Jennifer Griffin, M.D. Sutter Medical Group Integrative Medicine Empowering You Through Menopause: Group 3: Hormone Replacement Therapy

• Review physiologic effects of hormone loss • Explain hormone replacement therapies (HRT) • Bio-identical vs Synthetic HRT • Review Safety- Risks / Benefits of HRT • Women’s Health Initiative( WHI) Study ( 2002) • WHI follow up study conclusions • NAMS statement on HRT Objectives

• Brain - hot flashes, memory loss, cognitive decline • Heart – atherosclerosis/ cardiovascular disease • Gut – reduction in favorable gut bacteria • Bones – thinning/ osteoporosis • Skin – thinning skin and vaginal tissue/ dryness, loss of elasticity Effects Of Hormone Loss

Potential Benefits Of HRT • Reduces or eliminates hot flashes • Reduces vaginal dryness • Restores normal sleep patterns • Slows bone loss • Protects the heart when started within 5 yrs of menopause • Supports brain function, may protect against dementia • Reduces anxiety/ irritability

Hormone Replacement Therapy (HRT) Safe and effective for most women who need help controlling symptoms. Progesterone alone often helpful during perimenopause (insomnia, anxiety, irritability). Once in menopause, addition of estrogen for hot flashes, mood , sleep, vaginal dryness

Hormone Replacement Therapy (HRT) Estrogen works best when balanced with bio-identical progesterone, even in women who have had a hysterectomy. Some women with low testosterone symptoms and lab findings may benefit from testosterone replacement

Hormone Replacement Therapy (HRT) Risk Review The HRT scare started with WHI study in 2002 (Intention was to study heart disease) Risk per 10,000 women ( Premarin+ medroxyprogesterone): 7 heart attacks 18 blood clots ( Premarin) 8 strokes ( Premarin) 8 breast cancers ( Medroxyprogesterone) 6 LESS cases of colon cancer 6 LESS hip fractures 97.5% of women did not have any events

Hormone Replacement Therapy (HRT) Problems with WHI study : Avg age of participants was 63 yo, increasing risk for pre-existing cardiovascular disease. • Oral estrogen ( Premarin) was studied (not transdermal) – increases clotting factors and inflammation ( stroke, blood clots) • Progestin ( Medroxyprogesterone) – a progestin, not bio-identical progesterone

Hormone Replacement Therapy (HRT) Follow up study to WHI Lancet Oncology May 2012 – f/up to Premarin only arm after 5-9 yrs of use Premarin 0.27% incidence of breast cancer vs placebo 0.35% incidence. It appears medroxyprogesterone (AKA Provera) was what increased breast cancer risk. ( other studies support this too)

Question? What is the relationship between use of menopausal hormone therapy vs placebo for 5 to 7 years and mortality over 18 years of follow-up? Findings Among postmenopausal women who participated in 2 parallel randomized trials of estrogen plus progestin and estrogen alone, all-cause mortality rates for the overall cohort in the pooled trials were not significantly different for the hormone therapy groups vs the placebo groups (27.1% vs 27.6%; hazard ratio, 0.99 [95% CI, 0.94-1.03]). Meaning: Menopausal hormone therapy for 5 to 7 years was not associated with risk of long-term all-cause mortality. JAMA. 2017;318(10):927-938. doi:10.1001/jama.2017.11217 Hormone Replacement Therapy (HRT)

Hormone Replacement Therapy: North American Menopause Society Position Statement 2022 “In women in the WHI aged 50 to 59 years, CEE plus MPA (average, 5.6 years of use) or CEE alone (average, 7.2 years of use in women with previous hysterectomy) did not increase cancer mortality or CV mortality after a median of 18 years’ follow-up compared with placebo.” “In women aged 50 to 59 years at randomization, all-cause mortality was significantly reduced in the pooled trials versus placebo (HR, 0.69; 95% CI, 0.51-0.94). With age groups combined, breast cancer mortality was reduced in women using CEE alone (HR 0.55; 95% CI, 0.33-0.92), and Alzheimer disease or dementia mortality was reduced in women using CEE alone (HR, 0.74; 95% CI, 0.59-0.94) and in the pooled trials (HR, 0.85; 95% CI, 0.74-0.98) after a median of 18 years’ follow-up.” https://www.menopause.org/docs/default-source/professional/nams-2022-hormone-therapy- position-statement.pdf

Hormone Replacement Therapy: North American Menopause Society Position Statement 2022 “The risk of breast cancer related to hormone therapy use is low, with estimates indicating a rare occurrence (less than one additional case per 1,000 women per year of hormone therapy use or three additional cases per 1,000 women when used for 5 years with CEE plus MPA). (Level I)” https://www.menopause.org/docs/default-source/professional/nams-2022-hormone-therapy- position-statement.pdf

Hormone Replacement Therapy: North American Menopause Society Position Statement 2022 “Benefits of hormone therapy use generally outweigh risks for healthy women with bothersome menopause symptoms who are aged younger than 60 years or within 10 years of menopause onset. Because increasing risk is observed with advancing age and extended duration of use, women are advised to use the appropriate dose for the time needed to manage their symptoms. Because many women will experience bothersome VMS for many years, long- duration hormone therapy use may be needed, and an arbitrary age-based stopping rule is not clinically appropriate” https://www.menopause.org/docs/default-source/professional/nams-2022-hormone-therapy- position-statement.pdf

Hormone Replacement Therapy (HRT) What are bio-identical hormones? • Chemically identical ( a precise match) to those we naturally make. • Our bodies optimally recognize the hormone ( key matches the lock) • Made from soy and yam • Some are available commercially, some are not and need to be compounded

Hormone Replacement Therapy (HRT) What are non- bio-identical hormones? • Synthetic and/ or animal derived • Premarin- mix of estrogens made from pregnant mare’s (horse) urine • Provera – chemically altered progesterone • Oral contraceptive pills

Hormone Replacement Therapy (HRT) Synthetic vs. Bio-identical

Hormone replacement therapy (HRT) Synthetic vs. Bio-identical PREMARIN ESTRADIOL

Hormone Replacement Therapy (HRT)

FDA approved bio-identical hormones: estradiol patch, estradiol pill, progesterone pill, estradiol gel or spray, estradiol vaginal inserts • Often covered by insurance Hormone Replacement Therapy (HRT)

Compounded bio-identical hormones: estradiol, estriol, bi-est, progesterone, testosterone, DHEA (creams, gels, troches, injections) • Customized strength/dose. • Option to customize fillers in case of sensitivity / allergy • Not FDA approved. • Pharmacies are regulated by state boards and required to comply with USP quality standards • Not covered by insurance (possible exception if allergy to a covered medication) Hormone Replacement Therapy (HRT)

Vaginal Dryness / Genitourinary Syndrome of Menopause (GUSM) Thinning and dryness of vaginal tissues • Itching, painful sex, bladder infections (dec in lactobacilli), incontinence Vaginal estrogen is safe for most women • Estradiol cream, suppository, ring • Compounded estriol cream DHEA • Intrarosa (prescription) • Julva (OTC - DHEA, coconut oil, shea butter, vit E) 1/8 tsp daily

Vaginal Dryness / GUSM Non-hormonal options - OTC vaginal moisturizers • Revaree (hyaluronic acid) • Bezwecken Hydration Pearls (cocoa butter, vit E, beeswax) • Replens (water, glycerin, mineral oil, palm oil) Regular use needed to be effective

Vaginal Dryness / GUSM MonaLisa Touch • CO2 laser ( non-invasive) therapy • Stimulates development of new cells and formation of collagen o https://my.clevelandclinic.org/health/treatments/ 24779-monalisa-touch

Reasons not to use: • Unexplained vaginal bleeding • Active breast or uterine cancer • Blood clots or stroke (oral estrogen) • Active or gallbladder liver disease (oral estrogen) • Smoker *Important to work with a knowledgeable provider to discuss risks/ benefits before starting HRT. Hormone Replacement Therapy (HRT)

Risk management: • Routine breast cancer screening • Manage weight • Lead an ideal lifestyle to reduce breast cancer risk • Anti-inflammatory diet, routine exercise, minimize alcohol, manage stress • Reduce toxin exposures (EDC’s), adequate sleep Hormone metabolite testing (looks at how well estrogen is being detoxified). Hormone Replacement Therapy (HRT)

• Good nutrition is imperative! o Mito food plan for hormone balance, inflammation control, weight control, cancer and dementia prevention, longevity • Reduce exposure to hormone disrupting chemicals o Pesticides, meat/ dairy ( conventionally raised) plastics, make- up, etc. • Prioritize and optimize your sleep o Exercise routinely, limit screen time, stick to same wake/ bedtime routine, consider supplements if needed Summary

• Stay conscious of managing your daily stress. o Cortisol affects ALL hormones o Prolonged stress = prolonged hormone imbalance. • Consider herbs / supplements and acupuncture for hot flashes and other symptoms • Don’t fear HRT! o Effective and safe option for the majority of women when started within 10 years of menopause o Work with a knowledgeable provider to review your personal risk factors. Summary

Phytoestrogens: Phytoestrogens and Their Health Effect https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390141/ Soy Isoflavones and Breast Cancer Risk: A Meta Analysis https://pubmed.ncbi.nlm.nih.gov/35241506/ Breast Cancer Prevention Partners website https://www.bcpp.org/resource/phytoestrogens/ S-equol: A Potential Nonhormonal Agent for Menopause-Related Symptom Relief. J Womens Health (Larchmt). 2015 Mar;24(3):200-8. References

Hormone replacement therapy: Progesterone vs. Synthetic progestins and the risk of breast cancer: a systematic review and meta- analysis Syst Rev. 2016 Jul 26;5(1):121. doi: 10.1186/s13643-016-0294-5. PMID: 27456847; PMCID: PMC4960754. References NAMS Position Statement 2022 https://www.menopause.org/docs/default- source/professional/nams-2022-hormone- therapy-position-statement.pdf

Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial. JAMA. 2002;288(3):321–333. doi:10.1001/jama.288.3.321 Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality JAMA. 2017;318(10):927-938. doi:10.1001/jama.2017.11217 The relationship between menopausal syndrome and gut microbes https://bmcwomenshealth.biomedcentral.com/articles/10.1186/s12905-022-02029-w References

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