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.