1 The Pharmacological Management of Peri-Menopause and Menopause Debora Bear, FNP, MSN, MPH University Of New Mexico Hospital Hormones and other Treatments

2 Gwen Iffil, Stepmber 29, 1955 to November 14, 2016 Peabody Award-Winning Journalist Endometrial/Uterine Cancer new cases 7% of all cancers, 60,050 cases, death 4%, cervical cancer 12,990 cases, death (not in top 10), ovarian 22, 280 cases, 5% of all death for women

3 Disclosure Statement I have no real or perceived vested interests that relate to this presentation nor do I have any relationships with pharmaceutical companies, biomedical device manufacturers, and/or other corporations whose products or services are related to pertinent therapeutic areas. I will discuss some evidenced-based treatments that are not FDA approved.

4 Objectives: Following this knowledge-based presentation, the pharmacist participants will be able to: Choose safe and effective contraceptive options as per CDC/WHO medical eligibility criteria Choose safe and effective prescriptions among the available drug categories for vasomotor symptoms Choose safe and effective prescriptions for vaginal health Choose safe and effective prescriptions for bone health Review a variety of other medical issues and evidence for potential prevention and treatment of peri-menopausal and menopausal issues Following this knowledge-based presentation, the pharmacy technician participants will be able to: Aid the pharmacist in reviewing CDC/WHO medical eligibility criteria in order to safely choose safe and effective contraceptive options Review safe and effective prescriptions as well as benefits and risks of hormones nad other treatments for vasomotor symptoms Review safe and effective prescriptions for vaginal health Review safe and effective prescriptions for bone health Review safe and effective treatments for a variety of other symptoms associated with peri-menopause and menopause

5 Does not get mammograms due to concern for “radiation exposure”.Case study: 63 year old woman requests a refill of her “bio identical hormone” prescription. She takes this for her duodenitis, tendon pain, urinary incontinence, skin, hot flashes (she has tried EVERYTHING else and it is the ONLY thing that works), memory, leg swelling, varicose veins, bloating (had terrible IBS prior), osteopenia, and vaginal dryness. Does not get mammograms due to concern for “radiation exposure”. This patient, who was sent to me by a co-worker, exemplifies the challenge I face promoting health in some patients.

6 Describe the most common medical issues associated with peri-menopause and menopauseConsequences of decreased estrogen: cardiovascular changes, osteoporosis, lower urinary tract changes, alterations in cognitive function, sleep disturbances, depression/mood changes, vasomotor instability, vaginal atrophy, skin, hair, and nail changes

7 I have female patients in the 30s and 40s present with vasomotor symptoms who request hormonal panels to see if their symptoms are from perimenopause .

8 When is menopause Premature < 40 (1%),For women who miss three or more consecutives menses, measure HCG, FSH, estradiol, prolactin, TSH Consider AMH level, vaginal ultrasound, Karyotype and testing for fragile x permutation, thyroid peroxidase antibodies, adrenal antibodies, fasting glucose, serum calcium and phosphorus levels If not contraindicated: consider estrogen treatment early < 40 < 45 (5%) median age 52 There are no standard blood tests recommended for early or normal menopause. Most of today’s talk will focus on normal menopause. AMH = anti-Mullerian Hormone

9 Describe the most common medical issues associated with peri-menopause and menopauseNeed for use until 12 months after FMP 60%-85% (varies by culture): treat with hormone replacement, SSRIs and SNRIs, CBT Systemic replacement may not impact Estrogen & decreased risk of hip fracture Estrogen & stroke risk, memory not improved with HRT? Unopposed estrogen associated with endometrial cancer, Selective Estrogen Receptor Modulators decrease breast cancer Contraception Vasomotor Symptoms/ Mood Vaginal Bone Other: cardiovascular, memory, cancer The only reliable determination of menopause is 12 months of no menses off hormones. It is estrogen withdraw, rather than low circulating estrogen levels, that is the central change leading to hot flashes. Median duration of hot flushes is 12.2 years. Hormone replacement is the most effective treatment for vasomotor symptoms, but there are other treatments. Replacing estrogen helps with some menopausal medical conditions, but may not improve others and has risks.

10 Contraception During Peri-MenopauseMethods -CHC (Pills/Patch/Ring) -Progestin Only -LARC -Barrier Methods Other Benefits from Hormonal Contraception Key Points: Review Medical Eligibility Criteria Option to treat hot flashes When to use/when to stop/remove Femcap, Diaphragm, condoms Treats irregular uterine bleeding, reduce vasomotor symptoms, decrease ovarian and endometrial cancer, maintain bone mineral density Blood tests on or off contraceptive methods will not diagnosis menopause. CHC is combined hormonal contraception (estrogen and progesterone). There is a “new” diaphragm – “Caya”

11 United States Medical Eligibility Criteria (US MEC) for Contraceptive Use, 2016This is a very busy slide demonstrating medical eligibility criteria. Based on global guidance from the World Health Organization, CDC published the first US MEC in 2010 followed by the US SPR in Title X, endorsed by ACOG, and disseminated widely to women’s health, adolescent, and primary care providers. Use this as a reference to check on medical conditions that become more frequently seen later in a woman’s life. Think about increasing cardiovascular risk (how long have has the woman been a diabetic), migraines with aura, smokers.

12 Contraception: Case StudyA Fifty two year old woman presents for her “annual”. She is on a CHC and has menopause questions.

13 FSH at the end of the placebo time off the CHCIn a 52 year old woman, what testing can be offered to know when to stop the CHC? FSH while on the CHC FSH at the end of the placebo time off the CHC Stop the CHC and wait to see if there is no menses for 12 months Old text books recommend checking levels and reference menopause can be defined by levels of 17-B estradiol (less than 40pg/ml), and FSH (more than 40 mIU) Response Counter

14 For how long do you do you recommend to continue a CHC?Stop before or at least by age 52 Review medical eligibility criteria and continue through menopause Offer a non-hormonal method of contraception Both b and c Response Counter

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16 Treatments for Vasomotor SymptomsHormones SSRI/SNRI Gabapentin Clonidine Others: Isoflavones Botanicals Acupuncture Behavioral Estrogen most effective treatment Contra-indications (heart disease, breast cancer, active liver disease, thromboembolic disease) Shortest duration (< 4 yrs) Low dose: < 0.3mg CE, < 5mg oral micronized estradiol < μg transdermal estradiol, or < 0.25 μg ethinyl estradiol Progestogen required for women with a uterus FDA-Paroxetine(SSRI) 7.5mg-25mg (not w/Tamoxifen) Venlafaxine XL(SNRI) 37.5, 75, 150mg 900mg mg Studies are poor to good showing these are not effective more than placebo May help some women May provide relief when done for 20min 3xa day Do not prescribe Paroxetine in women taking Tamoxifen

17 Review over-the-counter and non-pharmaceutical treatmentsReview over-the-counter and non-pharmaceutical treatments. Many are no more effective than placebo, but non-harmful. Take a good look at cost. Provide Essential oil example.

18 Beliefs about what is “Natural”Fewer than 1 in 3 women choose to take conventional hormone treatment At least 36% of Americans use some form of complementary/alternative medicine (> 60% if prayer & megavitamins for health factored in) The media, and not women’s healthcare practitioners, have been the primary source of information concerning hormone benefits and risks The end product, physiologic effect, should be the concern Natural= Believed to be plant derived, not synthesized. Made without chemicals. Associated with fewer or no risks or adverse effects. It is equally or more effective than conventional hormone therapy Treats & prevents osteoporosis & has no heart disease risk The discrepancies between the Women’s Health Initiative and the Nurse’s Health Study have confused health care clinicians. There is wide spread mistrust of women’s health care clinicians and women are turning to alternative treatments.

19 What are Bioidentical HormonesDiosgenin extrated from high-yield soy and Mexican yams (Dioscorea) and chemically converted into progesterone History: 1930s the first BH preparations were both natural and bioidentical, they were derived from human pregnancy urine Estriol (biest/triest): currently component in most BHT. Considered by proponents to be “gentler and protective” Claim to Individualize therapy based on hormone levels Saliva tests provide poor reproducibility, lack evidence supporting the stability of samples in storage and handling, and are subject to large interassay variability. Hormone levels in saliva may vary depending on diet, time of day, the hormone being tested, and changes in other variables such as secretion rate. Much of the physiological effects are determined at the cellular level and not the sera level High failure rate of compounded progestin which is solely prescribed to protect women from estrogen-associated effects on endometrial tissue

20 There is some evidence that they may be more dangerousThere is some evidence that they may be more dangerous. North American Menopause Society, National Institute of Health, FDA, among others, recommend against prescribing bio identical hormones.

21 Table 1. Common Hormone Therapies for Relief of Menopausal Related SymptomsGeneric Brand Name Available generic Strength (mg) Route of Administration Indications Dosing Source of active ingredients FDA approved Bioidentical Branded hormone therapeutics Estrogen alone Conjugated estrogens Genestin No 0.625 0.9 Oral Moderate-severe VmS Continuous daily Synthesized from soy and yams Yes Conjugated synthetic estrogens Enjuvia 0.3 0.45 1.25 Synthesized from soy and Mexican yams Yams Premarin Moderate-severe VmS; moderate-severe vulval and vaginal atrophy Pregnant mares’ urine Vaginal cream Atrophic vaginitis; kraurosis vulvae Esterified estrogens (estrone, equiline) Menest 2.5 Moderate-severe VmS; atrophic vaginitis; kraurosis vulvae Micronized estradiol (estrone, equiline) Estrace 0.5 1 2 Moderate-severe VmS; atrophic vaginitis; kraurosis vulvae Prev.o st. Estropipate Ogen Moderate-severe VmS; moderate-severe vulvar and vaginal atrophy; Prev.o st. Continuous Synthesized from Mexican yams Ortho-Est Moderate-severe VmS; moderate-severe vulvar and vaginal atrophy; Prev.o st Synthesized from yams Estradiol Alora 0.025 0.05 0.075 0.1 Transdermal patch Twice weekly Synthetic? Climara 0.0375 Once weekly Synthesized from soy The following tables are for reference. This is the most comprehensive chart reviewing available products. I have patients object to a product made from pregnant mare’s urine. It may be possible to find a product that is both acceptable to the patient as well as medically appropriate to prescribe.

22 Table 1. Common Hormone Therapies for Relief of Menopausal Related SymptomsGeneric Brand name Available generic Strength (mg) Route of administration Indications Dosing Source of active ingredients FDA approved Bioidentical Estradiol Estraderm No 0.05 1 Transdermal patch Moderate-severe Vms; moderate-severe vulvar and vaginal atrohophy; Prev. o st. Continuous twice weekly Synthesized from Mexican yams Yes Estring 2 delivers 7.5μg/day Vaginal ring Moderate-severe vulvar and vaginal atrhophy Continuous q90 days Vivelle Vivelle-Dot 0.025 0.0375 0.075 0.1 Transdermal patch Estradiol acetate Femring 0.01 /day Moderate-severe VmS Continuous q3-months Synthesized from soy (prodrug converts to estradiol) Femtrace 0.45 0.9 1.8 Oral Continuous Yes (prodrug converts to estradiol) Estradiol cypionate Depo-Estradiol 5 Injection (in oil) Q3-4 weeks Cyclic Synthetic? Estradiol hemihydrate Estrasorb 8.7 (two 1.74-g pkgs) deliver 0.5/day Topical emulsion (micellar nanoparticle) Continuous daily Vagifem Vaginal tablet Atrophic vaginitis Continuous daily for 2 weeks twice weekly after Estradiol valerate Delestrogen Injection (in oil) Continuous q4 weeks cyclic Valergen- 10,20, or 40 10 20 40 Synthetic

23 Table 1. Common Hormone Therapies for Relief of Menopausal Related SymptomsGeneric Brand name Available generic Strength (mg) Route of administration Indications Dosing Source of active ingredients FDA approved Bioidentical Etinyl estradiol Estinyl No 0.02 0.05 0.5 Oral Moderate-severe VmS Continuous Syntehsized from soy and yams Yes Branded hormone therapeutics: Progestogens Medroxypro-gesterone acetate Amen 10 To reduce risk of endometrial hyperplasia in postmenopausal women who are taking estrogen and have an intact uterus Secondary amenorrhea Abnormal uterine bleeding due to hormonal imbalance Cyclic continuous Synthesized from soy or yams Medroxypro-gesteron acetate Cycrin 2.5 5 Provera oral Micronized progesterone Crinone 4% w/w (45); 8% w/w (90) Vaginal gel Synthesized from Mexican yams Prometrium 100 200 Norethindrone acetate Aygestin Cyclic Synthesized from soy Branded hormone therapeutics: Estrogens + progestogens Conjugated estrogens PremPhase CE MPA Moderate-severe VmS; moderate-severe vulval and vaginal atrophy; Prev. Ost. Pregnant mares’ urine Synthesized from soy and yams Congugated estrogens PremPro CE MPA Continuous combined

24 Table 1. Common Hormone Therapies for Relief of Menopausal Related SymptomsGeneric Brand name Available generic Strength (mg) Route of administration Indications Dosing Source of active ingredients FDA approved Bioidentical Esterified estrogens EstraTest No 1.25 2.5 Oral Moderate-severe VmS in patients not responsive to estrogen alone Continuous combined Synthesized from soy and yams Yes Methyltestosterone HS 0.625 Estradiol Activella 1 0.5 Moderate-severe VmS; moderate-severe vulval and vaginal atrophy; Prev. Ost. Norethindrone acetate Synthesized from soy Combi-patch E2 NETA Transdermal patch Moderate-severe VmS; moderate-severe vulval and vaginal atrophy 0.05/0.25/E2/ Continuous combined 0.05/0.14 or Synthesized from NETA per day Continuous cycling is achieved using Vivelle Mexican yams OrthoPrefest Tablet 1 Tablet 2 Pulsed Tablet 1 (days 1-5) Tablet 2 (days 4-6) and repeat Norgestimate Ethinyl estradiol Femhrt EE NETA Moderate-severe VmS; Prev. Ost. Continuous Branded hormone therapeutics: Testosterone Testosterone Androderm 5 NAMS: low libido Androgel 25 50 Testoderm 4 6 5 mg/day Synthetic?

25 Table 1. Common Hormone Therapies for Relief of Menopausal Related SymptomsGeneric Brand name Available generic Strength (mg) Route of administration Indications Dosing Source of active ingredients FDA approved Bioidentical Testosterone cypionate Depo-test-osterone Yes 100 mg/mL IM Low libido Twice/month Synthetic Yes (prodrug is metabolized into BH) Testosterone enanthate Delatestryl 100mg/mL 200mg/mL Synthetic? Compounded hormone therapeutics: Estrogens, progesterone, testosterone Estradiol Estriol Estrone (triest) N/A, Compounded Customized (usually 1.25, 2.5, 5) Customized for each patient, criteria vary: saliva, sera levels, or symptoms (usually 1.25, 2.5, 5) Oral, trans-dermal; sublingual, vaginal Claims vary Assumed: moderate-severe VmS/moderate-severe vulvar and vaginal atrophy Continuous twice daily (Claimed to be less commonly used due to Estrone content Synthesized from soy No (biest) Continuous twice daily, commonly 1.25 mg BID N/A, compounded Customized for each patient, criteria vary: saliva, sera levels, or symptoms Continuous

26 Table 1. Common Hormone Therapies for Relief of Menopausal Related SymptomsGeneric Brand name Available generic Strength (mg) Route of administration Indications Dosing Source of active ingredients FDA approved Bioidentical Progesterone N/A, compounded Customized for each patient, criteria vary: saliva, sera levels, or symptoms Oral, trans-dermal; sublingual, vaginal, injectable Claims vary FDA: protection from estrogen-associated endometrial hyperplasia and adenocarcinomas Continuous cyclic Synthesized from soy or yams Yes Testosterone NAMS: decreased libido; NAMS does not recommend the use of compounded product Continuous Synthesized from soy Oral and IM only Testosterone propionate IM Monthly Twice/month Synthetic? Yes (prodrug is metabolized into BH)

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28 Vasomotor: Case Study A fifty three year old woman presents for an annual check-up. She is two years post-menopausal, is currently taking Paroxetine for well controlled depression. She has no other chronic medical problems and was referred by her primary to talk about potential treatments for hot flashes. Vital signs include b/p 112/62 and bmi of 25. She has had yearly mammograms that are normal. This is another “true story”. Referral made by my medical director because “Debora” knows about that female stuff.

29 Oral estrogen Black Cohosh Vaginal estrogen ParoxetineThe patient would like to know what is the most effective method for vasomotor symptoms Oral estrogen Black Cohosh Vaginal estrogen Paroxetine Oral estrogen is the most effective. In her case, she had no contraindications. Black Cohosh probably would not help that much, but would not be contraindicated. Vaginal estrogen would probably not impact hot flashes. Paroxetine and Venlafaxine may be helpful, but she is already on Paroxetine. Response Counter

30 Sertraline Venlafaxine Paroxetine Oral EstrogenFor women with breast cancer who are taking Tamoxifen, what can be prescribed for vasomotor symptoms? Sertraline Venlafaxine Paroxetine Oral Estrogen Paroxetine inhibits Tamoxifen activity. Sertraline would not be contraindicated, but may not be effective. Oral estrogen is contraindicated.

31 My anecdotal contribution is far more than 20% of postmenopausal women experience urinary symptoms. I regularly ask about this during Pap smears especially.

32 Vaginal: vulvar & vaginal atrophy (dryness, dysparenunia, and atrophic vaginitis)Treatments OTC Water/Silicone based moisturizers & lubricants Topical Hormones Ospemifene (Selective Estrogen Receptor Modulator) Use moisturizers daily, use lubricants with sex Ring may be absorbed less systemically Treats moderate to severe dyspareunia, associated with ↑ hot flashes, ↑ stroke & thromboembolic events

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35 Vaginal Case Study Sixty-One year old woman with Rheumatoid arthritis. History of frequent clinic visits for dysuria and negative lab studies to support urinary infections. Had not been having sex for years. Vaginal exam with pale, dry introitus, rugae not present. BMI 42 I see patients that have been treated for recurrent urine infections or recurrent BV who have not had a vaginal exam. Some have been placed on preventive antibiotics which did not resolve their symptoms

36 What options are available to treat her atrophic vaginitis?Water or silicone-based moisturizers and lubricants Topical vaginal estrogens SERMs All of the above Patients BMI and pain from her Rheumatologic disorder physically prevented her from touching her vagina. Ultimately a vaginal ring was prescribed and she comes to clinic every three months for me to remove the old and insert a new ring for her. Response Counter

37 Differential of vulvar disease includes Lichen sclerosis, lichen simplex chronicus, psoriasis, Lichen planus, eczema, contact dermatitis. None of these are treated with testosterone.

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39 Bone Estrogen Calcium Vitamin D Decreased risk of hip fracture? Consider use for prevention Increasing calcium intake, through calcium supplements or dietary sources, should not be recommended for fracture prevention Estrogen Selective Estrogen Receptor Modulators: Raloxifene and Bazedoxifene (use with CE in women with a uterus) Calcium Vitamin D HT may be used conditionally for the prevention of osteoporosis when other interventions have been considered and are deemed inappropriate. In September, 2015 BMJ published “Calcium intake and risk of fracture: systematic review” which reversed years of recommendations to increase calcium in order to prevent fractures. The exception is for frail elderly women in extended care facilities.

40 Source: ARHP Details Talking Points: The diagnosis of osteoporosis is established by measurement of BMD or by the occurrence of adulthood hip or vertebral fracture in the absence of major trauma. Bone density test results are reported in two numbers, the Z-score and the T-score. The Z-score is the number of standard deviations above or below what is normally expected for someone of equivalent age, sex, weight, and ethnic or racial origin. The T-score is a patient’s bone density compared with the optimal peak bone density of a healthy young adult (30 years old) of the same sex. The T-score is the number of units (standard deviations) that your bone density is above or below the average. The more standard deviations below 0, indicated as negative numbers, the lower the BMD and the higher the risk of fracture. According to the International Society for Clinical Densitometry (ICSD): For BMD reporting in premenopausal females, the Z-score is preferred For BMD reporting in postmenopausal females, the T-score is preferred.

41 FDA, ACOG, NAMS: “do not use HT to prevent or treat osteoporosis”

42 Other Cardiovascular CognitiveNeither the prevention or primary or secondary CHD or dementia and cognitive decline has ever been an FDA-approved indication for HT

43 Does not get mammograms due to concern for “radiation exposure”.Case study: 63 year old woman requests a refill of her “bio identical hormone” prescription. She takes this for her duodenitis, tendon pain, urinary incontinence, skin, hot flashes (she has tried EVERYTHING else and it is the ONLY thing that works), memory, leg swelling, varicose veins, bloating (had terrible IBS prior), osteopenia, and vaginal dryness. Does not get mammograms due to concern for “radiation exposure”. The patient went for a mammogram. The results were initially BI-RADS 0. She returned to me requesting bio identical hormones. I referred her to a breast specialist. She did present to the breast specialist for care and again requested bio-iidentical hormones. Her imaging was re-read and interpreted as BI-RADS 4 and a diagnostic biopsies were ordered. She failed to return for follow-up to have the biopsies or to see me or her primary.

44 References: Alternative Medicine for Menopause. Endocrine Society. 2012 Association of Reproductive Health Professionals Bio-Identicals: Sorting Myths from Facts. U.S. Food and Drug Administration. 2004 Bioidentical Hormone Therapy: A Review of the Evidence. Journal of Women’s Health. 2007; 16(5) Calcium intake and risk of fracture: systematic review. The BMJ 2015; 351 Charting a Course Through Changing Tides: An Evidence-Based Examination of Hormone Therapy in Women’s Health. Compounded Bioidentical hormone therapy: time for a reality check? Andrew Kaunitz, Menopause, September 2015 Contraception. journal.org. Official Journal of Association of Reproductive Health Professionals. Vol 94,Number6, December 2016 The Endocrine Society Re-Issues Position Statement on Bioidentical Hormones, April, 2016 Global Consensus State Hormone Therapy. Endocrine Society. 2013 The Kronos Early Estrogen Prevention Study. Women’s Health (1):9-11 -care-recommendations NIH Asks Participants in Women’s Health Initiative Estrogen-Alone Study to Stop Pills, Begin Follow-up Phase. Barbara Alving. March 2, 2004. Perspectives in Prevention From the American College of Preventive Medicine U.S. Medical Eligibility Criteria for Contraceptive Use, 2016 The Women’s Health Initiative: The Role of Hormonal Therapy in Disease Prevention, Robert Wallace, 3(1), 2005