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Gonadal Hormones and Inhibitors

Gina Davis, Pharm.D. 2012 Idaho State University

Hypothalamus GnRH Anterior Pituitary FSH and LH Ovary Estrogen and Progesterone

FEMALES

Reference: Hansen L, Gunning K. Disorders Related to the Menstrual Cycle. In: Koda-Kimble et al. Applied TherapeuJcs; The Clinical Use of Drugs, Ninth EdiJon. LippincoN Williams & Wilkins, 2009: 47-1 to 47-27.

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Reference: Hansen L, Gunning K. Disorders Related to the Menstrual Cycle. In: Koda- Kimble et al. Applied TherapeuJcs; The Clinical Use of Drugs, Ninth EdiJon. LippincoN Williams & Wilkins, 2009: 47-1 to 47-27.

The Female Cycle

Follicular Phase
FSH stimulates a number of follicles (each containing

an ovum) begin to develop After 5 to 6 days, a dominant follicle forms The theca cells and granulosa cells of this dominant follicle multiply and synthesize and release estrogens. The estrogen inhibits FSH release and may cause regression of the immature follicles. Estrogen peaks just before midcycle and causes an LH and FSH surge. The LH surge leads to ovulation.

Chrousos G. The Gonadal Hormones & Inhibitors. In: Basic & Clinical Pharmacology. Editors: Betram G. Katzung, Susan B. Masters, Anthony J. Trevor, 11th edition. (2009) Mcgraw-Hill, New York, NY.

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The Female Cycle

Luteal Phase The theca cells and granulosa cells form the corpus luteum. The corpus luteum produces estrogen and progesterone. If pregnancy does not occur, the corpus luteum degenerates and stops producing hormones. This decline in hormones leads to endometrium shedding.

Chrousos G. The Gonadal Hormones & Inhibitors. In: Basic & Clinical Pharmacology. Editors: Betram G. Katzung, Susan B. Masters, Anthony J. Trevor, 11th edition. (2009) Mcgraw-Hill, New York, NY.

Estrogens
Estradiol is the major secretory hormone of the

ovary Estrone and estriol are mostly formed in the liver or in the peripheral tissues
Necessary for: 1. Female Maturation 2. Endometrial lining 3. Metabolic and Cardiovascular Effects 4. Blood coagulation

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Estrogens
Clinical

Uses:

Estrogen Replacement Therapy


Failure of ovary development Premature menopause Castration Menopause

Estrogens: Clinical Uses Continued


Post Menopausal Give estrogen to help with vasomotor symptoms - Benefit=Helps to stop bone loss Declined estrogen levels cause a rise in LDLs - Acceleration of atherosclerotic cardiovascular disease Womens Health Initiative Study - Estrogen plus progestin (Prempo) orally Increased risk of coronary heart disease Increased risk of blood clots Increased risk of stroke Increased risk of breast cancer

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Clinical Use: Estrogen for post-menopause


Examples: Estradiol containing products Human, Synthetic ie. Climara, estrace, Estraderm Conjugated estrogen-containing products Plant-derived, synthetic ie. Cenestin Preganant mare urine-derived Ie. Premarin Esterified estrogen-containing products Soybean-derived,synthetic ie. Menest Estropipate containing products Human, Synthetic
ie. Ogen

Clinical Use: Estrogen for post-menopause

Forms: Oral, Patch, gels, sprays, vaginal ring


Oral Undergoes first pass metabolism in the liver Can increase Triglycerides, but can increase HDL, decrease LDL, decrease TC Increases clotting factors Patch or topical No first pass effect in liver Little to no change in lipid levels or coagulation parameters compared to oral May have decreased risk of DVT compared to oral Vaginal administration Use for genital atrophy only

FDA safety warnings on all estrogen: Can increase risk of MI, stroke, breast cancer, thromboembolism Dosing: Use the lowest dose for shortest amount of time

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Clinical Use: Estrogen for post-menopause


Need

to give estrogen with a progestational agent if patient has uterus to protect against endometrial hyperplasia and endometrial cancer.

Clinical Use: Estrogen for post-menopause


Contraindications
Endometrial cancer Breast cancer Liver disease Undiagnosed vaginal bleeding History or presence of thromboembolic

disorder (venous or arterial) Heavy smokers

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Progesterone
Necessary for: Maturation and shedding of the

endometrium lining

Levels

phase

are increased during the Luteal

Uses
Hormone replacement
ie. medroxyprogesterone

Hormonal contraception
ie. Depo-Provera, Micronor, Mirena Intrauterine Device

(IUD)

Produces ovarian suppression for other reasons

Hormonal Contraception

Combined Hormonal Contraception (CHC)


Estrogen plus progesterone
Pills Patch Ring

Progesterone only options


Pills (POP) IM or SQ Implanon IUD

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Combined Hormonal Contraception (CHC)


MOA:
Stop ovulation Change of cervical mucus Change in uterine endometrium

Some Advantages of CHC

heavy menstrual bleeding (menorrhagia)

Progressive thinning of the lining of the endometrium

painful menstration (dysmenorrhea) Protection from endometrial cancer Protection from ovarian cancer and suppression of development of ovarian cysts Reduced risk of benign breast disease Decreased incidence of ectopic pregnancy Acne improvements

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Disadvantages of CHC

Compliance No STD protection in VTE, stroke, MI TG Blood pressure benign hepatocellular adenomas breast cancer ? cervical cancer

Contraindications of CHCs
Many

contraindications

Some of the contraindications or precautions

include presence or a history of:


Age 35 or older and smokes Heart aNack or stroke Blood clots (ie. DVT, PE) Chest pain (angina) HPTN Diabetes with vascular complicaJons or more than 20 years duraJon Headaches with focal neurological symptoms or personal history of stroke Breast cancer Liver disease or tumor Heart valve disorder ImmobilizaJon

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Common Complaints

Estrogen Excess

Progestin Excess

Nausea Bloating / Edema Hypertension Migraine HA Breast tenderness / fullness

Breast tenderness Headache Fatigue Changes in mood

Progestin Deficiency
Late breakthrough bleeding Amenorrhea Hypermenorrhea

Estrogen Deficiency

Early or mid-cycle breakthrough bleeding

Androgen excess

Increased appetite Weight gain Acne, oily scalp Hirsutism

CHC: Drug Interactions


Medications

that induce Cyt P450 3A4 will increase metabolism and, therefore, decrease combined oral contraceptive efficacy Some antibiotics can kill GI bacteria, which decrease serum levels of estrogen by interfering with enterohepatic recirculation

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Contraception:

Progesterone

Only Options

Progesterone Only Pills (ie. Micronor)


Advantages Can be used in women whom are:
Post partum period Lactation (start 6 weeks postpartum) Avoidance of estrogen ADR:

- Migraines, CV risk, HTN, smokers, history of thromboembolic disease

Protection against endometrial cancer

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Progesterone Only Pills (ie. Micronor)


Disadvantages Less effective than COC Irregular and unpredictable bleeding Compliance crucial Avoid in: Current DVT,PE (not on anticogulation) Systemic Lupus Erythematosus (positive antiphospholipid antibody) Breast CA (current or past) Active viral hepatitis, severe cirrhosis, liver tumors Undiagnosed vaginal bleeding

Depo-Provera (Medroxyprogesterone)
IM & SQ formulations (Depo-SubQ Provera) Q 3 month administration Advantages

- failure rate - or no menses - Every 3 months Disadvantages - Delayed return to fertility - If side effects occur, not able to discontinue immediately - Breakthrough bleeding - Weight gain - Office visits - May BMD

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Emergency Contraception: Levonorgestrel

Plan B (the morning-after pill)

Products:

Next ChoiceTM: 2 tablets of levonorgestrel 0.75 mg

Take 1 tablet ASAP, then take the 2nd tablet 12 hours later

Plan B One-Step: 1 tablet of levonorgestrel 1.5 mg OTC status for women 17yo and older Prescription for those <17yo

Availability:

CARE program (Convenient Access, Responsible Education)


Sold behind the pharmacy counter Must have a pharmacist on duty and available for counseling when product is sold.

Mifepristone
Uses: Strong inhibitor of progesterone receptor Abortifacient Side effects: vomiting, diarrhea, abdominal pain,

pelvic pain, or vaginal bleeding

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Selective estrogen receptor modulator (SERM)

Tamoxifen

MOA: competitive partial agonist inhibitor of estradiol Uses: Treatment and Prevention (in high risk women) of breast cancer May increase risk of endometrial cancer May increase risk of arterial and venous thromboembolism
Agonist=on lipid, bones, endometrium Antagonist=on breast tissue

Raloxifene

Uses: prevention of postmenopausal osteoporosis prophylaxis of breast cancer in women with risk factors MOA: May increase risk of arterial and venous thromboembolism
Agonist=on lipid and bone Antagonist= on the endometrium or breast tissue

Clomiphene
Ovulation-inducing

agent Partial estrogen agonist Inhibits estradiols negative feedback effect on the gonadotropins at the hypothalamus, leading to ovulation Will not help in patients with ovarian or pituitary failure Uses: Stimulate ovulation Adverse effects: hot flushes

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Males
The

most important androgen secreted by the testis is testosterone. 65% of circulating testosterone is bound to sex hormone-binding globulin (SHBG) In many target tissues, testosterone is converted to dihydrotestosterone.

Testosterone
Some

Clinical Uses:

Replacement therapy in men

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Testosterone Products
Buccal

Tablet= Striant Transdermal gels= Testim, Androgel Transdermal Patches= Androderm Injectables= Depo-Testosterone Oral products should not be used because can cause liver problems

Testosterone
Adverse

Effects:

In women=hirsutism, acne, amenorrhea,

deep voice In men=acne, sleep apnea, gynecomastia, erythrocytosis, azoospermia Sodium retention, edema (not common), hepatic dysfunction

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Contraindications and Cautions


Pregnancy Carcinoma

of the breast or prostate Infants and children Conditions with edema

5 reductase inhibitor
Finasteride

(Proscar, Propecia) Dutasteride (Avodart)


Testosterone 5 reductase Dihydrotestosterone

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Receptor Inhibitors

Flutamide Inhibits binding of androgens at the receptor Used in treatment of prostate cancer Liver failure (black box warning) Bicalutamide (Casodex) and Nilutamide (Nilandron) Androgen receptor inhibitor Used for Prostate cancer Spironolactone Competitive inhibitor of aldosterone and competes with dihydrotestosterone for androgen receptors Treats hirsutism in women

References:
Chrousos G. The Gonadal Hormones & Inhibitors. In: Basic & Clinical Pharmacology. Editors: Betram G. Katzung, Susan B. Masters, Anthony J. Trevor, 11th edition. (2009) Mcgraw-Hill, New York, NY. Hardman JL. Contraception. In: Koda-Kimble MA, et al,eds. Applied Therapeutics: the clinical use of drugs. Ninth Edition. Lipppincott Williams & Wilkins. 2009:45-1 to 45-28. Dickerson LM, Shrader SP, Diaz VA. Contraception. In: Dipiro, et al. Pharmacotherapy; a pathophysiolgical approach. Seventh Edition. The McGraw Hill Companies, Inc. 2008:1313-1343. Kalantaridou S, Davis S, Calis KA. In: Dipiro, et al. Pharmacotherapy; a pathophysiolgical approach. Seventh Edition. The McGraw Hill Companies, Inc. 2008:1351-1368. Hormonal contraception. Pharmacist's Letter/Prescriber's Letter 2007;23 (12):231207. (Update June 2010). Parent-Stevens L. The Transition Through Menopause. In: Koda-Kimble MA, et al,eds. Applied Therapeutics: the clinical use of drugs. Ninth Edition. Lipppincott Williams & Wilkins. 2009:48-1 to 48-9.

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