Vasomotor Symptoms of Menopause

Aka: Vasomotor Symptoms of Menopause, Hot Flashes, Hot Flushes, Flushing, Menopausal Diaphoresis

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II. Epidemiology

  1. Vasomotor symptoms occur in 85% of perimenopausal women
    1. Starts 1-2 years before Menopause
    2. Continues for up to 5 to 8 years

III. Differential Diagnosis

  1. Medications
    1. Isoniazid
    2. Disulfiram reaction
      1. Griseofulvin
      2. Flagyl
      3. Chlorpropamide
      4. Chloral Hydrate
    3. Niacin
    4. Hydralazine
    5. Calcitonin
    6. Aspirin sensitive
    7. Procardia
    8. Capsaicin
    9. MAO Inhibitor when taken with Tyramine (beer, cheese)
  2. Medication Withdrawal
    1. Clonidine Withdrawal
    2. Alpha-Methyldopa withdrawal
    3. Alcohol Withdrawal
  3. Pheochromocytoma
  4. Carcinoid
  5. Mastocytosis in Leukemia
    1. Histamine and Prostaglandin D Release
    2. Hypotensive episodes
    3. Dermatographia
  6. VIP-oma or WDHA: Diarrhea, Hypokalemia, achlorhydria
  7. Menopausal Flushing
  8. Emotional blushing
  9. Food and Environmental Stimuli
    1. Monosodium Glutamate
    2. Thermal stimuli
    3. Ethanol (worse with Rosacea, Carcinoid, Mastocytosis)
    4. Scombroid Fish Poisoning: Tuna, Mahi-mahi, Mackerel
  10. Syndrome obscure in women
    1. Characteristics
      1. Telangiectasia
      2. Urticaria
      3. Flushing
      4. Peptic Ulcer Disease
      5. Diarrhea
    2. Increased blood and urine Histamine
    3. Not associated with Mastocytosis or Carcinoid

IV. Management: Nonpharmacologic and Lifestyle

  1. Precautions
    1. No single lifestyle modification has been found consistently effective in Hot Flashes
    2. However, many lifestyle measures listed have broader health benefits (e.g. weight loss, Tobacco Cessation)
    3. (2015) Menopause 22(11): 1155-72 [PubMed]
    4. Kaunitz (2015) Obstet Gynecol 126(4): 859-76 [PubMed]
  2. General measures (no strong evidence of benefit)
    1. Wear cool clothing (e.g. breathable)
    2. Use a fan
    3. Drink cool liquids and eat cold foods
  3. Avoid Exacerbating food products (no strong evidence of benefit)
    1. Caffeine
    2. Alcohol in excess
    3. Spicy food
    4. Dietary Fat intake
      1. Associated with Hot Flushes in Postmenopause
      2. Riley (2004) J Gen Intern Med 19:740-6 [PubMed]
  4. Vitamin Supplementation (no strong evidence of benefit)
    1. Vitamin B6 may be helpful
    2. Vitamin E is no more effective than Placebo
  5. Weight loss
    1. Associated with less Hot Flushes in Perimenopause
    2. Riley (2004) J Gen Intern Med 19:740-6 [PubMed]
  6. Behaviorial Interventions
    1. Cognitive Behavioral Therapy
    2. Relaxation Therapy
    3. Mindfulness-based Stress Reduction
    4. Van Driel (2019) BJOG 126(3): 330-9 [PubMed]
  7. Regular Exercise has mixed results (no strong evidence of benefit)
    1. Original study supported Exercise as effective
      1. Ivarsson (1998) Maturitas 29:139-46 [PubMed]
    2. Recent study does not show benefit in Hot Flushes
      1. Aiello (2004) Menopause 11:382-8 [PubMed]
  8. Other measures without strong evidence of benefit in Vasomotor Symptom Reduction
    1. Tobacco Cessation
    2. Yoga
    3. Massage
    4. Meditation
    5. Leisurely bath

V. Management: Medications

  1. Hormonal agents (most effective, but review risks and contraindications)
    1. Estrogen Replacement Therapy
      1. Relieves symptoms in 80-90% of patients
    2. Progestin (less effective than Estrogen containing options)
      1. Progesterone transdermal cream (20 grams/day)
        1. Leonetti (1999) Obstet Gynecol 94:225-8 [PubMed]
      2. Megestrol acetate (Megace) 20 mg PO bid
        1. Relieves symptoms ~50% of cases
      3. Medroxyprogesterone acetate (Provera) 20 mg orally daily
        1. Relieves symptoms ~50% of cases
    3. Tissue-selective Estrogen Complex (TSEC): Estrogen with Selective Estrogen Receptor Modulator (SERM)
      1. Duavee is a combination of Estrogen AND Bazedoxifene (BZA)
      2. First TSEC released in U.S. 2019
      3. Significantly reduces vasomotor symptoms without affecting Breast tissue, endometrium or VTE or Cardiac Risk
      4. Lello (2017) Int J Endocrinol 2017:5064725 +PMID: 29358948 [PubMed]
  2. Serotonin Norepinephrine Reuptake Inhibitor (SNRI)
    1. Efficacy
      1. Venlafaxine appears to be most effective among SNRI and SSRI agents
      2. Venlafaxine does not affect Tamoxifen metabolism (unlike some SSRIs that are CYP2D6 Inhibitors)
      3. However, SNRIs also have more side effects than SSRIs (e.g. Nausea, Dry Mouth, Constipation, Somnolence)
    2. Desvenlafaxine (Khedezla)
    3. Venlafaxine (Effexor)
      1. Dose: 12.5 mg orally twice daily or 75 mg orally at bedtime
      2. (1998) J Clin Oncol 16:2377 [PubMed]
      3. Loprinzi (2000) Lancet 356:2059-63 [PubMed]
  3. Selective Serotonin Reuptake Inhibitors (SSRI)
    1. Efficacy
      1. More effective and better tolerated than Clonidine or Gabapentin
    2. Precaution: Avoid Prozac and Paxil in Breast Cancer patients on Tamoxifen
      1. CYP2D6 Inhibitors (e.g. Paroxetine, Fluoxetine, Bupropion) may decrease Tamoxifen efficacy
      2. Other SSRIs inhibit CYP2D6 but less potently
    3. SSRIs shown to be effective
      1. Paroxetine (Paxil CR)
        1. Paroxetine 12.5 to 25 mg orally daily
          1. Stearns (2003) JAMA 289:2827-34 [PubMed]
        2. Released as Brisdelle (7.5 mg Paroxetine) in 2013 specifically targeting Hot Flushes
          1. Paroxetine 10 mg generic tablet daily is nearly equivalent (at 6% of the Brisdelle cost)
      2. Fluoxetine (Prozac)
        1. Loprinzi (2002) J Clin Oncol 20:1578-83 [PubMed]
    4. SSRIs not found to be effective
      1. Citalopram (Celexa)
      2. Sertraline (Zoloft)
      3. Suvanto-Luukkonen (2005) Menopause 12:18-26 [PubMed]
  4. Miscellaneous agents with some efficacy against Hot Flushes
    1. Clonidine
      1. Start 0.1 mg orally at bedtime (or 0.1 mg weekly transdermal patch)
      2. May titrate to 0.2 mg orally at bedtime and up to 0.2 mg orally twice daily
      3. Modest benefit, but adverse effects (Hypotension, Dizziness) may limit use
      4. (1994) JCO 12:155
    2. Gabapentin (Neurontin)
      1. Dosing: Titrate to 300 mg orally three times daily
      2. Guttuso (2003) Obstet Gynecol 101:337-45 [PubMed]
    3. Neurokinin 3 Receptor Antagonist (e.g. Fezolinetant or Veozah)
      1. Fezolinetant (Veozah) 45 mg orally daily
      2. Requires hepatic profile monitoring (baseline, and at 3, 6, and 9 months)
      3. Cost $550 per month when released in 2023
      4. Less effective than hormonal therapy, but similar to SNRIs, SSRIs and Gabapentin in hot flash reduction
      5. Blocks neurokinin B (NKB) at the infundibular nucleus of the Hypothalamus
        1. Neurokinin B (NKB) regulates temperarture and its blockade can decrease Vasomotor Symptoms of Menopause (Hot Flashes)
  5. Other agents with historic use
    1. Aldomet 250 mg PO bid
    2. Bellergal-S 100
      1. Small risk of addiction

VI. Management: Herbals and Dietary Supplements

  1. Possible benefit
    1. Omega-3 Fatty Acids
    2. Black Cohosh
      1. Castelo-Branco (2021) Climacteric 24(2): 109-19 [PubMed]
      2. Hernandez (2003) Maturitas 44:S59-65 [PubMed]
    3. Soy Isoflavones or Phytoestrogens
      1. See Soy Protein
      2. Original studies with mixed results (prior to consideration of pharmacogenomic factors )
        1. Faure (2002) Menopause 9:329-34 [PubMed]
        2. Han (2002) Obstet Gynecol 99:389-94 [PubMed]
        3. Nikander (2003) Obstet Gynecol 101:1213-20 [PubMed]
      3. Effectiveness appears dependent on pharmacogenomic factors
        1. Equol is a soy metabolite with Estrogenic Activity
        2. Only 40% of North American women convert Soy Isoflavone (daidzein) to equol
          1. Conversion is most common in Asian and Hispanic women
          2. The majority who lack this conversion are unlikely to see benefit from soy
        3. References
          1. Clarkson (2011) Menopause 18(7):732-53 [PubMed]
  2. Unlikely benefit
    1. Dong Quai (No better than Placebo)
    2. Evening Primrose Oil
    3. Red Clover
      1. Tice (2003) JAMA 290:207-14 [PubMed]
    4. Vitamin E slightly better than Placebo
      1. Barton (1998) J Clin Oncol 16:495-500 [PubMed]

VII. References

  1. Carroll (2006) Am Fam Physician 73:457-67 [PubMed]
  2. Chang (2023) Am Fam Physician 108(1): 28-39 [PubMed]
  3. Diem (2020) Menopause 27(10): 1126-36 [PubMed]
  4. Handley (2015) J Am Assoc Nurse Pract 27(1): 54-61 [PubMed]
  5. Hill (2016) Am Fam Physician 94(11): 884-9 [PubMed]
  6. Israel (1997) Pharmacotherapy 17:970-84 [PubMed]
  7. Morelli (2002) Am Fam Physician 66(1):129-34 [PubMed]
  8. Shanafelt (2002) Mayo Clin Proc 77:1159-63 [PubMed]

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