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Menopause 2017 Guidelines: Looking at Special Populations and Building on Existing Practice Patricia Geraghty, MSN, FNP-BC, WHNP Disclosures

• Speaker Bureau • AbbVie • Therapeutics MD • Advisory Board • AbbVie (endometriosis) • Sharecare Inc. • Procedure Proctor • Bayer (Contraception) • Off label discussion will be included and identified in this discussion. Objectives

• Identify the benefits and risks of , , and non-hormonal pharmacological management of symptoms based on dosage, route of administration, pharmacokinetics, treatment population and duration of use. • Develop treatment strategies for special populations including premature ovarian insufficiency, prolonged symptoms, and women who are not candidates for estrogen. • Incorporate the NAMS 2017 Position Statement into patient counseling on the timeline of menopause symptoms and the termination of hormone therapy. Lifespan Median 34

322 BC Aristotle describes transition Menopause Through the Ages yr JAMA. Writing Groupfor Women'sthe Health Initiative Investigators. 2002;288(3):321 - 333. doi:10.1001/jama.288.3.321 333.

Treated with s/a 1800’s cohosh, cannabis, opium 1821 French physician DeGardanne 53 lifespan calls it “Menopause” Adult

- 1900’s Deficiency disease 55 1942 Premarin” copyright yr 1960’s “Forever Feminine” by Robert Wilson MD 1980’s-1990’s “Politics of Menopause” by Frances McCrea 2002 WHI- First large randomized control trial “My periods are different. Is This Menopause?” • Random cycling, sometimes early, sometimes late. • Flow variable with prodromal spotting, a long taper, or stopping and starting. • She has a day of very heavy flow.

• 77% have duration 10+ days, heavy bleeding 3+ days, spotting 6+ days

Paramsothy P, et al. BJOG. 2014 Nov;121(12):1564-73. doi: 10.1111/1471- 0528.12768. Epub 2014 Apr 16. A Well Controlled Conversation

Harvard Women’s Health Watch. Perimenopause. September 1999 from Santoro N et al. J Clin Enodrinol Metab. 1996;81:1495-1501. As The Follicles Age

(180 days)

Harvard Women’s Health Watch. Perimenopause. September 1999 from Santoro N et al. J Clin Endorinol Metab. 1996;81:1495-1501. Managing Cycle Irregularities

• Combined Hormonal Contraceptives • Only intervention that provides cycle control • Exposes patient to known risks of CHC • Progestin-Only Contraceptives • Levonorgestrel IUS • Endometrial Ablation Non-Pharmacologic • Hysterectomy True Menopause: Cessation of Menses

Harvard Women’s Health Watch. Perimenopause. September 1999 from Santoro N et al. J Clin Enodrinol Metab. 1996;81:1495-1501. Formation PROGESTERONE CYP-450*

Dehydroepiandrosterone PROGESTERONE (DHEA) 60%

Androstenedione Cortisol * * 5 α-Reductase Aromatase CYP-19 (DHT)

ESTRIOL EFFECTS OF ESTROGEN Estrogen Target Organs DECREASE

Vasomotor symptoms Cognition ?

Decrease arterial compliance, Increase BP, Endothelial change Decrease HDL, Increase LDL & triglycerides Bronchoconstriction Vasospasm Endothelial change Vulvovaginal Atrophy Arthritis Collagen loss “If Only I Could Sleep.”

North American Menopause Society. Menopause 2010: 17(2);242-255. Predicting Menopause: Final Menstrual Period (FMP) ▪ Salivary hormone levels not reflective of serum levels- no role in monitoring therapy ▪ Blood tests of little value

Wren BG et al. Climacteric 2000;3(3):155-160. Fuch-Berman A. Bythrow J. J Gen Intern Med 2007;22(7): 1030-1034. Harlow SD, et al. Menopause 2012; 19(4): 387-395. Duration of Menopause Symptoms (SWAN) • Median duration frequent vasomotor symptoms (≥ 6 days in previous 2 weeks) • Total duration 7.4 years with post-FMP persistence 4.5 y • 11.1 years: Women with symptoms before FMP (post- FMP persistence 9.4 y) • 3.4 years: Women w/symptom only after FMP • 10.1 years: African American women (longest total duration)

Avis NE, et al. JAMA Intern Med. 2015 Apr 1;175(4):531-9. doi: 10.1001/jamainternmed.2014.8063 15 Top Medical Organizations Agree: Joint Statement 2012 ▪ Hormone therapy is an acceptable option up to age 59 or within 10 years of menopause for moderate to severe symptoms ▪ Women need progestogen along with estrogen if uterus is intact

Steunkel CA, et al. Fertil Steril. 2012; 98(2):0015- 0282. http://dx.doi.org/10.1016/j.fertnstert.2012.05.051 Indications for Hormones: 2017

▪ Systemic estrogen therapy FDA approved for: ▪ Vasomotor Symptoms* ▪ Vulvovaginal Atrophy (Genitourinary Syndrome of Menopause)* ▪ Osteoporosis Prevention ▪ Premature hypoestrogenism ▪ Variable effectiveness in treating other sx ▪ No protection from pregnancy

The 2017 Position Statement of the North American Menopause Society Menopause. 2017 Nov;24(7):728-753. Addressing the Needs of All Women, Individually • Risk Assessment • <10 y since menopause, <60 y age • >10 y since menopause, >60 y age • Health Promotion • USPSTF says NO role postmenopause • Ignores QOL and associated risks of GSM • Symptom Management

Final Recommendation Statement: Hormone Therapy in Postmenopausal Women: Primary Prevention of Chronic Conditions . U.S. Preventive Services Task Force. December 2017. accessed online 7 Jan 2018 https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFin al/menopausal-hormone-therapy-preventive-medication1 Risk Assesment: Relative or Absolute? • Relative- WHI 26% Increased risk • Absolute- WHI E+P: 8 additional cases per 10,000 w/y use • E+P increase node positive at 11 years • Absolute risk 2 deaths per 10,000 women/year at 11 years Attributable breast cancer risk WHI- mean age 63 y, CEE+MPA

Two daily glasses of wine ESTROGEN ONLY GROUP? Obesity, Low physical activity One daily glass of wine Mortality Breast Cancer & Dementia 18-yr f/u Rossouw. JAMA. 2007; 297:1465. Chlebowski RT, et al. JAMA. 2010; 304(15): 1684-92. LaCroix AZ, et al. JAMA. 2011; 305(13): 1354-55. The 2017 Position Statement of the North American Menopause Society. Menopause. 2017 Nov;24(7):728-753. . Manson JE, et al. JAMA. 2017; 318:927-938. Duration of Use

• E+P: no increased risk < 5 years use ▪ Women who initiate E+P use soon after menopause, and continue for many years, appear to be at particularly high risk. ▪ 5-Year Estimated hazard ratio 1.64 (1.00, 2.68)

▪ 10-year estimated HR 2.19 (1.56, 3.08) ✗ • Personal History Breast Cancer (ER positive) • Dense breasts mammogram and biopsy but not cancer ✓ • Genetic risk breast cancer not further increased ✓ Prentice RL, et al. Am J Epidemiol. 2008 May 15;167(10):1207-16. The 2017 Position Statement of the North American Menopause Society. Menopause. 2017 Nov;24(7):728-753 15 Top Medical Organizations Agree: Joint Statement 2012 ▪ Hormone therapy is an acceptable option up to age 59 or within 10 years of menopause for moderate to severe symptoms ▪ Women need progestogen along with estrogen if uterus is intact ▪ Breast cancer risk increases with 5 or more years of continuous estrogen with progestin therapy, possibly earlier ▪ The risk decreases to rare (< 1:1000) after hormone therapy is stopped

Steunkel CA, et al. Fertil Steril. 2012; 98(2):0015- 0282. http://dx.doi.org/10.1016/j.fertnstert.2012.05.051 Safety Issues

• Endometrial Cancer • If she has a uterus, use progestin with estrogen • Cancer risk r/t dose and duration unopposed E • Cancer risk persists after discontinuing HT • Hx endometrial cancer, menopause symptoms • Low grade, early stage, surgically treated: benefits

may outweigh risks particularly in younger women ✗ • Higher grade, more advanced: HT not recommended The 2017 Position Statement of the North American Menopause Society Menopause. 2017 Nov;24(7):728-753

Best Endometrial Protection EFFECTIVENESS • Continuous combined E + P • No hormones • E with long cycle sequential P

Jaakkola S, et al. Obstet Gynecol 2009;114:1197-1204. Somboonporn W. et al. Menopause 2011;18:1060-1066. 2012 Hormone Therapy Position Statement of the North American Menopause Society. Menopause. 2012; 19(3):257-271. Progestin Lowest Effective Dose

▪Medroxyprogesterone 2.5 mg qd ▪Micronized progesterone 100 mg qd ▪Progestins oral ▪ Norethindrone acetate 0.1 mg

▪ Drosperinone 0.5 mg Products ▪Progestins transdermal ▪ Norethindrone acetate 0.14 mg }

▪ Levonorgestrel 0.015 mg Combination Off Label Progestogen

▪ Vaginal administration progestogen and LNG-IUS not FDA approved in postmenopausal women ▪ Progestin IUS protection equivalent to continuous E+P and superior to sequential E+P in one small study ▪ Close monitoring of endometrium recommended

2012 Hormone Therapy Position Statement of the North American Menopause Society. Menopause. 19(3):257-271. Estrogen + SERM: Vasomotor Sx and Osteoporosis Prevention • Conjugated / 0.45 mg/20 mg (Duavee®) • “Purposely paired” with non-progesterone • Yet still protects endometrium • For women with a uterus and should have risk osteoporosis • 4% trial population age 65 – 74 years • 74% reduced severity/freq vasomotor sx 12 wks • No incidence VTE clinical trials- boxed warning • Unknown risk for breast cancer

Pinkerton JV, et al. Climacteric. 2012 Oct;15(5):411-8. doi: 10.3109/13697137.2012.696289. 2012 Joint Statement: Safety Issues Both estrogen alone and estrogen with progestin increase the risk of blood clots. The risk is rare in • VTE women aged 50-59 • Strong evidence increased risk all ages- oral

• Cochrane Review RR 1.74; CI 1.11-2.73 ✗ • Do not use with hx VTE or inherited  risk • Ameliorate risk • Transdermal estrogen (II+++) Largely Observational + • Lower dose estrogen (I ) Data; few RCTs • Micronized progesterone (I+) • Vaginal estrogen no excess risk VTE or CVD

The 2017 Position Statement NAMS Menopause. 2017 Nov;24(7):728-753. Boardman HM, Hartley L, Eisinga A, et al. Cochrane Database Syst Rev. 2015;(3):CD002229. Crandall CJ, Hovey KM, Andrews CA et al. Menopause 2018;25(1):11-20. Risk Thromboembolism by Age

Silverstein, M. D. et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch. Intern. Med. 1998;158(6):585–593. Risk Reduction: Lowest Effective Dose ▪17ß- estradiol orally as conjugated equine or synthetic (0.3-0.45 mg) ▪Estradiol (0.5 mg) ▪Ethinyl Estradiol (5 mcg) ▪Estradiol transdermally ▪ osteoporosis prevention 0.014 mg ▪ vaginal atrophy 0.025 mg ▪ vasomotor symptom relief 0.0375 mg

The 2017 Position Statement of the North American Menopause Society. Menopause. 2017 Nov;24(7):728-753 - Age of HT Initiation

No Change: Decrease: No Change: All-cause Mortality All-cause Mortality All-cause Mortality Cardiovascular Death Cardiovascular Cardiovascular Nonfatal MI Disease Disease Angina Pre-existing Revascularization Surrogate markers CVD (carotid artery intima- ✗ media thickness) mixed  Stroke 6/1000 No increase stroke  Stroke and VTE  VTE  VTE The 2017 Position Statement of the North American Menopause Society Menopause. 2017 Nov;24(7):728-753. Boardman HM, Hartley L, Eisinga A, et al. Cochrane Database Syst Rev. 2015;(3):CD002229. Safety Issues

• Gallbladder Disease • Increased risk both E+P and ET • CEE oral > Estradiol oral > Estradiol transdermal • Million Women Study (observational) cholecystectomy/100 women over 5 years • 1.1 never users • 1.3 transdermal • 2.0 oral

The 2017 Position Statement of the North American Menopause Society Menopause. 2017 Nov;24(7):728-753. Liu B, Beral V, Balkwell A, et al. BMJ 2008;337 doi: doi.org/10.1136/bmj.a386 accessed 9 Jan 2018 HT & Other Symptoms- Sleep Problems • 23 studies reviewed • 9 with neutral or negative results • 14 with positive results- Larger, more recent • Pooled analysis 4 RCT MsFLASH- CBTi best • Significant improvement- exercise, yoga, estradiol, venlafaxine XR 75 mg • Not FDA indicated • Oral progesterone mild reduction wakefulness w/o daytime cognition changes

Attarian H, Hachul H, Guttuso T, et al. Menopause. 2015;22:674-684. The 2017 Position Statement of the North American Menopause Society Menopause. 2017 Nov;24(7):728-753. Guthrie KA, Larson JC, Ensrud KE, et al. Sleep. 2018;41(1):zsx190 Genitourinary Syndrome of Menopause*

• (GSM) reported by 50% postmenopausal women. • Dryness • Itching • Burning • Pain with intercourse • Improved GSM  sexual function • Beyond the bedroom • Urinary Incontinence • Falls • Social Isolation

*Previously called Vulvovaginal Atrophy (VVA) Portman DJ, Gass MLS. Menopause 2014; 21(10):557-563. DOI: 10.1097/gme.0000000000000329

The Endocrine Society ( SocietyEndocrine The American The Societyfor Reproductive ( Medicine Society American( Menopause North The Options for GSM

• Long-acting vaginal

moisturizer www.endo

• Vaginal lubricants - • Local topical estrogen if only society.org

vaginal symptoms* www.menopause.org

• (DHEA)* ) • Ospemiphene* www.asrm.org *FDA

• Laser* Approved

) ) Estrogen & Sexual Function

• Systemic and vaginal ET improves • vaginal blood flow • lubrication • Sensation • Vaginal estrogen safe w/o progestin- 1 year data • Consider transdermal ET- less effect on -binding globulin and free testosterone • E2 transdermal +/- MP  sexual function • CEE oral +/- MP and placebo no change

June 2018: FDA refuses to remove warnings VTE, cancer from locally acting products.

The 2017 Position Statement of the North American Menopause Society Menopause. 2017 Nov;24(7):728-753. Taylor HS, Tal A, Pal L, et al. JAMA Intern Med. 2017;177(10):1471-1479 Prasterone / Intrarosa® ( – DHEA) 6.5 mg

• Daily vaginal suppository •  45.9% parabasal cells and  6.8% superficial cells at 12 weeks treatment • 1.5 score unit severity VVA • Serum steroid levels remain in normal postmenopausal range

Labrie F, Archer D, Bouchard C. et al. Menopause. 2009 Sep- Oct;16(5):907-22. doi: 10.1097/gme.0b013e31819e8e2d Systemic Treatment for Genitourinary Syndrome of Menopause

• an Estrogen /antagonist 60mg (Osphena®) • Significant changes histology, pH, and dyspareunia in 12- week trial • Contraindicated in • genital bleeding unknown etiology • estrogen-dependent neoplasia • DVT or PE hx or current • Arterial thromboembolic disease s/a stroke, MI • May increase hot flashes. Also saw increase UTI • Same boxed warning as , risk VTE Bachmann GA, et al. Menopause. 2010;17(3):480-486, Weight

• ERα  fat accumulation, while ERβ  ... In general. • ER deletion and oophorectomy promote abdominal adipose, insulin resistance, and hyperlipidemia • HT no effect or a small  body mass CEE+MPA in WHI •  Diabetes Type 2 in WHI • 19% reduction CEE+MPA = 16/10,000 fewer cases • 14% reduction CEE only = 21/10,000 fewer cases

• Blocking FSH reduces abdominal adipose and improves bone density… in mice.

The 2017 Position Statement of the North American Menopause Society Menopause. 2017 Nov;24(7):728-753. Lui P, Ji Y. Yuen T, et al. Nature. 2017 Jun 1:546(7656)107-112. Kohrt WM, Wierman ME. Preventing fat gain by blocking follicle-stimulating hormone. N Engl J Med. 2017;377(3):293-295. Mood and Cognition

• Not for preventing or treating decline in cognition or dementia • WHI Memory Study initiated CEE+MPA > 65 y with 23/10,000 increased dementia indicates need for caution initiating HT this age group • ET may help cognition initiated early after surgical menopause but effect neutral in early natural menopause • Women with perimenopause depression responsive to HT may experience recurrence when estradiol stopped • Women may experience mood swings w/progesterone The 2017 Position Statement of the North American Menopause Society Menopause. 2017 Nov;24(7):728-753 Arthralgia and Myalgia

• Both joints and muscles have estrogen receptors • Demonstrated protection of joint structure and function • Link to osteoarthritis less clear • Significant reduction arthralgia in WHI both arms • Less information on muscle effect • Role estrogen plays when combined with exercise to maintain muscle mass suggested

The 2017 Position Statement of the North American Menopause Society Menopause. 2017 Nov;24(7):728-753. Bone

• ET and HT both reduce bone loss via inhibition of osteoclast resorption • Results in  BMD and  fractures hip, spine, all fractures • Lower doses- no sufficiently powered studies to demonstrate fracture reduction Estradiol 0.014 mg transdermal • Protection BMD dissipates rapidly when HT stopped  bone density • Some residual fracture protection WHI CEE+MPA 13 y f/u • No head-to-head studies with other bone agents • “For women with VMS aged < 60 y or within 10 y of menopause,…ET, EPT or CEE + bazedoxifene… is probably the most appropriate bone-active therapy…” The 2017 Position Statement of the North American Menopause Society Menopause. 2017 Nov;24(7):728-753 Prescribing Hormones

▪ Counseling on benefits vs. risks ▪ Choose product ▪ Estrogen component ▪ Endometrial protection component ▪ Regimen ▪ Route of administration ▪ Dose

The 2017 Position Statement of the North American Menopause Society. Menopause. 2017 Nov;24(7):728-753 Estrogen formulations differ?

• Conjugated Equine Estrogen (CEE) or Estradiol (E2)

CVD  Risk1* or Vasomotor No data4 *Not head-to- No difference2 head studies Breast Cancer No difference2 GSM No data Stroke No difference2 Sexual No data Function PE  Risk3 Weight No data VTE  Risk3 Bones No data Gall Bladder  Risk3 Sleep No data 1.Mikkola T, Tuomikoski P, Lyytinen H, et al. Menopause; Sept 2015:22(4):976-983. 2. Crandall CJ, Hovey KM, Andrews C et al. Menopause. 2017 Oct;;24(10):1145-1153. 3. The 2017 Position Statement of the North American Menopause Society Menopause. 2017 Nov;24(7):728-753. 4. Schierbeck LL, Rejnmark L, Tofteng CL et al. BMJ. 2012;345:e6409 Route of Administration Differ?

• Oral or Transdermal

CVD No difference1 Vasomotor No data Breast Cancer No difference1 GSM  efficacy Stroke No difference1 Sexual  efficacy4 Function PE  Risk2 Weight No data VTE  Risk2 Bones No data Gall Bladder  Risk3 Sleep No data

1. Crandall CJ, Hovey KM, Andrews C et al. Menopause. 2017 Oct;;24(10):1145-1153. 2. The 2017 Position Statement of the North American Menopause Society Menopause. 2017 Nov;24(7):728-753. 3. . Liu B, Beral V, Balkwell A, et al. BMJ 2008;337 doi: doi.org/10.1136/bmj.a386 accessed 9 Jan 2018. 4. Taylor HS, Tal A, Pal L, et al. JAMA Intern Med. 2017;177(10):1471-1479 Compounded Hormones Role?

• Only consider if FDA approved therapy not tolerated for reasons s/a allergies to inert ingredients, or dose or formulation not available. • Document medical indication • 1 – 2.5 million women use CHT • Accounts for 68% hormone use • Salivary testing unreliable • 86% users unaware not FDA approved • “Bio-identical” (similar to endogenous) FDA approved hormones available including estradiol, micronized progesterone • Have package inserts, including black box warnings PELLETS • Monitored for safety in production and use SUBDERM • Supplied in tested combinations and routes of administration The 2017 Position Statement of the North American Menopause Society Menopause. 2017 Nov;24(7):728-753. Pinkerton JV. Menopause. 2015; doi10.1097/GME.0000000000000420 Special Populations

• Age and Menopause • Early menopause or Primary Ovarian Insufficiency • Prolonged use • Women who can’t or won’t use estrogen • Pharmacological alternatives • OTC and the evidence • Lifestyle and behavioral

• Sexual Function beyond hormones 44 y Amenorrhea 12 Months AMH 0.1 ng/ml

 She has vasomotor symptoms, insomnia and some vaginal dryness  She is worried about starting menopausal hormone therapy so young  Early natural menopause, POI and surgical menopause › Bone loss › Cognition changes  Risk › GSM and decreased sexual function › Mood issues.  Hormone therapy or combined contraceptive recommended at least until median age menopause (52 y) The 2017 Position Statement of the North American Menopause Society Menopause. 2017 Nov;24(7):728-753 Vertebral fractures in 66 year old

 Osteoporosis not responsive to bisphosphinates › Has 3 months Forteo therapy remaining  Painful kyphosis now progressed to 93°  Had uterus removed  Using estradiol patch 0.0375 mg 77 year old using combination estradiol/progestin patch

 No vasomotor symptoms or vaginal dryness on therapy  Multiple trials weaning, last 3 yrs ago  Exercise water aerobics  Adequate calcium, vitamin D  “The quality of my life is worth a lot.” No General Rule Stop Age 65y

• 42% women 60-65 y moderate/severe vasomotor symptoms • 16% of women > 85 y have VMS several times weekly • Beers Criteria recommendation routinely stop systemic HT by 65 years not supported by data • Continued use in women who started HT < 60 y & w/o new health risk more favorable safety profile • Care w/initiation or restart hormones after age 65 y • Counsel risks/benefits, potentially change to transdermal route • Annual reevaluation reviewing co-morbidities • Periodic trials lowering dose or discontinuing

The 2017 Position Statement of the North American Menopause Society Menopause. 2017 Nov;24(7):728-753 Breast Cancer Risk with Estrogen Only

 WHI non-significant decreased risk in all age groups (50-59, 60-69, 70-79) › Decreased risk significant at 13 years f/u in women who were 80% compliant › Decreased mortalilty significant at 18 yr  Observational studies showed risk lower than with E+P but present after long duration use

Stefanik ML, et al. JAMA 2006;295:1647-1657. 2012 Hormone Therapy Position Statement of the North American Menopause Society. Menopause. 19(3):257-271. The 2017 Position Statement of the North American Menopause Society Menopause. 2017 Nov;24(7):728-753. . Manson JE, et al. JAMA. 2017; 318:927-938. Document Carefully

 Consider non-hormonal product  Consider estrogen/bazedoxifene  Evidence says ameliorate risk VTE with transdermal route  8/10,000/WY cases breast cancer from WHI probable underestimate in older population  Patient “self-managed” risk reduction by using one patch weekly vs. on-label use of bi-weekly dosing. Women Who Can’t or Won’t Use Hormones

 No products are as efficacious as estrogen  80% of women use complimentary and alternative medicine (CAM) for menopause › Highest use among Whites and Japanese (60%) › Lowest use among Hispanics (20%)

Bair YA. Menopause. 2008 Jan-Feb;15(1):32-43. The 2017 Position Statement of the North American Menopause Society. Menopause. 2017 Nov;24(7):728-753 Prescription Non-hormonal Agents for Hot Flashes

▪ SSRI, SNRI and clonidine all reduced 1 /day > placebo ▪ All have the same risks of increased suicidal ideation as higher doses ▪ Paroxetine 10-25 mg/d* ▪ Citalopram 10-20 mg/d ▪ Escitalopram 10-20 mg/d ▪ Venlafaxine 37.5-150 mg/d ▪ Desvenlafaxine 100-150 mg /d ▪ 64%  frequency, 31%  severity vs. placebo ▪ Clonidine 0.1 mg/d ▪ More likely to report sleep problems 41% vs 21%

*

The North American Menopause Society. Position Statement. Menopause. 2015 Nov;22(11):1155-72 Gabapentin 300 mg TID

▪ More effective than placebo in 3 studies. ▪ Gabapentin 2400 mg/d or CEE 0.625 mg ▪ Hot flash composite score reduction ▪ Gabapentin 71% ▪ Estrogen 72% ▪ Placebo 54% ▪ Gabapentin 25% complain of headaches, dryness, disorientation ▪ Start at 900 mg/d. Titrate dose up

Guttoso TJ. et al. Obstet Gynecol. 2003; 101(2):337-45. Panya KJ et al. Lancet. 2005;366(9488)818- 24. Reddy SY. Obstet Gynecol. 2006;108(1)141-8. The North American Menopause Society. Menopause. 2015 Nov;22(11):1155-72 Botanicals: Fine Tuning the Data

 Major sources are soy and red clover › › Daidzein- converted by intestinal bacteria to s- › Only 30% North American women metabolize  S-equol is biologic ER-β agonist  Intense scrutiny- soy no more effective than placebo in VMS  Japanese studies s-equol supplement 10 mg

The North American Menopause Society. Position Statement. Menopause. 2015 Nov;22(11):1155-72 Pollen Extract (Relizen®) supplement • Multiple trials but few in peer reviewed journals, few RCT • 12-week RCT 65% reduction v 38% reduction vasomotor symptoms, n = 541 • 12-week 85.5% peri-/91% post-  hot flashes • n = 324, no control2 • a mean decrease of 41.7±23.6 (P<.0001) for frequency • a mean decrease of 45.8±23.0 (P<.0001) for severity • Over 60% had significant improvement (P<.0001) • Irritability (from 41.8±31.5 to 16.5±20.0) • Fatigue (from 45.5±31.2 to 19.8±22.4) • 70% improvement quality of life scores, in 71.9% of the subjects • No evidence CYP2D6 inhibition (ok with paroxetine)3 1Winther K, Rein E,Hedman C. Climacteric. 2005;8(2):162-70. 2Simon J, Druckman, R. Obstetrics & Gynecology: May 2016 doi: 10.1097/AOG.0000000000001373. 3Goldstein S, Espié M, Druckmann, R. Menopause. 2015;22(11) 1212–1214 doi: 10.1097/GME.0000000000000535 Botanicals Ineffective (Level II Evidence) or w/o Evidence • Black cohosh (Actaea • Flaxseed- in cell racemosa) 40 mg wall only bioavailable • Crinum- no studies when milled • Dioscorea (wild yam)- • Gut microbiota convert • D. villosa aka D. mexicana to weakly estrogenic contain disogenin a sterol sterols precursor used in • manufacture synthetic • Hops • no in vivo conversion of • Maca- in vitro but not to progesterone in vivo estrogen • Dong quai aka Angelica effects, Peurpuria sinensis, dang gui, tang kuei (Peuraria mirifica) • Siberian Rhubarb

The North American Menopause Society. Position Statement. Menopause. 2015 Nov;22(11):1155-72 “I’m just not interested in sex.”

KNOWLEDGE

SOCIAL ROLES

PAIN

Kingsberg SA, Slthof S, Simon JA et al. J Sex Med. 2017;14:1463-1491. Hypoactive Sexual Desire Disorder + DSM 5: Female Sexual Arousal Disorder Gender Specific-6 Months-Distress • Female Sexual Interest/Arousal Disorder at least 3: • Little interest in sex • Few thoughts related to sex FSIAD • Decreased start and rejecting of sex • Little pleasure during sex most of the time • Decreased interest in sex even when exposed to erotic stimuli • Little genital sensations during sex most of the time

American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013. Neuroendocrine Influences Phase III but not FDA approved * FDA Approved

• Inhibition • Serotonin (5HT) • Trophic Effect • Endocannabinoids* • Opiates • Modulate Sensations • Excitatory • Sex Steroids act on:*

• Oxytocin • Vasoactive Intestinal Genital Central Peptide • Norepinephrine * • Neuropeptide Y • Dopamine * • Nitric oxide • Melanocortin • Cytokines • Organizational/Activa • Etc. tional • Sex Steroids E/P/A Sex Steroids Serum Levels ≠ Sexual Function Kingsberg SA, Slthof S, Simon JA et al. J Sex Med. 2017;14:1463-1491. Pharmacological Approaches Increased number satisfactory sexual events Increased intensity sexual desire Decreased distress associated with FSAID • Topical estrogen, but not systemic, effective • Flibanserin (Addyi®) 100 mg q hs • 5HT inhibition, dopamine & norepinephrine increase • REMS d/t interaction with • Bremelanotide (Vylessi®) 1.75 mg subq • Not approved for postmenopause women • Contraindicated uncontrolled HTN and known cardiac dz • May cause transient increase BP and decrease heart rate, focal hyperpigmentation

Kingsberg SA, Slthof S, Simon JA et al. J Sex Med. 2017;14:1463-1491. Wierman ME, Basson R, Davis SR, et al. Clin Endo Metab, 2006;91(10):3697–371 Testosterone Global Consensus

• Moderately effective for HSDD in postmenopause women • Laboratory measurement direct assays unreliable in women. • Liquid/gas chromatography and tandem mass spectrometry • Measure to r/o supraphysiologic levels (above premenopause status) before and during tx • No adverse events • Transdermal delivery to avoid lipid panel changes • Not associated with blood glucose, HbA1c or blood pressure increase; not associated with VTE or breast cancer • No data beyond 24 months • No FDA approved doses appropriate for women • Studies of pellets & injectable show supraphysiologic levels

Davis SR, et al. Climacteric. Doi.org/10.1080/13697137.2019.1637079 access 9 Sept 2019 Additional Pharmacologics Positive v. Placebo • Buproprion (antidepressant) • Dopamine and norepinephrine reuptake inhibition, no 5HT effect • Trazodone (antidepressant) • 5HT antagonist • Buspirone (anxiolytic)

• Partial 5HT1A agonist • Bremelanotide sub-Q in phase III trials. NDA submitted • Synthetic melanocortin analog of α–melanocyte-stimulating hormone • May facilitate translation of sexual cues to genital response • Significant improved desire, arousal, orgasm, satisfying sexual events • Premenopause Kingsberg SA, Slthof S, Simon JA et al. J Sex Med. 2017;14:1463-1491. Palatin Tech Press Release, June 4, 2018 https://www.drugs.com/nda/bremelanotide_180326.html accessed 1 Oct 2018 Individualize

Estrogen Benefits and risks

Dosage

Duration of use