreased testicular size and function• Feminization in men, gynecomastia• Masculinization in women: Hirsutism, deepening of

voice, menstrual irregularities• Hepatic dysfunction, Cholestatic jaundice• Psychotic symptoms

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Antiandrogens

– Gonadotropin release inhibitors

– Androgen Receptor blockers

– 5a-reductase inhibitor– Androgen synthesis

inhibitors

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Gonadotropin release inhibitors

• Long acting GnRH analogs– Leuprolide– Goserelin– Nafarelin

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Androgen Receptor blockers• Nonsteroidal antiandrogens

– Flutamide– Bicalutamide

• They block the action of dihydrotestosterone on testosterone receptors and inhibit the synthesis of new proteins in prostate and prostate cancer cells.

• Combined with GnRH analogs to treat inoperable prostate Ca.

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Androgen receptor blockers: Adverse effects

• Gynecomastia or nipple tenderness• Diarrhea• Hepatotoxicity • Impotence

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5a-reductase inhibitor

• In the prostate, testosterone is converted into dihydrotestosterone (DHT) by the action of 5a-reductase

• DHT acts on prostate cells to stimulate new growth

• Finastride: synthetic testosterone derivative– It inhibits the synthesis of Dihydrotestosterone

(DHT) by inhibiting 5a-reductase

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5a-reductase inhibitor

Therapeutic uses:• Benign prostatic hyperplasia• Male pattern baldness

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Androgen synthesis inhibitors

• Ketoconazole:– It is an antifungal agent.– It inhibits gonadal & adrenal steroid synthesis by

inhibiting cholesterol side chain cleavage (inhibits P450SCC).

Adverse effects:– Gynecomastia– hepatotoxicity

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Hormones in cancer chemotherapy

Used as adjunctive therapy

Breast Ca Prostate Ca

Anastrozole, Exemestane Flutamide, Bicalutamide

Tamoxifen Leuprolide, Goserelin

Leuprolide, Goserelin

Glucocorticoids