HOT FLUSHES

HOT FLUSHES - Jennifer W. McCaul, MD; Sandra M. Sulik, MD
BASICS
DESCRIPTION
• Sensation of heat experienced by the patient accompanied by perspiration, flushing, anxiety, and palpitations
- Lasting 4-10 minutes
- Followed by a drop in core temperature with or without shivering
- May be experienced as night sweats
- Can occur several times per hour to several times per week
• System(s) Affected: Thermoregulatory; Psychiatric; Cutaneous; Cardiovascular
GENERAL PREVENTION
Unknown
EPIDEMIOLOGY
• Less common in Asian women
• More common in African American and Caucasian women
• Predominant Age: Menopausal and perimenopausal women; younger women and males can be affected if surgically or chemically induced.
Incidence
90% after surgical menopause.
Prevalence
Thirty percent to 80% of menopausal women; 10-20% find them intolerable.
RISK FACTORS
• Low circulating estradiol or estrone concentration in menopausal women
• Abrupt menopause: Surgical, chemotherapy, radiation, drug-induced
• Underweight, lack of exercise, smokers
• Menopause at a younger age
PATHOPHYSIOLOGY
Inappropriate peripheral vasodilation with increased cutaneous blood flow and perspiration
• Results in decreased core temperature, causing shivering
ETIOLOGY
Currently unknown, theories include
• Decreased circulating estrogen or increased circulating gonadotropins causing alteration in hypothalamic thermoregulatory set point
• Decreased estrogen causes decline in serotonin, increasing sensitivity of hypothalamic serotonin receptors involved in thermoregulation.
• Endogenous opiod peptide withdrawal associated with estrogen deficiency


DIAGNOSIS
SIGNS AND SYMPTOMS
Subjective sensation of heat accompanied by perspiration, palpitations, flushing, and anxiety
• May be followed by shivering
• Frequency and severity vary by individual.
• Other symptoms of menopause include joint pain, sleep problems, fatigue, forgetfulness, and urinary incontinence.
History
Menstrual irregularity, vaginal dryness, and above symptoms can help confirm diagnosis.
• Symptoms may appear after surgical menopause or after treatment for breast or prostate cancer.
Physical Exam
Signs of menopause include skin thinning, vaginal atrophy, hirsutism, and central adiposity.
Lab
Not usually necessary however
• Can check FSH and estradiol in patients 40 or who have regular menses
• Can check FSH and estradiol in older patients on oral contraceptives who wish to stop
• FSH >40 mIU/mL or Estradiol 30 pg/mL helps confirm menopause.
DIFFERENTIAL DIAGNOSIS
Other causes are rare but include (1)
• Diseases: Carcinoid, mastocytosis, anxiety, carcinomas (pancreatic, renal cell, medullary thyroid), pheochromocytoma, dumping syndrome, migraine, brain or spinal cord lesion
• Drugs: Alcohol, opiates, calcium channel blockers, cholinergics, cephalosporins, azoles, aromatase inhibitors
• Additives: MSG, sodium nitrate, sulfites
TREATMENT
GENERAL MEASURES
Avoid or reduce cigarette smoking.
Activity
No restrictions
Complementary and Alternative Therapies
• Herbal remedies
- Black Cohosh (Remifemin) decreased hot flushes in several short studies, but no long term safety information is available. (2)[B]
- Dong Quai, Ginseng, Red Clover, Chaste Tree Berry, and Evening Primrose oil have all shown no benefit over placebo. (2)[B]
- Wild yam/Progesterone cream1 trial showed significant improvement in symptoms but also induced worrisome postmenopausal bleeding in some patients. (2)[B]
• Dietary Phytoestrogens decreased symptoms in multiple studies, but effects are modest and lasted 6 weeks. (20)[B] Soy foods are assumed safe; however, no safety information is available for high dose extracts.
• Vitamin E has shown no significant improvement over placebo. (2)[B]
• Acupuncture and Paced Respiration, behavioral therapy, have shown some benefit in frequency of hot flushes. Studies are limited. (2)[B]
MEDICATION (DRUGS)
First Line
Estrogen or combined estrogen/progesterone
• Various treatment regimens resulted in a 75% mean reduction in frequency of hot flushes and a significant reduction in severity when compared with placebo. (3)[A]
- Of note, there was a 58% reduction in hot flush frequency in the placebo group at the end of the study. (3)[A]
• Common regimens include
- Premarin 0.625 mg + Provera 2.5 mg daily
- Premarin 0.625 mg daily + Provera 5 mg during the last 14 days or the month.
- Can increase premarin to 1.25 mg/d for refractory cases. However, lowest dose possible should always be used.
- Combination therapiesPrempro, Premphase.
- Transdermal estradiol can also be used for estrogen component. (0.05-0.1 mg/d patch applied once or twice weekly
- Vaginal conjucated estrogen creams give unpredictable blood levels and should not be used for hot flush treatment.
• With an intact uterus, progestins must always be used to protect against endometrial hyperplasia.
• Contraindications: Hormone-dependent cancers (Breast, Uterine), history of DVT, Liver dysfunction or undiagnosed vaginal bleeding.
• Side effects include nausea, breast pain, vaginal bleeding, headache, libido change.
• Serious adverse effects of long term use
- Increased risk of cardiac event in years 1-4 of combined therapy (no significant risk seen after 5 years. (4)[A] RR 1.37 (95% CI 1.05-1.79) to 1.74 (95% CI 1.05-2.89).
- Increased risk of stroke after 3 or more years of therapy. (4)[A] RR 1.37 (95% CI 1.1.08-1.73) to 1.47 (95% CI 1.02-2.11).
- Increased risk of venous thromboembolism with >1 year of therapy. (4)[A] RR 2.09 (95% CI 1.60-2.74) to 3.59 (95% CI 1.95-6.61).
- Increased risk of dementia in combined HT, RR 1.97 (95% CI 1.16-3.33). (4)[A]
- No statistically significant risks for TIA.
- Breast cancer risk may be increased with >5 years use of combined therapy.
- No Increase in colorectal cancer, endometrial cancer, or death from any cause were found. (4)[A]
- The majority of data for these risks was obtained from the WHI study, only enrolling women >65.These risks may or may not be present for younger women with shorter courses of HT.
• Therapy should be discontinued gradually or slowly tapered to prevent recurrence of symptoms.
• There may be a decreased risk of hip fracture with long term HT; however, studies conflict.
Second Line
• Selective serotonin reuptake inhibitors
- Have been found to decrease hot flush frequency by 50-60% in RCTs (placebo resulted in 20-36% decrease). (1)[B]
- Studied medications include Venlafaxine, Fluoxetine and Paroxetine.
- Represent a reasonable alternative for women in whom HT is contraindicated
- Adverse effects are rare and include GI symptoms, sexual dysfunction and SIADH.
- The dose of SSRI helpful for hot flushes may be less than that for depression. It is appropriate to start at the lowest dose. Additionally, improvement is usually seen sooner than when used for depression.
• Neurontin (Gabapentin) has been shown to be more effective than placebo in limited studies, more research is needed.
• Clonidine (0.1 mg PO b.i.d.) has been shown to be moderately more effective then placebo for mild to moderate hot flush relief. Studies are limited. (1)[B]
- Side effects such as dry mouth, constipation, and orthostatic hypotension limit use.
• Tibolone is a synthetic steroid widely used in Europe known to increase bone density. There is a possible increase in breast cancer in a large observational study. (1)[C]
• Testosterone: Adding testosterone to a HT regimen has been shown to increase sexual function and libido. It also had the effect of lowering HDL; the amount of decrease varied with dosing regimen. (5)[A]
Complementary and Alternative Medicine
Some positive evidence exists for the use of soy isoflavones and black cohosh, though better quality studies are needed (6,7).
FOLLOW-UP
DISPOSITION
May consider further workup looking for atypical causes or specialist referral for symptoms with no response to conventional hormone therapy
Issues for Referral
Usually only necessary if no response to conventional hormone therapy
PROGNOSIS
• Hot flushes resolve spontaneously within 5-6 years in 80-90% of patients.
• Some may continue up to 15 years.
• Most patients will experience at least some relief in frequency or severity of hot flushes with therapy.
PATIENT MONITORING
Due to nature of symptoms and risks involved in therapy, patients should be seen frequently and medications adjusted until symptoms are managed.
• Decisions regarding treatment should be made collaboratively with patient awareness of risks and benefits.
REFERENCES
1. Stearns V, Ullmer L, et al. Hot Flushes. Lancet. 2002;360:1851-1861.
2. Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: A review of randomized controlled trials. Ann Intern Med. 2002;137:805-813.
3. McLennan AH, Broadbent JL, et al. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. The Cochrane Database of Systemic Reviews 2004, Issue 4. Art. No.: CD002978. pub2. DOI:10. 1002/14651858. CD002978.pub2.
4. Farquhar CM, Marjoribanks J, et al. Long term hormone therapy for perimenopausal and postmenopausal women. The Cochrane Database of Systemic Reviews 2005, Issue 3. Art. No.: CD004143.pub2. DOI: 10.1002/14651858.CD004143.pub2.
5. Somboonporn W, Davis S, et al. Testosterone for peri- and postmenopausal women. The Cochrane. Database of Systematic Reviews 2005, Issue 4. Art. No.: CD004509.pub2.DOI: 10.1002/14651858.CD004509.pub2.
6. Upmalls DH, Lobo R, Bradley L, et al. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study. Menopause. 2000;7(4):236-242.
7. Pockaj BA, Gallagher JG, Loprinzi CL, et al. Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes. J Clin Oncol. 2006 Jun 20;24(18):2836-41.