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Alternatives for Hot Flushing
By Leon Speroff, MD
The vasomotor flush is viewed as the hallmark of the female climacteric, experienced to some degree by most postmenopausal women. In the Massachusetts Women’s Health Study, the incidence of hot flushes increased from 10% during the premenopausal period to about 50% just after cessation of menses.1 In a community-based Australian survey, 6% of premenopausal women, 26% of perimenopausal women, and 59% of postmenopausal women reported hot flushing.2 Although the flush can occur in the premenopause, it is a major feature of postmenopause, lasting in most women for 1-2 years but in some (as many as 25%) for longer than 5 years. In cross-sectional surveys, up to 40% of premenopausal women and 85% of menopausal women report vasomotor complaints.3
The treatment of choice for vasomotor symptoms is hormone therapy. However, there exists a substantial number of women who either cannot or will not accept hormone therapy. The alternative choices that have been available in the past offered only a modest benefit. Transdermal clonidine, applied with the 100-mg dose once weekly was a common choice, but the reduction in hot flushing was only slightly better than that obtained with placebo treatment.4,5 Clonidine, bromocriptine, and naloxone given orally are only partially effective for the relief of hot flushes and require high doses with a high rate of side effects. Bellergal treatment (a combination of belladonna alkaloids, ergotamine tartrate, and phenobarbital) is slightly better than a placebo and a potent sedative in the short-term; however, one study documented a similar response with bellergal and placebo after 8 weeks.6,7 Veralipride, a dopamine antagonist that is active in the hypothalamus, is relatively effective in inhibiting flushing at a dose of 100 mg daily but is associated with major side effects, including mastodynia and galactorrhea.8-10 Medroxyprogesterone acetate (10-20 mg daily) and megestrol acetate (20 mg b.i.d.) are also effective, but concerns regarding exogenous steroids (especially in patients who have had breast cancer) would apply to progestins as well.11,12 Vitamin E, 800 IU daily, is barely more effective than placebo.13 Isoflavones (including soy protein) have been demonstrated to have little clinical difference compared with placebo treatment.
In the last few years, selective serotonin reuptake inhibitors (SSRIs) have gained a reputation for significant efficacy in treating hot flushing. The drugs that have been studied include fluoxetine (Prozac), paroxetine (Paxil), and venlafaxine (Effexor). In addition, an antiseizure medication, gabapentin (Neurontin), has been demonstrated to reduce vasomotor symptoms.
In the study with paroxetine (the controlled-release product), 61% of the treated group (a general population of postmenopausal women with only 12 individuals who were breast cancer survivors) at the end of the study had at least a 50% reduction in frequency and severity of flushing, an effect that was about 2.5 times better than placebo with the higher dose.14 An important feature of this study was that individuals with clinically significant mood disorders were excluded. Venlafaxine was studied in breast cancer survivors; although the optimal dose was 75 mg, an appreciable response with 37.5 mg indicated that it would be worthwhile to begin treatment with the lower dose.15,16 The response was very rapid, within days, and therefore the dose can be increased in 1-2 weeks. The main side effects were mouth dryness, anorexia, nausea, and constipation. The efficacy of venlafaxine was demonstrated to be the same in women taking or not taking tamoxifen. Fluoxetine was also studied in breast cancer survivors; its effect appeared to be more modest.17
Gabapentin is a g-aminobutyric acid analogue that has been used for seizures since 1994. It is also effective for migraine headaches, tremors, and panic disorder. In the gabapentin clinical trial, 67% of the treated women experienced more than a 50% reduction in flushes at week 12, compared with 38% in the placebo group.18 The most common side effects were somnolence (20%) and dizziness (13%). Peripheral edema occurs occasionally because of an induced decrease in serum protein. The potency of this agent appears to be more modest than the SSRIs.
Important Questions Remain Unanswered:
1. The available studies are all very short in duration (4-12 weeks); will long-term therapy maintain its efficacy? An open-label continuation of the venlafaxine trial documented maintenance of efficacy, but the length of the study was only 8 weeks.19
2. How does the potency of the SSRIs compare with hormone therapy? No comparative trial has been reported.
3. What is the lowest effective dose of each SSRI?
4. Is venlafaxine more effective than the other SSRIs (because it is both a serotonergic and a noradrenergic drug)? Conclusions regarding potency require appropriately designed studies comparing the effects of the drugs in the same population.
The published reports have indicated that larger and longer clinical trials are under way, and perhaps answers to these questions will emerge. Until then, it seems to me that the SSRIs are the best choice after hormone therapy. It is worth trying to titer the dose down to its lowest effective level because of a low but bothersome incidence of decreased libido. The SSRIs may be the best choice for flushing due to tamoxifen treatment. In a report at the most recent San Antonio Breast Cancer Symposium, hormone therapy was ineffective in reducing the flushing associated with tamoxifen.20 Either the presence of tamoxifen blocks hormone action or the mechanism of tamoxifen-induced flushes is different than those associated with a reduction in estrogen. Nevertheless, SSRIs are effective for flushing secondary to both tamoxifen and hypoestrogenemia. An added advantage of the SSRIs is the fact that the clinical studies have also reported improvements in depression, anxiety, and sleep.
1. McKinlay SM, et al. Maturitas. 1992;14:103-115.
2. Guthrie J, et al. Obstet Gynecol. 1996;88:437-442.
3. Oldenhave A, et al. Am J Obstet Gynecol. 1993;168: 772-780.
4. Nagamani M, et al. Am J Obstet Gynecol. 1987;156: 561.
5. Goldberg RM, et al. J Clin Oncol. 1994;12:155-158.
6. Lebherz TB, French LT. Obstet Gynecol. 1969;33: 795-799.
7. Bergmans MG, et al. Maturitas. 1987;9:227-234.
8. David A, et al. Am J Obstet Gynecol. 1988;158: 1107-1115.
9. Melis GB, et al. Obstet Gynecol. 1988;72:688-692.
10. Wesel S, et al. Curr Med Res Opin. 1984;8:696-700.
11. Lobo RA, et al. Am J Obstet Gynecol. 1984;63:1-5.
12. Loprinzi CL, et al. N Engl J Med. 1994;331:347-352.
13. Barton DL, et al. J Clin Oncol. 1998;16:495-500.
14. Stearns V, et al. JAMA. 2003;289:2827-2834.
15. Loprinzi CL, et al. J Clin Oncol. 1998;16:2377-2381.
16. Loprinzi CL, et al. Lancet. 2000;356:2059-2063.
17. Loprinzi CL, et al. J Clin Oncol. 2002;20:1578-1583.
18. Guttuso T Jr, et al. Obstet Gynecol. 2003;101:337-345.
19. Barton DL, et al. Oncol Nursing Forum. 2002;29: 33-40.
20. Duncan AJ, et al. No difference in menopausal symptoms and severity of hot flashes (HF’s) comparing combined hormone replacement therapy (HRT) plus tamoxifen (Tam) to tamoxifen alone in peri- or postmenoausal women at high risk for developing breast cancer. San Antonio Breast Cancer Symposium 2002;Abstract 657.
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Clinicians are familiar with the writings of Leon Speroff, MD, especially as the senior author of Clinical Gynecologic Endocrinology and Infertility currently in its 6th edition. Now Dr. Speroff’s writing has taken a new direction, a biography entitled Carlos Montezuma, M.D., A Yavapai American Hero, The Life and Times of an American Indian, 1866-1923. The book is the culmination of four years of research and work, a product of the same enthusiasm and dedication as his medical writing. Look for this historical narrative about a remarkable man, one of the first Native-American physicians, available this summer from Arnica Publishing, Inc. A special pre-publication purchase price is available for readers of OB/GYN Clinical Alert at www.arnicapublishing.com.