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OCP HRT

SHELAGH LARSON, WHNP, NCMP UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER

HISTORY OF THE PILL • 1873:THE U.S. CONGRESS PASSES THE COMSTOCK LAW, WHICH PROHIBITS THE DISTRIBUTION OF OBSCENE MATERIAL THROUGH THE U.S. MAIL OR ACROSS STATE LINES. IT SPECIFICALLY IDENTIFIES CONTRACEPTIVES AS OBSCENE. • 1912: RADICAL FEMINIST MARGARET SANGER CONCEIVES OF A "MAGIC PILL" CONTRACEPTIVE. SANGER LATER FOUNDED THE AMERICAN BIRTH CONTROL LEAGUE, WHICH EVENTUALLY BECAME THE PLANNED PARENTHOOD FEDERATION. • 1930:ON AUGUST 15, MEETING OF THE ANGLICAN CHURCH'S BISHOPS APPROVES THE USE OF CONTRACEPTIVES. AFTER 1930, OTHER PROTESTANT DENOMINATIONS BEGIN TO ALLOW CONTRACEPTION. POPE PIUS XI REAFFIRMS THE CATHOLIC CHURCH'S CONSTANT TEACHING AGAINST CONTRACEPTION AND ABORTION • 1951:SANGER OBTAINS A PLANNED PARENTHOOD GRANT FOR DR. GREGORY PINCUS, A BIOLOGIST, TO RESEARCH HORMONAL CONTRACEPTIVES • 1954 PINCUS AND DR. JOHN ROCK, A CATHOLIC OB-GYN BEGIN HUMAN TRIALS OF THE PILL. TO BYPASS MASSACHUSETTS'S ANTI-BIRTH CONTROL LAWS, THEY CLAIM THE STUDY IS ABOUT INFERTILITY. FIFTY FEMALE INFERTILITY PATIENTS. 1955:THE PILL IS PROVEN TO PREVENT OVULATION IN ALL 50 WOMEN. • 1956:LARGE-SCALE HUMAN CLINICAL TRIALS OF THE PILL BEGIN, TO GAIN APPROVAL BY (FDA). PINCUS CHOOSES PUERTO RICO AS THE LOCATION BECAUSE IT A LARGE POOL OF POOR, UNEDUCATED WOMEN WHO CAN BE EASILY MONITORED. • 1957:THE FDA APPROVES USAGE OF THE PILL TO TREAT SEVERE MENSTRUAL DISORDERS. REQUIRES THAT ITS P.I. INCLUDE A WARNING THAT IT WILL PREVENT OVULATION. • 1960:THE PHARMACEUTICAL COMPANY G.D. SEARLE OBTAINS FDA APPROVAL TO SELL THE PILL AS A CONTRACEPTIVE IT BECOMES THE FIRST FDA-APPROVED DRUG TO BE GIVEN TO HEALTHY PATIENTS FOR LONG-TERM USE AND FOR SOCIAL PURPOSES.

HORMONES IN OCPS

ETHINYL ESTRADIOL PROGESTIN • THE ESTROGEN TYPICALLY CONTAINED IN ALL • THE TERM PROGESTIN IS USED FOR ANY COMBINATION BIRTH CONTROL PILLS NATURAL OR MAN-MADE SUBSTANCE THAT • WORK BY PREVENTING THE FORMATION OF A HAS PROPERTIES SIMILAR TO NATURAL FOLLICLE PROGESTERONE. CLASSIFIED BY ESTROGEN LEVEL: • ONE OF EIGHT KINDS OF PROGESTIN. • LOW DOSE PILLS (LEAST AMOUNT) (20 MCG) • INHIBIT THE LUTEINIZING HORMONE (LH) • REGULAR DOSE PILLS CONTAIN 30–35 MCG SURGE, WHICH IS REQUIRED FOR • HIGH DOSE PILLS HAVE ABOUT 50 MCG OVULATION

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ESTROGENIC EFFECTS

• ESTROGENIC ACTIVITY HAS TO DO WITH ETHINYL ESTRADIOL, • HIGHER NUMBER OF MICROGRAMS LEAD TO MORE POTENT ESTROGENIC EFFECTS. • HIGHER AMOUNT HELPS TO DECREASE ANDROGEN-RELATED SIDE EFFECTS. • HOWEVER, PROGESTINS TEND TO COUNTER SOME OF THE ESTROGENIC EFFECTS • PREVENTS THE RELEASE OF FOLLICLE-STIMULATING HORMONE (FSH) FROM THE ANTERIOR PITUITARY. WHEN KEPT LOW, A FOLLICLE IS NOT ABLE TO FORM AND OVULATION IS PREVENTED. • LUTEINIZING HORMONE AND THUS ANDROGEN PRODUCTION FROM THE OVARY, AND ENHANCES HEPATIC PRODUCTION OF SHBG, THEREBY REDUCING FREE PLASMA TESTOSTERONE.

TYPES OF PROGESTINS

• EACH HAS A DIFFERENT ACTIVITY A/O EFFECTS IN TERMS OF: • PROGESTATIONAL • ESTROGENIC • ANDROGENIC

• THE RESULT IS DEPENDENT ON THE COMBINATION OF THE TYPE AND LEVEL OF PROGESTIN AND THE LEVEL OF ESTROGEN

PROGESTATIONAL EFFECTS

• PROGESTATIONAL EFFECTS: REFERS TO HOW THE PROGESTIN STIMULATES THE PROGESTERONE RECEPTORS (THEREBY HELPING TO PREVENT OVULATION AND TO LESSEN MENSTRUAL BLEEDING).

• A PROGESTATIONAL SELECTIVITY, IS THE DEGREE TO WHICH PROGESTATIONAL EFFECTS ARE MAXIMIZED AND ANDROGENIC EFFECTS ARE MINIMIZED.

• *TYPICALLY, THE GOAL OF A BIRTH CONTROL PILL IS TO ACHIEVE A HIGH LEVEL OF PROGESTATIONAL SELECTIVITY

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ANDROGENIC EFFECTS:

• ANDROGENIC EFFECTS: THE LIKELIHOOD THAT THE PROGESTIN MAY CAUSE UNPLEASANT SIDE EFFECTS.

• HIGHER ANDROGENIC ACTIVITY: INCREASES THE CHANCES OF ANDROGEN- RELATED SIDE EFFECTS (MAINLY, ACNE AND HIRSUTISM)

• LESS ANDROGENIC ACTIVITY: LITTLE - NO EFFECT ON CARBOHYDRATE METABOLISM, WHICH IS HOW THE BODY BREAKDOWNS AND SYNTHESIZES SIMPLE SUGARS INTO SMALLER UNITS THAT CAN THEN BE USED BY THE BODY FOR ENERGY.

CLASSIFICATION OF PROGESTINS:

THE ESTRANE FAMILY THE GONANE FAMILY DROSPIRENONE FIRST GENERATION PROGESTINS SECOND GENERATION WHICH HAVE •THE NEWEST (4TH) GENERATION. (TYPICALLY) VARYING DEGREES OF ANDROGENIC IT DIFFERS BECAUSE IT IS DERIVED AND ESTROGENIC ACTIVITIES. CONSIST OF NORETHINDRONE AND FROM 17A-SPIROLACTONE, NOT OTHER PROGESTINS THAT METABOLIZE INCLUDES: LEVONORGESTREL FROM THE 19-NORTESTOSTERONE TO NORETHINDRONE. NORGESTREL. DERIVATIVES. THIRD GENERATION HAVE THE LEAST ANDROGENIC EFFECTS INCLUDES: NORETHINDRONE ACETATE INCLUDES: DESOGESTREL ETHYNODIOL DIACETATE NORGESTIMATE.

3RD GENERATION MAY CARRY A HIGHER RISK OF BLOOD CLOTS

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• FIRST-GENERATION PROGESTIN • LOW PROGESTATIONAL NORETHINDRONE • SLIGHT ESTROGENIC ACTIVITY • TENDS TO BE LESS ANDROGENIC THAN THE SECOND- GENERATION PROGESTINS (LEVONORGESTREL AND NORGESTREL), BUT MORE ANDROGENIC THAN NEWER PROGESTINS, LIKE DESOGESTREL. • IMPROVES LIPID PROFILES BY RAISING HDL AND LOWERING LDL. • AVAILABLE IN MONOPHASIC, BIPHASIC AND TRIPHASIC , FORMULATIONS. Ortho-Novum 7/7/7

• A FIRST-GENERATION PROGESTIN • MEDIUM PROGESTATIONAL ACTIVITY. ETHYNODIOL DIACETATE • IT HAS MINOR ESTROGENIC EFFECTS AND LITTLE ANDROGENIC ACTIVITY. • A DERIVATIVE OF NORETHINDRONE, SO IT IS EASILY CONVERTED TO NORETHINDRONE WITHIN THE BODY. • TEND TO BE ASSOCIATED WITH ^ EARLY OR MID-CYCLE BREAKTHROUGH BLEEDING AND SPOTTING • HOWEVER, HIGHER ESTROGEN DOSAGES CAN COUNTERACT THE LIKELIHOOD OF BREAKTHROUGH BLEEDING, SO PILL BRANDS THAT CONTAIN HIGHER LEVELS OF ESTROGEN CAN ALLEVIATE THIS SIDE EFFECT.

• FIRST-GENERATION PROGESTIN • LOW PROGESTATIONAL ACTIVITY NORETHINDRONE • SLIGHT ESTROGENIC AFFECTS. ACETATE • LESS ANDROGENIC THAN THE SECOND-GENERATION PROGESTINS, BUT MORE ANDROGENIC THAN NEWER PROGESTINS, LIKE DESOGESTREL. • “ESTROSTEP” WAS DESIGNED TO MORE CLOSELY MIMIC A WOMAN'S NATURAL MENSTRUAL CYCLE BY PROVIDING INCREASING LEVELS OF ESTROGEN WITH A CONSTANT PROGESTIN DOSE. • IT IS THE ONLY TRIPHASIC BRAND WITH THIS PROGESTIN. • HELPFUL FOR WOMEN WHO EXPERIENCE MINOR ESTROGEN-RELATED SIDE EFFECTS SUCH AS NAUSEA, MIGRAINES OR FLUID RETENTION WITH OTHER PILLS

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• A SECOND-GENERATION PROGESTIN NORGESTREL • A MIXTURE OF AN INACTIVE AND ACTIVE ISOMER -- DEXTRO-NORGESTREL (INACTIVE) AND LEVONORGESTREL (BIOLOGICALLY ACTIVE).

• HIGH PROGESTATIONAL • STRONG ANTI-ESTROGEN EFFECTS • HIGH IN ANDROGENIC ACTIVITY. • IT MAY CAUSE LDL CHOLESTEROL TO BE INCREASED WHILE ALLOWING FOR HDL CHOLESTEROL TO BE LOWERED.

• A SECOND-GENERATION PROGESTIN • THE MOST WIDELY PRESCRIBED CONTRACEPTIVE PROGESTIN LEVONORGESTREL WORLDWIDE. Levonorgestrel • HIGH PROGESTATIONAL AND ANDROGENIC EFFECTS. • LEVONORGESTREL NEGATIVELY AFFECTS SERUM LIPOPROTEINS. • SEVERAL LOW-DOSE ESTROGEN BRANDS CONTAINING THIS PROGESTIN ARE AVAILABLE. • APPROVED FOR EMERGENCY CONTRACEPTION (SUCH AS PLAN B ONE-STEP AND NEXT CHOICE). • THE FDA STATED ALL OCPS WITH THIS PROGESTIN ARE SAFE AND EFFECTIVE FOR EMERGENCY CONTRACEPTION UNDER THE YUZPE METHOD. • THE FDA HAS ALSO APPROVED THREE EXTENDED CYCLE PILL BRANDS THAT USE THIS PROGESTIN -- SEASONALE, SEASONIQUE, AND LYBREL.

• A THIRD-GENERATION PROGESTIN • HAS HIGH PROGESTATIONAL ACTIVITY WHILE SHOWING SLIGHT NORGESTIMATE ESTROGENIC EFFECTS • TENDS TO BE LESS ANDROGENIC. • MINIMAL EFFECT ON SERUM LIPOPROTEINS AND CARBOHYDRATE METABOLISM. • THE LOW ANDROGENIC EFFECTS SUCCESSFUL TREATMENT OF ACNE. • ARE THE ONLY ONE FDA APPROVED TO HELP REDUCE ACNE. • ORTHO TRI-CYCLEN LO IS MID-LEVEL DOSE OF ESTROGEN. • MAY BE HELPFUL IN LOWERING SIDE EFFECTS SUCH AS NAUSEA AND VOMITING WHILE NOT CAUSING AN INCREASED INCIDENCE OF SPOTTING (TYPICALLY ASSOCIATED WITH LOW- ESTROGEN PILLS).

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• A THIRD-GENERATION PROGESTIN • WITH HIGH PROGESTATIONAL SELECTIVITY, MINIMIZING DESOGESTREL ANDROGENIC EFFECTS AND ESTROGENIC ACTIVITY. • LESS NEGATIVE IMPACT ON METABOLISM, WEIGHT GAIN, ACNE, AND OTHER SIDE EFFECTS TYPICAL OF OLDER PROGESTINS. • IT SHOWS POSITIVE EFFECTS ON LIPOPROTEINS AS SEEN BY A SLIGHT RISE OF HDL CHOLESTEROL. • A POSSIBLY HIGHER RISK OF NON-FATAL VENOUS THROMBOSIS WITH DESOGESTREL PILLS VERSUS THOSE WITH LEVONORGESTREL. • MIRCETTE (A LOW-DOSE ESTROGEN/DESOGESTREL PILL) PROVIDES A SHORTER PLACEBO INTERVAL, WHICH MAY BE HELPFUL FOR WOMEN WHO HAVE MIGRAINES, DYSMENORRHEA, OR OTHER NEGATIVE ISSUES DURING THAT WEEK. • A LOW ESTROGEN/VARYING DESOGESTREL TRIPHASIC PILL, CYCLESSA, IS ALSO AVAILABLE

• IS THE ONLY PROGESTIN DERIVED FROM 17A-SPIROLACTONEIS. • IT HELPS SUPPRESS THE SECRETION OF THE HORMONES THAT DROSPIRENONE REGULATE THE BODY'S WATER AND ELECTROLYTES. • LOW ANDROGENIC ACTIVITY. • WITH ESTROGEN, LESSEN SYMPTOMS ASSOCIATED WITH MILD PMS (INCREASED APPETITE, NEGATIVE MOOD, AND WATER RETENTION). • MAY CAUSE HIGHER POTASSIUM LEVELS, SO WOMEN WITH KIDNEY, LIVER, OR ADRENAL DISEASE SHOULD NOT USE IT. • 24 DAYS OF ACTIVE PILLS AND 4 DAYS OF PLACEBO PILLS MAY CAUSE FEWER HORMONE FLUCTUATIONS THAN TYPICAL PILL PACKS. • “YAZ” FDA APPROVED TO HELP TREAT PREMENSTRUAL DYSPHORIC DISORDER AND TREAT MODERATE ACNE IN FEMALES AGED 14 YEARS AND UP. • NOT FROM THE 19-NORTESTOSTERONE DERIVATIVES. • INHIBITION OF OVARIAN AND ADRENAL ANDROGEN PRODUCTION, BLOCKAGE OF DHT BINDING TO SKIN ANDROGEN RECEPTORS, ELEVATION OF SHBG LEVELS, INCREASED TESTOSTERONE CLEARANCE FROM THE BODY, AND DECREASED 5Α-REDUCTASE ACTIVITY.

CHOOSING A BIRTH CONTROL PILL BY MINIMIZING ITS SIDE EFFECTS

Side Effect (Problem) Progestin/Estrogen/Androgenic Use These Pill Brands Effects (to minimize side effect)

Absent period or too light higher estrogen, lower progestin potency Brevicon, Modicon, Necon 1/35, Necon 1/50, Norinyl menstrual flow 1/35, Norinyl 1/50, Ortho-Cyclen, Ortho-Novum 1-35,Ortho-Novum 1/50, Ovcon 35

Acne higher estrogen, lower androgen potency Demulen 1/50, Brevicon, Mircette, Modicon, Necon, Othro-Cyclen, Ortho-TriCyclen, Yasmin

Break through bleeding higher estrogen, higher progestin potency, Demulen 1/50, Desogen, Ortho-Cept, Ovcon 50, Yasmin, (spotting) lower androgen potency Zovia 1/50E, Estrostep FE**

Breast soreness lower estrogen, lower progestin potency Alesse, Levlite

Depression lower estrogen, lower progestin potency Alesse, Brevicon, Levlite, Modicon, Necon 1/35, Ortho- Cyclen, Othro-TriCyclen, Ovcon 35,Tri-Levlen, Triphasil, Trivora

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CHOOSING A BIRTH CONTROL PILL BY MINIMIZING ITS SIDE EFFECTS

Side Effect (Problem) Progestin/Estrogen/Androgenic Use These Pill Brands Effects (to minimize side effect)

Endometriosis or lower estrogen, Demulen 1/35, Levlen, Levora, Loestrin 1.5/30, Loestrin endometriosis prevention higher progestin potency, 1/20 Fe, LoOvral, Nordette, Zovia 1/35E, higher androgen potency (continuously, no placebo pills or only 4 days of placebo pills for prevention) Headaches (not menstrual lower estrogen, lower progestin potency Alesse, Brevicon, Levlite, Modicon, Necon 1/35, migraines) Ortho-Cyclen, Othro-TriCyclen, Ovcon 35 , Tri- Levlen, Triphasil, Trivora

Moodiness or irritability lower progestin potency Alesse, Levlite, Loestrin 1/20 Fe, Yasmin, (or any pill with less estrogen than currently on)

Severe menstrual cramps higher progestin potency Demulen 1/35, Demulen 1/50, Desogen, Mircette, Loestrin 1.5/30, Ortho-Cept, Yasmin, Zovia 1/35E, Zovia 1/50E

Weight gain higher progestin potency Alesse, Levlite, Loestrin 1/20 Fe, Yasmin, (or any pill with less estrogen than currently on)

ADVERSE EFFECTS ASSOCIATED WITH TYPE OF HORMONAL ACTIVITY ESTROGENIC PROGESTATIONAL ANDROGENIC

BLOATING HEADACHES ACNE/OILY SKIN

NAUSEA/VOMITING BREAST PAIN/TENDERNESS WEIGHT GAIN BREAST FULLNESS HYPERTENSION HIRSUTISM BREAKTHROUGH BLEEDING FATIGUE IRRITABILITY DEPRESSION HEADACHES HYPERTENSION

ESTROGEN DOSE RELATED ADVERSE EFFECTS

EXCESS DEFICIENCY

• NAUSEA/VOMITING • EARLY CYCLE SPOTTING/BTB • BLOATING/EDEMA • AMENORRHEA • HYPERTENSION • VAGINAL DRYNESS • MIGRAINES • BREAST TENDERNESS • DECREASED LIBIDO • WEIGHT GAIN • HEAVY MENSTRUAL FLOW • LEUKORRHEA

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PROGESTIN DOSE RELATED ADVERSE EFFECTS

EXCESS DEFICIENCY • ACNE • LATE BREAKTHROUGH BLEEDING • ^ APPETITE/WEIGHT GAIN • AMENORRHEA • FATIGUE • HEAVY MENSTRUAL FLOW • HTN • DEPRESSION • HIRSUTISM • VAGINAL YEAST INFECTION

CONTRAINDICATION TO COMBINATION HORMONAL ACTIVITY ABSOLUTE CONTRAINDICATION RELATIVE CONTRAINDICATION

• HYPERSENSITIVITY • HYPERTENSION • KNOWN/SUSPECTED PREGNANCY • MIGRAINES • SMOKERS >35YEARS OLD > 15 CIGARETTES/ • DIABETES DAY • EPILEPSY • CEREBROVASCULAR OR CORONARY ARTERY DISEASE • OBSTRUCTIVE JAUNDICE IN PREGNANCY • THROMBOEMBOLIC DISORDERS: PE, MI DVT, • GALLBLADDER DISEASE STROKE, THROMBOPHLEBITIS • SURGERY WITH PROLONGED • KNOWN/SUSPECTED BREAST CANCER IMMOBILIZATION • UNDIAGNOSED AUB • SICKLE CELL DISEASE • MARKED LIVER FUNCTION IMPAIRMENT

POLYCYSTIC OVARIAN SYNDROME

• ONE OF THE MOST COMMON ENDOCRINOPATHIES IN REPRODUCTIVE-AGE WOMEN. • SPECTRUM OF DISORDERS WITH ANY COMBINATION OF OLIGO/ANOVULATION, CLINICAL AND/OR BIOCHEMICAL EVIDENCE OF ANDROGEN EXCESS, OBESITY, INSULIN RESISTANCE AND POLYCYSTIC OVARIES ON ULTRASOUND. • INHIBITION OF OVARIAN AND ADRENAL ANDROGEN PRODUCTION, BLOCKAGE OF DHT BINDING TO SKIN ANDROGEN RECEPTORS, ELEVATION OF SHBG LEVELS, INCREASED TESTOSTERONE CLEARANCE FROM THE BODY, AND DECREASED 5Α-REDUCTASE ACTIVITY. • USE OF OCP AND SPIRONOLACTONE FOR THE TREATMENT OF HIRSUTISM, AND THE HIGHLY EFFECTIVE METFORMIN IF THERE IS OBESITY AND EVIDENCE OF INSULIN RESISTANCE. • THESE ARE PRESCRIBED WITH EMPHASIS ON THE FACT THAT HEALTHY DIET AND REGULAR EXERCISE ARE THE BEST WAY TO TREAT PCOS SYMPTOMS AND PREVENT COMPLICATIONS OF OBESITY AND INSULIN RESISTANCE.

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PCOS TREATMENT

• ORAL CONTRACEPTIVE THERAPY IS USED TO REDUCE ANDROGEN AND LH LEVELS WITH RESULTANT IMPROVEMENT IN ACNE AND HIRSUTISM, AND THE INDUCTION OF REGULAR MENSES. • ANTI-ANDROGENS ARE USUALLY REQUIRED FOR A SUBSTANTIAL IMPROVEMENT IN HIRSUTISM SCORE. • INSULIN SENSITIZERS BY IMPROVING INSULIN SENSITIVITY AND DECREASING INSULIN LEVELS, WHICH ALSO HELPS TO INCREASE SHBG, DECREASE ANDROGEN LEVELS AND INDUCE OVULATION.

PCOS

• ENDOCRINOLOGIST STILL PREFER TO USE OCPS WITH LOW ANDROGENIC POTENTIAL: • DEMULEN 1/50® (USEFUL IN OBESE PATIENTS, WHO REQUIRE HIGHER DOSES OF ESTROGEN), • ORTHO-TRI-CYCLEN® (FDA APPROVED FOR TREATMENT OF ACNE IN WOMEN) OR • YASMIN®, WHICH CONTAINS DROSPIRENONE (SPIRONOLACTONE-RELATED, ANTI- MINERALOCORTICOID WITH ANTI-ANDROGENIC ACTIVITY).

HORMONE THERAPY FOR PERIMENOPAUSE & MENOPAUSE

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WHAT IS MENOPAUSE?

• A NORMAL, NATURAL EVENT, DEFINED AS THE FINAL MENSTRUAL PERIOD (FMP), CONFIRMED AFTER 1 YEAR OF NO MENSTRUAL BLEEDING • REPRESENTS THE PERMANENT CESSATION OF MENSES RESULTING FROM LOSS OF OVARIAN FOLLICULAR FUNCTION, USUALLY DUE TO AGING • NATURALLY (SPONTANEOUSLY) AVERAGE AGE 51.4 • PREMATURELY FROM MEDICAL INTERVENTION (BILATERAL OOPHORECTOMY, CHEMOTHERAPY) • AT ANY TIME FROM IMPAIRED OVARIAN FUNCTION

LIFETIME MENSTRUAL EVENTS

PREGNANCY MENOPAUSAL • AVERAGE AGE: 23 • AVERAGE AGE 51 • AVERAGE OLDEST AGE: 44 • AVERAGE DEATH RATE: 81/85 • CHILDBEARING YEARS: 21 • AVERAGE YEARS: 31 • AVERAGE MONTHS : 21 • PERIMENOPAUSE: 4 YEARS • MENARCHE AGE: 12.5 • OVER 1/3 LIFE

2012 CONSENSUS STATEMENT ON HORMONE THERAPY

• AGREE THAT THE DECISION TO INITIATE HORMONE THERAPY SHOULD BE FOR THE INDICATION OF TREATMENT OF MENOPAUSE RELATED SYMPTOMS.

• HORMONE THERAPY HAS AN IMPORTANT ROLE IN MANAGING SYMPTOMS FOR WOMEN DURING THE MENOPAUSAL TRANSITION AND IN EARLY MENOPAUSE.

Fertility and Sterility® Vol. 98, No. 2, August 2012

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2012 CONSENSUS STATEMENT FOR HORMONE THERAPY: OVERVIEW

• SYSTEMIC HORMONE THERAPY IS AN ACCEPTABLE OPTION FOR RELATIVELY YOUNG (UP TO AGE 59 OR < 10 YEARS OF MENOPAUSE)

• INDIVIDUALIZATION IS KEY

• CONSIDERATION SHOULD BE GIVEN TO QUALITY-OF-LIFE PRIORITIES AND PERSONAL RISK FACTORS: AGE, TIME SINCE MENOPAUSE, AND HER RISK OF BLOOD CLOTS, HEART DISEASE, STROKE, AND BREAST CANCER.

2012 CONSENSUS STATEMENT FOR HORMONE THERAPY: MEMBERS

• ACADEMY OF WOMEN'S HEALTH • ASSOCIATION OF REPRODUCTIVE HEALTH • AMERICAN ACADEMY OF FAMILY PROFESSIONALS PHYSICIANS, • THE ENDOCRINE SOCIETY • AMERICAN ACADEMY OF PHYSICIAN • NATIONAL ASSOCIATION OF NURSE ASSISTANTS, PRACTITIONERS IN WOMEN'S HEALTH, • AMERICAN SOCIETY FOR REPRODUCTIVE • MEDICINE NATIONAL OSTEOPOROSIS FOUNDATION, • THE AMERICAN ASSOCIATION OF CLINICAL • THE NORTH AMERICAN MENOPAUSE SOCIETY ENDOCRINOLOGISTS, • SOCIETY FOR THE STUDY OF REPRODUCTION, • AMERICAN MEDICAL WOMEN'S • SOCIETY OF OBSTETRICIANS & ASSOCIATION, GYNAECOLOGISTS OF CANADA, • ASOCIACION MEXICANA PARA EL ESTUDIO • SIGMA CANADIAN MENOPAUSE SOCIETY. DEL CLIMATERIO, Not on the list: American College of Obstetrics and Gynecology (ACOG)

HORMONAL THERAPY

• HRT INCREASED EXPONENTIALLY BETWEEN THE 1960S AND THE MIDDLE OF THE 1990S, • 1999 AN ESTIMATED 20 MILLION POSTMENOPAUSAL WOMEN WERE USING HRT WORLDWIDE. • THE POTENCY OF ESTROGENS IN HRT PREPARATIONS IS 6 TIMES LOWER THAN THE POTENCY OF ETHINYL ESTRADIOL CONTAINED IN CURRENTLY AVAILABLE OCPS • UNOPPOSED ESTROGEN REPLACEMENT IS ASSOCIATED ^ RATES OF ENDOMETRIAL HYPERPLASIA AND CANCER: WOMEN WITH UTERUS'S NEED TO PROTECT WITH PROGESTERONE, • WITH HYSTERECTOMY: ESTROGEN ALONE

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THE WHI……… WHY THINGS CHANGED

COMPOUNDS: DRUG QUALITY AND SECURITY ACT

• IN 2008, FDA TOOK ACTION AGAINST SEVEN COMPOUNDERS OF BHT FOR FALSE AND MISLEADING CLAIMS. • FDA FOUND THAT THE LEVELS OF HORMONES WERE NOT WHAT WAS STATED ON THE PRESCRIPTION • IN 2013, AFTER AN OUTBREAK OF INFECTIONS AND SOME RESULTING DEATHS FROM A COMPOUNDED DRUG, CONGRESS PASSED THE DRUG QUALITY AND SECURITY ACT • COMPOUNDERS THAT MAKE UP ANY HORMONE PRESCRIPTION CONTAINING ESTRIOL (WHICH IS NOT AN FDA-APPROVED DRUG) MUST OBTAIN AN INVESTIGATIONAL NEW DRUG APPLICATION (IND)

ESTROGENS USED IN HRT

CONJUGATED EQUINE ESTROGENS (CEE/CE) MICRONIZED ESTRADIOL • COMPLEX COMPOSITION OF AT LEAST 9 • 17 BETA ESTRADIOL DIFFERENT ESTROGENS • ESTERIFIED ESTROGEN • 1.25 MG OF CCE BEING EQUIVALENT TO MUCH LESS THAN 50 MICRG OF ETHINYL ESTRADIOL

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HT STARTING DOSAGES • LOWER DAILY DOSES TYPICALLY USED WITH SYSTEMIC ET: • 0.3 MG ORAL CE/CEE • 0.5 MG ORAL MICRONIZED 17ß-ESTRADIOL • 0.014-0.025 MG TRANSDERMAL 17ß-ESTRADIOL PATCH

• TYPICAL LOWEST DOSES OF PROGESTIN: • 1.5 MG ORAL MEDROXYPROGESTERONE ACETATE • 0.1 MG ORAL NORETHINDRONE ACETATE • 0.5 MG ORAL DROSPIRENONE • 50 MG ORAL MICRONIZED PROGESTERONE

NAMS position statement. Menopause 2010.

ESTROGEN THERAPY PRODUCTS APPROVED FOR POSTMENOPAUSAL USE IN THE US

Oral products Composion Product name(s) Range of available dose strengths Conjugated equine Premarin 0.3-1.25 mg estrogens Synthec conjugated Cenesn 0.3-1.25 mg estrogens, A* Synthec conjugated Enjuvia 0.3-1.25 mg estrogens, B** Esterified estrogens Menest, EstraGyn 0.3-1.25 mg 17β-estradiol + Estrace, various 0.5-2.0 mg generics Estradiol acetate Femtrace 0.45-1.8 mg Estropipate Ortho-Est, Ogen 0.625 mg (0.75 mg estropipate, calculated as sodium estrone sulfate 0.625 mg) to 5.0 mg (6.0 mg)

Transdermal products Composion Product name(s) Dose details 17β-estradiol matrix Alora, Climara, Esclim, 0.014-0.1 mg delivered daily; patch Fempatch, Menostar, applied once or twice weekly Minivelle, Vivelle, Vivelle- Dot, various generics

17β-estradiol reservoir Estraderm 0.05-0.1 mg delivered daily; patch applied twice weekly

17β-estradiol EstroGel, Elestrin, Divigel Applied daily via metered pump or transdermal gel packet delivering 0.52-0.75 mg of 17β- estradiol in gel 17β-estradiol topical Estrasorb 2 packets applied daily emulsion 17β-estradiol Evamist 1 spray/d, up to 2-3/d if needed transdermal spray

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Vaginal products Composion Product name(s) Dose details 17β-estradiol vaginal cream* Estrace Vaginal Cream Inially 2-4 g/d for 1-2 wk, followed by Vulvovaginal atrophy (VVA) maintenance dose of 1 g/d (0.1 mg acve ingredient/g) Conjugated estrogens cream* Premarin Vaginal Cream For vaginal atrophy: 0.5-2 g/d for 21 d then off 7 d Atrophic vaginis, For dyspareunia: 0.5 g/d for 21 d then off 7 d , or moderate-severe dyspareunia twice weekly (0.625 mg acve ingredient/g)

17β-estradiol vaginal ring Estring Device containing 2 mg releases Moderate-severe VVA 7.5 µg/d for 90 days (for vulvovaginal atrophy) Estradiol acetate vaginal ring Femring Device containing 12.4 mg or 24. 8 mg estradiol Vasomotor symptoms, severe acetate releases 0.05 mg/d or 0.10 mg/d estradiol VVA for 90 days (both doses release systemic levels for treatment of vulvovaginal atrophy and vasomotor symptoms) Estradiol hemihydrate vaginal Vagifem Inially 1 tablet/d for 2 wk, followed by 1 tablet tablet twice weekly (tablet 10 µg of estradiol Atrophic vaginis hemihydrates, equivalent to 10 µg of estradiol; for vulvovaginal atrophy)

*N.B. Higher doses of vaginal estrogen are systemic, meant to relieve hot flashes as well as vaginal atrophy; the lower doses are intended for vaginal symptoms only even though a small amount does get absorbed.

Combinaon EPT products comparing estrogen and progesn doses Product name(s) Estrogen Progestogen Prempro, PremPhase,PremPlus 0.3, 0.45 0.625 mg conjugated 1.5, 2.5 or 5 mg MPA Estrogens Femhrt 5 µg ethinyl estradiol 0.5, 1 mg norethindrone acetate (Ortho Novum 1/35, LoEstrin, Estrostep, Junel)

Acvella 0.5, 1 mg 17β-estradiol 0.1, 0.5 mg norethindrone acetate

Angeliq (Yasmin, Yaz, B-Yaz) 0.25, 0.5 mg 17β-estradiol 0.5, 1 mg Drospirenone

CombiPatch 0.05 mg 17β-estradiol 0.14, 0.25 mg norethindrone acetate Twice a week Climara Pro 0.045 mg 17β-estradiol 0.015 mg Levonorgestrol Once a week

Other Oral products

Product name(s) dosage Estrogen Other Duavee Moderate- sever vasomotor 0.45 conjugated Bazedoxifene 20mg symptoms estrogens

Osphena moderate-severe dyspareunia None Ospemifene 60mg

Brisdelle Moderate-severe vasomotor None Paraxene 7.5mg symptoms

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NON-HORMONAL PRESCRIPTION DRUGS (OFF-LABEL USE):

• ANTICONVULSANT: GABAPENTIN (NEURONTIN) • ANTIDEPRESSANT • SSRI: FLUOXETINE (PROZAC), PAROXETINE (PAXIL), ESCITALOPRAM (LEXAPRO) • SNRI: VENLAFAXINE (EFFEXOR XR) AND DESVENLAFAXINE (PRISTIQ) • ANTIHYPERTENSIVE: CLONIDINE (CATAPRES) • HYPNOTIC: ESZOPICLONE (LUNESTA) • NEUROPATHIC PAIN DRUG: PREGABALIN (LYRICA)

HORMONE TESTING

• TESTING HORMONE LEVELS IS NOT REQUIRED • THE OPTIMAL HORMONE LEVELS HAVE NOT BEEN ESTABLISHED. • SYMPTOMS RESPONSE TO A PARTICULAR IS THE ONLY RELIABLE GUIDE. • SALIVA TESTING IS NOT ONLY UNNECESSARY AND NOT BEEN PROVEN TO BE ACCURATE OR RELIABLE. • BECAUSE HORMONE LEVELS VARY DAY TO DAY AS WELL AS THROUGHOUT THE DAY, EVEN A BLOOD TEST CANNOT ACCURATELY REFLECT THE BODY’S HORMONE LEVELS. • THE COMMON HORMONE TEST THAT MAY BE FSH TO HELP DETERMINE IF A WOMAN IS IN MENOPAUSE

REFERENCES

• RICE,C., THOMPSON,J. ELECTING AND MONITORING HORMONAL CONTRACEPTIVES: AN OVERVIEW OF AVAILABLE PRODUCTS. 6/20/2006. USPHARMACIST.COM/CONTENT/D/FEATURED_ARTICLES/C/ 11635/#STHASH.D8CDJD0K.DPUF • BOSTON COLLABORATIVE DRUG SURVEILLANCE PROGRAM, BOSTON UNIVERSITY MEDICAL CENTER, SURGICALLY CONFIRMED GALLBLADDER DISEASE, VENOUS THROMBOEMBOLISM, AND BREAST TUMORS IN RELATION TO POSTMENOPAUSAL ESTROGEN THERAPY. N ENGL J MED. 1974;29015- 19 • GOMES, M.; DEITCHER, S. RISK OF VENOUS THROMBOEMBOLIC DISEASE ASSOCIATED WITH HORMONAL CONTRACEPTIVES AND HORMONE REPLACEMENT THERAPY:A CLINICAL REVIEW ARCH INTERN MED. 2004;164(18):1965-1976.

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