the gonadal hormones and inhibitors presentation. 2011. davis 1

7/31/2019 The Gonadal Hormones and Inhibitors Presentation. 2011. DAVIS 1

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Gonadal Hormones and Inhibitors

Gina Davis, Pharm.D.

2012

Idaho State University

Hypothalamus

AnteriorPituitary

Ovary

GnRH

FSHandLH

EstrogenandProgesterone

Reference:HansenL,GunningK.DisordersRelatedtotheMenstrualCycle.In:Koda-Kimbleetal.AppliedTherapeuJcs;

TheClinicalUseofDrugs,NinthEdiJon.LippincoWilliams&Wilkins,2009:47-1to47-27.

FEMALES


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Reference:HansenL,GunningK.DisordersRelatedtotheMenstrualCycle.In:Koda-

Kimbleet

al.AppliedTherapeuJcs;TheClinicalUseofDrugs,N

inthEdiJon.Lippinco

Williams&Wilkins,2009:47-1to47-27.

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 causeregression of the immature follicles.

Estrogen peaks just before midcycle and causes anLH 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 andprogesterone.

If pregnancy does not occur, the corpus luteumdegenerates and stops producing hormones. Thisdecline 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, NewYork, NY.

Estrogens

Estradiol is the major secretory hormone of theovary

Estrone and estriol are mostly formed in the liveror in the peripheral tissues

Necessary for:1. Female Maturation2. Endometrial lining3. Metabolic and Cardiovascular Effects4. 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 cardiovasculardisease

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


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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Need to give estrogen with aprogestational agent if patient has

uterus to protect against endometrial

hyperplasia and endometrial cancer.


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 are increased during the Lutealphase

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 theendometrium

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:

Age35orolderandsmokes Heartaackorstroke Bloodclots(ie.DVT,PE) Chestpain(angina) HPTN DiabeteswithvascularcomplicaJonsormorethan20years

duraJon

Headacheswithfocalneurologicalsymptomsorpersonalhistoryofstroke

Breastcancer Liverdiseaseortumor Heartvalvedisorder ImmobilizaJon


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Common Complaints

Estrogen Excess Nausea Bloating / Edema Hypertension Migraine HA Breast tenderness / fullness

Estrogen Deficiency Early or mid-cycle breakthrough

bleeding

Progestin Excess Breast tenderness Headache Fatigue Changes in mood

Progestin Deficiency Late breakthrough bleeding Amenorrhea Hypermenorrhea

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 withenterohepatic 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 ofthromboembolic 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 administrationAdvantages

- 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 Availability:

OTC status for women 17yo and older Prescription for those


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Selective estrogen receptor modulator

(SERM)

Tamoxifen MOA: competitive partial agonist inhibitor of estradiol

Agonist=on lipid, bones, endometrium Antagonist=on breast tissue

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

Raloxifene Uses:

prevention of postmenopausal osteoporosis prophylaxis of breast cancer in women with risk factors

MOA: Agonist=on lipid and bone Antagonist= on the endometrium or breast tissue May increase risk of arterial and venous thromboembolism

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 orpituitary failure

Uses: Stimulate ovulationAdverse effects: hot flushes


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Males The most important androgen secreted by

the testis is testosterone.

65% of circulating testosterone is bound tosex hormone-binding globulin (SHBG)

In many target tissues, testosterone isconverted 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

TestosteroneAdverse 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

Dihydrotestosterone

5 reductase


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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 & ClinicalPharmacology. Editors: Betram G. Katzung, Susan B.Masters, Anthony J. Trevor, 11th edition. (2009) Mcgraw-Hill, NewYork, NY.

Hardman JL. Contraception. In: Koda-Kimble MA, et al,eds. AppliedTherapeutics: the clinical use of drugs. Ninth Edition. LipppincottWilliams & Wilkins. 2009:45-1 to 45-28.

Dickerson LM, Shrader SP, Diaz VA. Contraception. In: Dipiro, et al.Pharmacotherapy; a pathophysiolgical approach. Seventh Edition. TheMcGraw Hill Companies, Inc. 2008:1313-1343.

Kalantaridou S, Davis S, Calis KA. In: Dipiro, et al. Pharmacotherapy; apathophysiolgical approach. Seventh Edition. The McGraw HillCompanies, 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-KimbleMA, et al,eds. Applied Therapeutics: the clinical use of drugs. NinthEdition. Lipppincott Williams & Wilkins. 2009:48-1 to 48-9.

the gonadal hormones and inhibitors presentation. 2011. davis 1

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