C A S E - B A S E D L E A R N I N G

L E I G H M O R R I S O N , M D

O C T O B E R 5 , 2 0 1 8

F A L L U P D A T E I N F A M I L Y M E D I C I N E

Menopause Management: Hormone Therapy

Goals & Objectives

Review the evidence for complementary and alternative therapies for vasomotor symptoms

Review recommendations regarding hormone therapy in special populations

Uses clinical cases to apply knowledge for treatment of vasomotor symptoms

Complementary and Alternative Therapies

Phytoestrogens (Red Clover, Soy)

Black Cohosh

Hypnotherapy and Mindfulness Meditation

Acupuncture

Yoga

Phytoestrogens

Plant-derived substances with estrogenic activity Isoflavones: genistein and diadzein

Soybeans, soy products, red clover

Natural history: Asian women with diets rich in phytoestrogens

Experience fewer vasomotor symptoms

Lower risk of estrogen-sensitive cancer compared to Caucasian women

ACOG 2014

Phytoestrogens

2007, Cochrane meta-analysis 30 placebo-controlled trials

High levels of phytoestrogens

No evidence of benefit vs. placebo

No evidence of detrimental affects with use up to 2 years, but long-term safety data lacking

Lethaby, et al. 2007

Black Cohosh

Actaea racemosa or Cimicifuga racemosa plant

Conflicting data on safety and efficacy Limited study quality

Liver toxicity

Insufficient evidence

Acupuncture & Behavioral Changes

Acupuncture: 2009, meta analysis Six RCTs

No benefit over placebo for vasomotor symptoms

Lifestyle solutions:

Layering clothing, maintaining a lower ambient temperature, consuming cold drinks

Avoid alcohol and caffeine, may increase severity and frequency of vasomotor symptoms

Limited supporting data

Lee et al. 2009. Greendale, Gold 2005.

Compounded Bioidentical Hormones

Plant-derived hormones

Chemically similar or structurally identical to those produced by the body

FDA approved: Micronized progesterone, estradiol

Non-regulated:

Compounded preparations

Most lack rigorous clinical testing for safety & efficacy

Questionable purity, potency, quality

ACOG, 2014

Special Populations

Early menopause

Primary ovarian insufficiency

Premature surgical menopause

Breast cancer survivor

Family history of breast cancer

BRCA positivity without breast cancer

Early Menopause

HT is recommended until at least the median age of menopause (52 years) for women: With premature ovarian failure or premature surgical

menopause

Without contraindications

Observational studies only suggest benefits > risks: Bone, heart, cognition, genitourinary syndrome of menopause,

sexual function, and mood

Breast Cancer Survivor

NAMS 2017: Non-hormonal therapies are recommended

“… decisions about systemic HT should be made for compelling reasons after non-hormone or complementary options have been unsuccessful and after detailed counseling, with shared decision making and in conjunction with an oncologist”

Family History of Breast Cancer

Observational data only

HT does not further alter the risk of breast cancer in women with a family history of breast cancer

However, family history is one of many risks that should be assessed when counseling women

BRCA-Positive Without Breast Cancer

Higher genetic risk of breast cancer, primarily estrogen-receptor negative cancers

Limited observational studies

Bilateral risk-reducing mastectomy: Low baseline future risk of breast cancer

Bilateral oophorectomy: Benefits of supplemental estrogen to decrease risks caused by

premature loss of estrogen need to be considered

Case #1

54 year old female with bothersome hot flashes LMP age 52, intact uterus

Recent mammogram and TSH normal

Vasomotor symptoms result in poor sleep quality, irritability, “brain fog”

Desires treatment for her symptoms

Her best friend (age 59) was just diagnosed with breast cancer

“Will HT cause breast cancer if I take it?”

Breast Cancer – All Ages

EPT: Increase in breast cancer risk

Hazard ratio: 1.24, 95% CI, 1.01-1.53

9 additional cases per 10,000 person-years

Observational studies suggest that micronized progesterone may have less impact on breast cancer risk

JE Manson, et al. JAMA 2013

Absolute Risk by Age: EPT

Breast Cancer

Comparisons: Slightly greater risk than observed with one daily glass of wine

Less risk than two daily glasses of wine

Similar risk reported with obesity, low physical activity, and other medications

Breast cancer is common with or without HT

Only 1 in 5 breast cancers occurring in women using EPT can be attributed to HT

WY Chen, et al. 2011

Absolute Risk by Age: ET

Case #2

41 year old female with surgical menopause Hysterectomy at 40 years old for uterine fibroids

Severe vasomotor symptoms impacting overall quality of life

History of DVT at age 34

Recent mammogram and TSH normal

“I can’t live like this, what are my options for treatment?”

Indications for HT

Moderate-to-severe vasomotor symptoms Women <60 years old or within 10 years of menopause onset

Without contraindications

Prevention of osteoporosis among women at high risk of osteoporotic fracture who are unable to tolerate standard preventive therapy

Contraindications for HT

Absolute:

Unexplained vaginal bleeding

Liver disease

History of DVT/PE

Known clotting disorder or thrombophilia

Untreated hypertension

History of breast, endometrial, or other estrogen-dependent neoplasia

Hypersensitivity to hormone therapy

History of coronary vascular disease, stroke, or TIA

Relative:

Triglycerides >400

Gallbladder disease

Elevated risk of breast cancer

Oral vs. Transdermal ET

No RCT data comparing risks and benefits

Case-control and cohort studies suggest no increased risk of VTE or stroke from transdermal ET

Biologically plausible as transdermal ET avoids the first pass hepatic effect

Treating Vasomotor Symptoms

Gold Standard:

Hormone therapy

Less effective:

SSRIs

SSNRIs

Clonidine

Gabapentin

Case #3

46 year old female: return visit for depression Prozac 10 mg PO daily is working well

Improved mood, irritability, and anxiety

Side effects: hot flashes multiple times daily, poor sleep, fatigue, brittle hair and hair loss

Total abdominal hysterectomy

TSH normal, declines mammography

How would you counsel and treat this patient?

Case #4

52 year old female PMHx: type 2 DM, HTN, tobacco use, chronic low back pain

with sciatica

Normal mammogram and TSH

Bothersome vasomotor symptoms

“What are my options for treatment of these hot flashes?”

Gabapentin

Gabapentin 900 mg daily 2003 RCT, n=59

45% reduction in hot flash frequency (29% with placebo)

54% reduction in composite score (31% with placebo)

Greater reduction with higher, 0pen-label dosing

Gabapentin 600 mg daily vs. low-dose transdermal estradiol (25 mcg) 2010 RCT, n=45

Symptom relief more effective in the estrogen group

T Guttuso, et al. Obstet Gynecol 2003

Gabapentin

Adverse effects Dizziness

Somnolence

Peripheral edema

Venlafaxine 75 mg daily vs. gabapentin 300 mg TID 2010 Cross-over RCT, n=56, breast cancer survivors

68% preferred venlafaxine

32% preferred gabapentin

Both agents reduced hot flash scores by 66%

Case #5

48 year old breast cancer survivor Premature ovarian failure due to prophylactic BSO

BRCA-1 carrier

ER-negative breast cancer

Bothersome vasomotor symptoms, worse than side effects from chemotherapy

“What are my options for treatment?”

References

ACOG Practice Bulletin No. 141: Management of menopausal symptoms. Obstet Gynecol. 2014 Jan; 123(1):202-16.

Lethaby A, Marjoribanks J, Kronenberg F, Roberts H, Eden J, Brown J. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD001395.

Frei-Kleiner S, Schaffner W, Rahlfs VW, Bodmer C, Birkhauser M. Cimicifuga racemosa dried ethanolic extract in menopausal disorders: a double-blind placebocontrolled clinical trial. Maturitas 2005;51:397–404.

Nappi RE, Malavasi B, Brundu B, Facchinetti F. Efficacy of Cimicifuga racemosa on climacteric complaints: a randomized study versus low-dose transdermal estradiol. Gynecol Endocrinol 2005;20:30–5.

Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K, Guiltinan J. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern Med 2006;145:869–79.

References

Greendale GA, Gold EB. Lifestyle factors: are they related to vasomotor symptoms and do they modify the effectiveness or side effects of hormone therapy? Am J Med 2005;118(suppl 12B):148–54

Kaunitz AM, Manson JE. Management of Menopausal Symptoms. Obstet Gynecol. 2015 Oct; 126(4): 859-76.

Leach MJ, Moore V. Black cohosh (Cimicifuga spp.) for menopausal symptoms. Cochrane Database Syst Rev. 2012 Sep 12;9:CD007244. doi: 10.1002/14651858. CD007244.pub2.

Lee MS, Shin BC, Ernst E. Acupuncture for treating menopausal hot flushes: a systematic review. Climacteric 2009;12:16–25

Pockaj BA, Gallagher JG, Loprinzi CL, Stella PJ, Barton DL, Sloan JA, et al. Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes: NCCTG Trial N01CC1. J Clin Oncol 2006;24:2836–41.