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

Objectives:

1. Describe the most common medical issues associated with menopause

2. Apply the scientific evidence regarding the risks and benefits of medical therapies as well as risks and benefits of alternative treatments 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”. Describe the most common medical issues associated with peri-menopause and menopause

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 Describe the most common medical issues associated with peri-menopause and menopause

• • Contraception Need for use until 12 months after FMP

• • Vasomotor Symptoms/ 60%-85% (varies by culture): treat with hormone replacement, SSRIs and SNRIs, CBT • Mood

• Vaginal • Systemic replacement may not impact • Bone • Estrogen & decreased risk of hip fracture

• Estrogen & stroke risk, memory not improved • Other: cardiovascular, memory, cancer with HRT?

• Unopposed estrogen associated with endometrial cancer, Selective Estrogen Receptor Modulators decrease breast cancer Contraception During Peri-Menopause

Methods Key Points:

-CHC (Pills/Patch/Ring) • Review Medical Eligibility Criteria

-Progestin Only • Option to treat hot flashes

• When to use/when to remove

-LARC

-Barrier Methods • Femcap, Diaphragm, condoms

Other Benefits from • Treats irregular uterine bleeding, reduce Hormonal Contraception vasomotor symptoms, decrease ovarian and endometrial cancer, maintain bone mineral density

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

Treatments for Vasomotor Symptoms

• Hormones • 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 < 0.25 µg transdermal estradiol, or < 0.25 µg ethinyl estradiol • Progestogen required for women with a uterus • SSRI/SNRI • FDA-Paroxetine(SSRI) 7.5mg-25mg (not w/Tamoxifen) • Venlafaxine XL(SNRI) 37.5, 75, 150mg • Gabapentin • 900mg • Clonidine • 0.05-0.15mg • Others:

Isoflavones • Studies are poor to good showing these are not effective more than placebo Botanicals

Acupuncture • May help some women

Behavioral • May provide relief when done for 20min 3xa day

Beliefs about what is “Natural”

• Fewer than 1 in 3 women choose • Natural= Believed to be to take conventional hormone plant derived, not treatment synthesized. Made without chemicals. • At least 36% of Americans use some form of complementary/ alternative medicine (> 60% if • Associated with fewer or prayer & megavitamins for no risks or adverse health factored in) effects. It is equally or more effective than • The media, and not women’s conventional hormone healthcare practitioners, have therapy been the primary source of information concerning hormone benefits and risks • Treats & prevents osteoporosis & has no heart disease risk • The end product, physiologic effect, should be the concern What are Bioidentical Hormones

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

Table 1. Common Hormone Therapies for Relief of Menopausal Related Symptoms

Generic Brand Available Strength (mg) Route of Indications Dosing Source of active FDA Bioidentical Name generic Administration ingredients approved

Branded hormone therapeutics Estrogen alone

Conjugated estrogens Genestin No 0.625 Oral Moderate-severe VmS Continuous Synthesized from soy and Yes No 0.9 daily yams

Conjugated synthetic Enjuvia No 0.3 Oral Moderate-severe VmS Continuous Synthesized from soy and Yes No estrogens 0.45 daily Mexican yams 0.625 Yams 1.25

Conjugated estrogens Premarin No 0.3 Oral Moderate-severe VmS; moderate- Continuous Pregnant mares’ urine Yes No 0.45 severe vulval and vaginal atrophy daily 0.625 0.9 1.25

0.625 Vaginal cream Atrophic vaginitis; kraurosis vulvae

Esterified estrogens Menest No 0.3 Oral Moderate-severe VmS; atrophic Continuous Synthesized from soy and Yes No (estrone, equiline) 0.625 vaginitis; kraurosis vulvae daily yams 1.25 2.5

Micronized estradiol Estrace Yes 0.5 Oral Moderate-severe VmS; Continuous Synthesized from soy Yes Yes (estrone, equiline) 1 atrophic vaginitis; kraurosis daily and yams 2 vulvae Prev.o st.

Estropipate Ogen Yes 0.625 Oral Moderate-severe VmS; Continuous Synthesized from Yes Yes 1.25 moderate-severe vulvar and Mexican yams 2.5 vaginal atrophy; Prev.o st.

Estropipate Ortho-Est Yes 0.625 Oral Moderate-severe VmS; Continuous Synthesized from yams Yes Yes 1.25 moderate-severe vulvar and vaginal atrophy; Prev.o st

Estradiol Alora No 0.025 Transdermal Moderate-severe VmS; Continuous Synthetic? Yes Yes 0.05 patch moderate-severe vulvar and Twice weekly 0.075 vaginal atrophy; Prev.o st 0.1

Estradiol Climara No 0.025 Transdermal Moderate-severe VmS; Continuous Synthesized from soy Yes Yes 0.0375 patch moderate-severe vulvar and Once weekly 0.05 0.06 vaginal atrophy; Prev.o st 0.075 0.1 Table 1. Common Hormone Therapies for Relief of Menopausal Related Symptoms

Generic Brand Available Strength (mg) Route of Indications Dosing Source of active FDA approved Bioidentical name generic administration ingredients

Estradiol Estraderm No 0.05 Transdermal patch Moderate-severe Vms; Continuous Synthesized Yes Yes 1 moderate-severe vulvar twice weekly from Mexican and vaginal atrohophy; yams Prev. o st.

Estradiol Estring No 2 Vaginal ring Moderate-severe vulvar Continuous q90 Synthesized Yes Yes delivers and vaginal atrhophy days from Mexican 7.5μg/day yams

Estradiol Vivelle No 0.025 Transdermal Moderate-severe Vms; Continuous Synthesized Yes Yes Vivelle- 0.0375 patch moderate-severe vulvar twice weekly from Mexican Dot 0.05 and vaginal atrohophy; yams 0.075 Prev. o st. 0.1

Estradiol Femring No 0.05 Vaginal ring Moderate-severe VmS Continuous q3- Synthesized Yes Yes acetate 0.01 months from soy (prodrug converts /day to estradiol)

Estradiol Femtrace No 0.45 Oral Moderate-severe VmS Continuous Synthesized Yes Yes (prodrug acetate 0.9 from soy converts to 1.8 estradiol)

Estradiol Depo- Yes 1 Injection Moderate-severe VmS Continuous Synthetic? Yes Yes (prodrug cypionate Estradiol 5 (in oil) Q3-4 weeks converts to Cyclic estradiol)

Estradiol Estrasorb No 8.7 Topical emulsion Moderate-severe VmS Continuous daily Synthesized Yes Yes hemihydrate (two 1.74-g pkgs) (micellar from soy deliver 0.5/day nanoparticle)

Estradiol Vagifem No 0.025 Vaginal tablet Atrophic vaginitis Continuous daily Synthesized Yes Yes hemihydrate for 2 weeks from soy twice weekly after

Estradiol Delestroge Yes 1 Injection (in oil) Moderate-severe VmS Continuous q4 Synthetic? Yes Yes (prodrug valerate n 5 weeks cyclic converts to estradiol)

Estradiol Valergen- Yes 10 Injection (in oil) Moderate-severe VmS Continuous q4 Synthetic Yes Yes (prodrug valerate 10,20, or 40 20 weeks cyclic converts to 40 estradiol) Table 1. Common Hormone Therapies for Relief of Menopausal Related Symptoms

Generic Brand name Available Strength (mg) Route of Indications Dosing Source of active FDA Bioidentical generic administration ingredients approved

Etinyl estradiol Estinyl No 0.02 Oral Moderate-severe Continuous Syntehsized from soy and Yes No 0.05 VmS yams 0.5

Branded hormone therapeutics: Progestogens

Medroxypro- Amen Yes 10 Oral To reduce risk of Cyclic Synthesized from soy or Yes No gesterone acetate endometrial continuous yams hyperplasia in postmenopausal Medroxypro- Cycrin Yes 2.5 Oral women who are Cyclic Synthesized from soy or Yes No gesteron acetate 5 taking estrogen continuous yams 10 and have an intact uterus

Medroxypro- Provera Yes 2.5 oral Cyclic Synthesized from soy or Yes No Secondary gesteron acetate 5 continuous yams amenorrhea 10

Abnormal Micronized Crinone No 4% w/w (45); 8% Vaginal gel uterine bleeding Cyclic Synthesized from Mexican Yes Yes progesterone w/w (90) continuous yams due to hormonal

imbalance Micronized Prometrium No 100 Oral Cyclic Synthesized from Mexican Yes Yes progesterone 200 continuous yams

Norethindrone Aygestin No 5 Oral Cyclic Synthesized from soy Yes No acetate

Branded hormone therapeutics: Estrogens + progestogens

Conjugated PremPhase No CE MPA Oral Moderate-severe Cyclic Pregnant mares’ urine Yes No estrogens 0.625 0.625 VmS; moderate- severe vulval and vaginal Medroxypro- 0 5 atrophy; Prev. Synthesized from soy and No gesterone acetate Ost. yams

Congugated PremPro No CE MPA Oral Continuous Pregnant mares’ urine Yes No estrogens 0.3 1.5 combined 0.45 1.5 Medroxypro- 0.625 2.5 Synthesized from soy and gesteron acetate 0.625 2 yams Table 1. Common Hormone Therapies for Relief of Menopausal Related Symptoms

Generic Brand Available Strength (mg) Route of Indications Dosing Source of active FDA Bioidentical name generic administration ingredients approved

Esterified estrogens EstraTest No 1.25 Oral Moderate-severe VmS in Continuous combined Synthesized from soy Yes No patients not responsive to and yams estrogen alone 2.5 Methyltestosterone Synthesized from soy No and yams

Esterified estrogens EstraTest No 0.625 Oral Moderate-severe VmS in Continuous combined Synthesized from soy Yes No HS patients not responsive to and yams estrogen alone

Methyltestosterone 1.25 Synthesized from soy No and yams

Estradiol Activella No 1 Oral Moderate-severe VmS; Continuous combined Synthesized from soy Yes Yes moderate-severe vulval and and yams vaginal atrophy; Prev. Ost. 0.5 Norethindrone Synthesized from soy No acetate

Estradiol Combi- No E2 NETA Transdermal Moderate-severe VmS; Continuous combined Synthesized from soy Yes Yes patch 0.62 2.7 patch moderate-severe vulval and 0.05/0.14 or 0.51 4.8 vaginal atrophy 0.05/0.25/ Synthesized from E2/ NETA per day Norethindrone Mexican yams No Continuous cycling is acetate achieved using Vivelle

Estradiol OrthoPref No Tablet 1 Tablet 2 Oral Moderate-severe VmS; Pulsed Tablet 1 (days Synthesized from soy Yes Yes est 1 1 moderate-severe vulval and 1-5) Tablet 2 (days 4-6) vaginal atrophy; Prev. Ost. and repeat

Norgestimate Synthesized from soy No 0 0.09

Ethinyl estradiol Femhrt No EE NETA Oral Moderate-severe VmS; Prev. Continuous Synthesized from soy Yes No 0.0025 0.5 Ost. 0.0025 0.5 0.005 1 Norethindrone Synthesized from soy No 0.005 1 acetate

Branded hormone therapeutics: Testosterone

Testosterone Androderm No 2.5 Transdermal NAMS: low libido Continuous Synthesized from soy No Yes 5 patch

Testosterone Androgel No 25 Transdermal NAMS: low libido Continuous Synthesized from soy No Yes 50 patch

Testosterone Testoderm No 4 Transdermal NAMS: low libido Continuous Synthetic? No Yes 5 patch 5 mg/day 6

Table 1. Common Hormone Therapies for Relief of Menopausal Related Symptoms

Generic Brand name Available Strength (mg) Route of Indications Dosing Source of FDA Bioidentical generic administration active approved ingredients

Testosterone cypionate Depo-test- Yes 100 mg/mL IM Low libido Twice/month Synthetic Yes Yes (prodrug is osterone metabolized into BH)

Testosterone enanthate Delatestryl Yes 100mg/mL IM Low libido Twice/month Synthetic? Yes Yes (prodrug is 200mg/mL metabolized into BH)

Compounded hormone therapeutics: Estrogens, progesterone, testosterone

Estradiol N/A, Customized Oral, trans-dermal; Claims vary Continuous Synthesized No Yes Estriol Compounded (usually 1.25, 2.5, 5) sublingual, vaginal Assumed: twice daily from soy Estrone Customized for moderate- (Claimed to (triest) each patient, severe VmS/ be less criteria vary: saliva, moderate- commonly sera levels, or severe vulvar used due to symptoms (usually and vaginal Estrone 1.25, 2.5, 5) atrophy content

Estradiol N/A, Customized for Oral, trans-dermal; Claims vary Continuous Synthesized No Yes Estriol Compounded each patient, sublingual, vaginal Assumed: twice daily, from soy (biest) criteria vary: saliva, moderate- commonly sera levels, or severe VmS/ 1.25 mg BID symptoms (usually moderate- 1.25, 2.5, 5) severe vulvar and vaginal atrophy

Estriol N/A, Customized for Oral, trans-dermal; Claims vary Continuous Synthesized No Yes compounded each patient, sublingual, vaginal Assumed: from soy criteria vary: saliva, moderate- sera levels, or severe VmS/ symptoms moderate- severe vulvar and vaginal atrophy

Table 1. Common Hormone Therapies for Relief of Menopausal Related Symptoms

Generic Brand name Available Strength Route of Indications Dosing Source of FDA Bioidentical generic (mg) administrati active approved on ingredients

Progesterone N/A, Customized Oral, trans- Claims vary Continuous Synthesized Yes Yes compounded for each dermal; FDA: cyclic from soy or sublingual, protection yams patient, criteria vary: vaginal, from saliva, sera injectable estrogen- levels, or associated symptoms endometrial hyperplasia and adenocarcino mas Testosterone N/A, Customized Oral, trans- Claims vary Continuous Synthesized Oral and Yes compounded for each dermal; NAMS: from soy IM only patient, sublingual, decreased criteria vary: vaginal, libido; NAMS saliva, sera injectable does not levels, or recommend symptoms the use of compounded product

Testosterone N/A, Customized IM Monthly Synthetic? Yes Yes (prodrug is propionate compounded for each Twice/month metabolized into patient, BH) criteria vary: saliva, sera levels, or symptoms

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.

Vaginal: vulvar & vaginal atrophy (dryness, dysparenunia, and atrophic vaginitis)

Treatments • Use moisturizers daily, • OTC Water/Silicone based use lubricants with sex moisturizers & lubricants

• Topical Hormones • Ring may be absorbed less systemically

• Ospemifene (Selective Estrogen • Treats moderate to Receptor Modulator) severe dyspareunia, associated with ↑ hot flashes, ↑ stroke & thromboembolic events

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

Bone

• Decreased risk of hip • Estrogen fracture

• ? Consider use for prevention

• Selective Estrogen Receptor Modulators: Raloxifene and Bazedoxifene (use with CE in women with a uterus)

• Calcium • Increasing calcium intake, • Vitamin D through calcium supplements or dietary sources, should not be recommended for fracture prevention

Other

• Cardiovascular

• Cognitive 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”. References: Alternative Medicine for Menopause. Endocrine Society. 2012 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)600-631 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 Global Consensus State Hormone Therapy. Endocrine Society. 2013 The Kronos Early Estrogen Prevention Study. Women’s Health. 20139 (1):9-11 http://www.menopause.org/publications/clinical -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 The Women’s Health Initiative: The Role of Hormonal Therapy in Disease Prevention, Robert Wallace, 3(1), 2005