Tara K. Ortiz, MD
Judd W. Moul, MD, FACS
BASICS
DESCRIPTION
• Hot flushes are typically described as a feeling of intense heat with associated flushing, sweating, rapid heart rate, and anxiety
• Sometimes called “hot flashes”
• Common side effect of androgen ablation therapy in men with metastatic or locally advanced prostate cancer
• Flushing can be associated with wide ranges of other conditions and medications
• This section primarily discusses this condition in males
EPIDEMIOLOGY
Incidence
Occurs in 50–80% of men on androgen deprivation therapy (1)
Prevalence
N/A
RISK FACTORS
• Age, race and ethnicity, educational level, smoking, cardiovascular risk including body mass index, and genetics
• Prostate cancer
Genetics
N/A
PATHOPHYSIOLOGY
• Exact mechanism unknown; majority of theories based on studies in postmenopausal women
• Hot flushes in prostate cancer patients result from decreased feedback of testosterone to the hypothalamus.
• Central control of thermoregulation is preoptic/anterior area in the brain
• Increases in internal and/or skin temperature sensed in the anterior pituitary results in cutaneous vasodilatation (flushing) and sweating.
• Thermoregulatory zone is disrupted:
– Reduced thermoneutral zone between an upper threshold for sweating and a lower threshold for shivering
• Alterations in glucose transport across blood–brain barrier theorized to be a trigger:
– Hot flushes are counterregulatory attempts to increase cerebral blood flow and cerebral glucose levels.
• Decreased plasma sex hormones results in loss of negative feedback, thus increasing hypothalamic norepinephrine (NE) levels
• NE decreases thermoneutral zone
– Thermoregulatory center in hypothalamus is anatomically close to the GnRH-secreting neurons
– These neurons are stimulated by NE to secrete GnRH
– Increased GnRH stimulation, by being in close proximity to the thermoregulatory center, might activate heat-losing mechanisms (flushing, sweating).
ASSOCIATED CONDITIONS
• Osteopenia, osteoporosis
• Erectile dysfunction/loss of libido
• Metabolic syndrome (insulin resistance, unfavorable lipid profile, increased fat mass)
• Gynecomastia
• Normocytic, normochromic anemia
• Fatigue
GENERAL PREVENTION
• Identification of triggers
– Avoid hot beverages, spicy foods, alcohol, abrupt change in ambient temperature
• Keep environment cool
DIAGNOSIS
HISTORY
• Abrupt onset of warmth, frequently followed by profuse sweating requiring change of clothes
• More likely to occur at night
• Sensation typically affects the face and trunk
• Attacks normally last 1–5 min, but can persist for up to 20 min
• Can occur occasionally or multiple times daily:
– Majority of patients have daily episodes
• Frequently experienced at night
• Onset is typically seen within the 1st yr after androgen ablation:
– 1/3 of men will develop symptoms within the 1st mo
PHYSICAL EXAM
• During acute episode, facial flushing common
• Perspiring frequently present
• Mild tachycardia secondary to vasodilation or anxiety
• Slight increase in oral and forehead temperature
• Usually normal exam in between hot flush episodes
• May have gynecomastia, increased fat mass secondary to androgen deprivation
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• No routine lab evaluation indicated
• No pattern of characteristic changes in testosterone, follicle-stimulating hormone (FSH), leuteinizing hormone (LH), or prolactin
Imaging
N/A
Diagnostic Procedures/Surgery
N/A
Pathologic Findings
N/A
DIFFERENTIAL DIAGNOSIS
• Febrile states or hyper thermia
• Emotional blushing
• Systemic illness:
– Carcinoid syndrome
– Pheochromocytoma
– Medullary thyroid tumors
– Pancreatic islet cell tumors
– Renal cell carcinoma
• Other illness:
– Rosacea
• Neurologic disorders
• Medications:
– Phosphodiesterase 5 inhibitors (sildenafil, vardenafil, tadalafil, avanafil),
– Any vasodilatory agent (nitroglycerine, etc.)
– Nicotinic acid
– Calcium channel blockers most commonly nifedipine, nisoldipine, amlodipine
– Opiates
– Tamoxifen
– Antibiotics (vancomycin, amphotericin B)
– IV contrast media
• Dietary
– Ethanol ingestion
– Monosodium glutamate or other food additives
TREATMENT
GENERAL MEASURES
• For flushing related to androgen deprivation therapy
– Reassurance if symptoms mild
– Attempt to identify and avoid lifestyle triggers
– Keep environment cool
– Many men will experience resolution after several years without therapy
MEDICATION
First Line
• For androgen deprivation therapy related hot flushes most are hormonal agents
• Megestrol acetate (Megace) 20 mg/d:
– Synthetic derivative of progesterone
– 1 study demonstrated complete resolution of symptoms in 90% of patients, >50% improvement in 25% (2)[B]
– Side effects include chills, weight gain, nausea, carpal tunnel–like syndrome, disease progression
• Medroxyprogesterone acetate (Depo Provera) 400 mg/d IM:
– 91% with symptomatic improvement (1)[B]
– 46% have complete response as defined as total elimination of hot flushes.
– Side effects could include weight gain, congestive heart failure exacerbation, loss of bone mineral density, disease progression
• Transdermal estrogen patch 0.05 or 0.1 mg/d (1,3)[B]:
– 3 studies with over 70% of men reporting complete resolution
– Side effects include breast swelling, nipple tenderness
• Diethylstilbestrol (DES): 0.30–1 mg/d:
– 70–90% of men achieve excellent results (1)[B]
– Side effects include painful gynecomastia.
– At low doses, thromboembolic events are not a significant problem.
– Generic drug, inexpensive though difficult to obtain in US.
• Cyproterone acetate (Androcur) 100 mg/d
– Not approved for use in US
– Steroidal antiandrogen, antigonadotropin with progestin-like activity
– May interfere with ADT regimen
– 1 study demonstrated resolution of symptoms in 84% of patients, >50% improvement in 37% (2)[B]
– Side effects include fatigue, increased risk of thrombosis, anemia, potential hepatotoxicity, gynecomastia
Second Line (Nonhormonal Therapy)
• Venlafaxine (Effexor) 12.5 mg/d PO:
– Antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) type
– Median weekly hot flush scores decreased 54% from baseline after 1 mo (2)[B]
– Side effects include lack of sexual desire, delayed orgasm, and increase in suicidal ideation.
• Paroxetine (Paxil-CR) 12.5–37.5 mg/d:
– Antidepressant of the selective serotonin reuptake inhibitor (SSRI) class
– In 1 study, daily hot flushes decreased from 6.2–2.5. (4)[B]
– Side effects include sexual dysfunction, somnolence
• Ergotamine/belladonna/phenobarbital (EBP): 1 tablet PO BID:
– Ergot alkaloid used primarily to treat migraine headache
– Use with caution with patients on monoamine oxidase inhibitors (MAOIs), central nervous system (CNS) depressants, anticholinergic agents
– Generally not recommended for the treatment of hot flushes in men
• Gabapentin (Neurontin) 900 mg/d (300 mg TID, titrated) (5)[B]
– Anticonvulsant/treatment of neuropathic pain
– Modest 46% reduction in hot flush symptom score at target dose of 900 mg
– Side effects include nausea, vomiting, dizziness, and somnolence
• Clonidine (Catapres) 0.1–1 mg/d (PO or patch formulations):
– Centrally acting α-adrenergic agonist used for treatment of hypertension (HTN)
– 1/3 of men will report a partial response although similar to placebo (1)[B].
– Side effects include hypotension, dry mouth, skin irritation from patches.
SURGERY/OTHER PROCEDURES
N/A
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
Behavioral therapy: Slow, deep breathing may reduce frequency of hot flushes
Complementary & Alternative Therapies
• Acupuncture:
– 10–12 wk (twice weekly × 2 wk then once weekly × 8–10 wk)
– 43–78% reduction in frequency of flushes, average 9-mo duration of effect (1)[B]
• Vitamin E:
– 30% reduction vs. 22% of women receiving placebo in 1 study (not studied in men)
– May increase the risk of prostate cancer; unclear effect on existing cancer (1)[B]
• Soy products:
– Contain phytoestrogens which might decrease severity of hot flushes (1)[C]
– Also have shown benefit with regard to cardiac and bone health
• Black cohosh:
– Has been used in some postmenopausal women for treatment of hot flushes
– Mechanism is unknown
– In 1 trial, no difference found with men taking placebo (1)[C]
ONGOING CARE
PROGNOSIS
• Most men have symptom improvement with medical or complementary therapy.
• At 8 yr of treatment with ADT over 40% of men still had flashes.
• In 1 study, 72% of patients noted that hot flashes interfered with sleep and 59% reported they interfered with the quality of life.
COMPLICATIONS
Some men have side effects from medications taken to alleviate hot flushes (bloating, weight gain, hypertension)
FOLLOW-UP
Patient Monitoring
• Ask patients on androgen deprivation at each follow-up clinical evaluation about the presence and severity of hot flushes:
– Inquire about side effects from therapy
– Intermittent cessation of treatment can be used if side effects become bothersome.
May have positive effect on quality of life, but may decrease survival
Patient Resources
N/A
REFERENCES
1. Jones JM, Kohli M, Loprinzi CL, et al. Androgen deprivation therapy-associated vasomotor symptoms. Asian J Androl. 2012;14(2):193–197.
2. Irani J, Salomon L, Oba R, et al. Efficacy of venlafaxine, medroxyprogesterone acetate, and cyproterone acetate for the treatment of vasomotor hot flushes in men taking gonadotropin-releasing hormone analogues for prostate cancer: A double-blind, randomised trial. Lancet Oncol. 2010;11:147–154.
3. Langenstroer P, Kramer B, Cutting B, et al. Parenteral medroxyprogesterone for the management of luteinizing hormone releasing hormone induced hot flashes in men with advanced prostate cancer. J Urol.2005;174:642–645.
4. Naoe M, Ogawa Y, Shichijo T, et al. Pilot evaluation of selective serotonin uptake inhibitor antidepressants in hot flash patients under androgen-deprivation therapy for prostate cancer. Prostate Cancer Prostatic Dis.2006;9(3):275–278.
5. Moraska AR, Atherton PJ, Szydlo DW, et al. Gabapentin for the management of hot flashes in prostate cancer survivors: A longitudinal continuation study—NCCTG Trial N00CB. J Support Oncol. 2010;8:128–132.
ADDITIONAL READING
• Baum NH, Torti DC. Managing hot flashes in men being treated for prostate cancer. Geriatrics. 2007;62:18–21.
• Engstrom CA, Kasper CE. Physiology and endocrinology of hot flashes in prostate cancer. Am J Men Health. 2007;1:8–17.
• Sharifi N, Gulley JL, Dahut WL, et al. Androgen deprivation therapy for prostate cancer. JAMA. 2005;294:238–244.
See Also (Topic, Algorithm, Media)
• Andropause (Late-Onset Hypogonadism)
• Menopause, Urologic Considerations
• Testosterone, Decreased (Hypogonadism)
CODES
ICD9
• 780.2 Syncope and collapse
• 780.8 Generalized hyperhidrosis
• 782.62 Flushing
ICD10
• R23.2 Flushing
• R55 Syncope and collapse
• R61 Generalized hyperhidrosis
CLINICAL/SURGICAL PEARLS
• Symptoms are usually reversible with cessation of ADT usually within 3–4 mo of stopping treatment.
• Most effective treatment is hormonal therapy with estrogen or progesterone derivatives.
• There are limited data to support alternative/complementary therapies.