Alternative Therapies for Reducing Hot Flashes in Patients on Lutenizing Hormone-Releasing Hormone Agonist Treatment/Orchiectomy for Prostate Cancer: A Review and the Need for More Research

Mark A. Moyad, MPH

•     The treatment of hot flashes in women using nontraditional approaches has received some attention, whereas this same condition in men, a common side effect of treatment with luteinizing hormone-releasing hormone (LHRH) agonists or orchiectomy, has not attracted an adequate amount of attention to date. 

•     Of the nontraditional treatments for vasomotor symptoms, vitamin E and soy products have received most of the attention; however, these studies too have focused exclusively on postmenopausal women.

•     Some supplements (such as soy) may have some estrogenic activity, and should provide the impetus to begin clinical trials to determine whether or not nontraditional treatments have a role in decreasing hot flashes resulting from prostate cancer treatment.

•     These supplements may also be attractive because of their reduced cost, patient control and potential inhibitory effects on various prostate cancer cell lines.  Therefore, we and others have initiated a series of studies to determine preliminarily whether or not these alternatives hold any promise.

Introduction
Vasomotor hot flashes are a common problem in menopausal women.  They also are a common occurrence in women being treated with anti-estrogens to prevent or treat breast cancer.1,2  Hormone replacement therapy (HRT) is an effective treatment for hot flashes in women, but there is some controversy regarding its potential to increase breast cancer risk.3  In men, hot flashes are also a common problem after orchiectomy or receiving an LHRH agonist, generally occurring in more than half to two thirds of these men.4  Prescribed treatments for hot flashes in men on hormonal ablation treatment for prostate cancer is also well documented.  Diethylstilbestrol (DES), megestrol acetate and cyproterone acetate have been used in previous clinical trials with good results.5-7  However, DES, even at low dosages, can result in painful gynecomastia and deep venous thrombosis, while the long-term effects of megestrol acetate are unknown, and cyproterone acetate is not commonly used in the United States.  Therefore, the search for other agents that can concomitantly reduce hot flashes with fewer side effects continues. 

Recently, there has been an interest in treating hot flashes in women using nontraditional treatments because of the side effects and other possible consequences of long-term prescribed treatments, and the desire of women to have some control over their health.8  For example, women treated with vitamin E or soy products in 2 separate prospective, randomized and placebo-controlled trials experienced some relief (more so with soy products) in the number and severity of hot flashes.9,10  In the first study, women ingested 800 IU of vitamin E succinate daily for 3 months, while in the second study women received  60 g of soy protein powder (containing 76 mg of isoflavones=plant estrogens) daily for 3 months.  These types of treatment may also be an exciting possibility for men.  In fact, individuals who experience hot flashes may be able to rate their vasomotor symptoms using a general scale adapted from previous studies with women.10-12  The hot flash rating scale we utilize is based on the personal observations of the patient, which is the primary determining factor of the score (1, 2 or 3) assigned to the hot flash (Table 1).

Table 1.

     Summary of Hot Flash Scoring Scale

Severity             Score           Length/Duration        Observations

Mild                  1                <1 minute                Warm and slightly uncomfortable,

                                                                        no perspiration

Moderate            2                <5 minutes               Warmth involving more

                                                                        of the body, perspiration,

                                                                        taking off some layers

                                                                        of clothing

Severe               3                >5 minutes               Burning warmth,

                                                                        disruption of normal life

                                                                        activities such as sleep,

                                                                        excessive perspiration,

                                                                        thermostat changes

Comment and the Need for More Research
A whole host of nontraditional treatments and supplements have been proposed by magazines, the Internet and some studies that may or may not be effective for women experiencing hot flashes.  In placebo-controlled studies, various treatments have shown some or no benefit, while others apparently have some estrogenic activity or have not been adequately tested.8-10,13-28  These supplements are listed in Table 2.

Table 2.

Supplements Proposed to Reduce Hot Flashes in Women

Supplement (Genus species or components)

•     American or Asian ginseng (Panax quinquefolius or Panax ginseng)13-15

•     Beta-sitosterol (compound found in saw palmetto-Serenoa repens)16

•     Bioflavonoids (found in grapefruit and other fruits)17,18

•     Evening primrose oil (Oenothera biennis)19

•     Black cohosh (Cimicifuga racemosa)20

•     Blue cohosh (Caulophyllum thalictroides)8

•     Chasteberry (Vitex agnus-castus)21

•     Dong quai (Angelica sinensis)22

•     Flaxseed (Linum usitatissimum)23

•     Hops (Humulus lupulus)24,25

•     Licorice (Glycyrrhiza glabra)25

•     PC-SPES (mixture of 8 herbs—some are estrogenic)13-16,25,26

•     Red clover (Trifolium pratense)25,27

•     Soy (Glycine max)10,25

•     Thyme (Thymus spp.)25

•     Turmeric (Curcuma longa)25

•     Verbena (Verbena spp.)25

•     Vitamin E (tocopherols)9

•     Wild yam (Dioscorea villosa)28

Presently, soy and vitamin E have the most promising data when considering which agents may have been adequately tested and demonstrate a partial reduction in hot flashes in women.9,10  However, other supplements may be more effective because of their demonstrated in vitro or in vivo estrogenic activity, but they have not been tested in  a placebo-controlled trial.25-27 

There are several possible explanations for the reduction in hot flashes in trials conducted to date.  First, one cannot eliminate the possibility of a placebo effect.  In 2 separate double-blind placebo trials of soy supplementation in postmenopausal women, there were reductions of 30% and 33% in hot flashes in the placebo arms.10,29  A separate study of vitamin E in breast cancer survivors demonstrated a 22% reduction in hot flashes in the placebo group.9 

Another possible explanation for this reduction is the estrogenic contribution of soy or other products.  Therefore, a large soy intake and a large source of isoflavone is necessary in a future trial.  For example, a recent study of women with breast cancer who received soy tablets equivalent to 3 glasses of soy milk a day did not show a reduction in hot flashes greater than that caused by placebo.29  However, studies have demonstrated that soy milk is a poor source of plant estrogens compared with some other soy products, such as soy protein powder.30-32  Therefore, the choice of an adequate soy product is essential when conducting trials in this area.  Soy products, in our opinion, are also not safe for testing in women with hot flashes who have been diagnosed with breast cancer, because the natural estrogens that they contain may encourage tumor growth.33   This problem is not currently a concern for prostate cancer patients because of the history of benefits of estrogen treatment

for prostate cancer, the potential for isoflavone to reduce risk, the demonstrated inhibition of prostate cancer cell lines with genistein in vitro and in vivo and a possible additive cholesterol-lowering effect.34-38 

How vitamin E may be reducing hot flashes is unknown, apart from a possible placebo effect.9  Whether some forms of vitamin E are more effective than others in potentially reducing hot flashes is also unknown at this time.  For example, it has been demonstrated that gamma-tocopherol exhibited greater inhibition of a human prostate cancer line vs synthetic vitamin E, but whether or not this would translate into a greater hot flash reduction remains to be determined.39  Regardless, it has been shown that vitamin E is safe for use in healthy men at 800 IU daily, and a possible benefit for men with prostate cancer based on past studies in vitro, in vivo and in a clinical trial.40-43  Slightly higher dosages (1,050 IU) may not be safe and may cause ascorbic acid reductions and exert an overall pro-oxidant effect, so this must be noted in any future clinical trial attempting to administer more than 800 IU per day.44  Synthetic vitamin E is probably not the best choice for hot flash reductions in a clinical trial because of its ambiguous results vs soy protein powder in previous trials.9,10 

Whether the use of vitamin E and soy together may provide an added or synergistic effect is unknown at this time.  There is also the possibility of a natural reduction in hot flashes the longer a man remains on hormonal ablation, and theoretically this may coincide with the time at which the nontraditional treatment commences.  Additionally, the potential role of exercise, dietary additions (eg, caffeine, alcohol, spicy foods, warm liquids) and relaxation treatments in the number and severity of hot flashes needs to be mentioned to study participants and taken into account.  Their actual impact (positive, neutral or negative) on hot flashes is not known at this time.11,45  Indeed, factors affecting hot flashes in men have not received a great deal of attention.

Side effects of potential hot flash treatments also must be addressed.  In a recent trial, soy protein caused a significant number of gastrointestinal side effects (less than that found with placebo, however), causing a number of subjects to withdraw from the study.9  Other supplements, such as ginseng, when used in excess, may be associated with nervousness, insomnia, diarrhea and hypertension.46  Other estrogenic supplements in small dosages, such as licorice, have  the potential of further decreasing testosterone levels, which could potentially exacerbate vasomotor symptoms.47  Potential side effects of placebo must  also be considered.  These issues can only be addressed with an adequate placebo-controlled trial.

Conclusions
In reality, all information on hot flashes to date comes from studies of women experiencing these symptoms.  Using nontraditional treatments for hot flashes may allow the patient to:  1) gain some control over his health; 2) experience less or no toxicity from these treatments in the correct dosage; 3) incur a low out-of-pocket cost for such treatments; and 4) experience reduced risk of other diseases due to the potential of some of these treatments to have an inhibitory effect on cancer cells.  Therefore, some of these nontraditional treatments and others deserve attention in the area of hot flash therapy during or following prostate cancer treatment. 

Interestingly, a recent small pilot study demonstrated that acupuncture may be effective in reducing hot flashes in men on LHRH agonist treatment.48  The goal is that this review and others will further encourage clinical trials and the proper evaluation of these nontraditional treatments to reduce side effects from conventional medicine treatments.  Therefore, we and others have initiated a series of clinical trials utilizing soy products and other plant estrogens.  A partial and preliminary insight as to whether or not these supplements will have any effect on vasomotor symptoms resulting from prostate cancer treatment will be determined in the near future.

References

1.   Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med.  1989;320:479-484.

2.   Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the national surgical adjuvant breast and bowel project P-1 study. J Natl Cancer Inst.  1998;90:1371-1388.

3.   Coldiz GA, Hankinson SE, Hunter DJ, et al. The use of estrogen and progestin and the risk of breast cancer in postmenopausal women. N Engl J Med.  1995;332:1589-1593.

4.   The Leuprolide Study Group. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N Engl J Med.  1989;311:1281.

5.   Miller JI, Ahmann FR. Treatment of castration-induced menopausal symptoms with low dose diethylstilbestrol in men with advanced prostate cancer. Urology.  1992;40:499.

6.   Eaton AC, McGuire N. Cyproterone acetate in treatment of post-orchiectomy hot flushes: double-blind cross-over trial. Lancet.  1983;2:1336.

7.   Smith JA. Management of hot flushes due to endocrine therapy for prostate carcinoma. Oncology.  1996;10:1319-1322.

8.   Seidl MM, Stewart DE. Alternative treatments for menopausal symptoms: qualitative study of women’s experiences. Can Fam Phys.  1998;44: 1271-1276.

9.   Barton DL, Loprinzi CL, Quella SK, et al. Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. J Clin Oncol.  1998;16:495-500.

10. Albertazzi P, Pansini F, Bonaccorsi G, et al. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol.  1998;91:6-11.

11. Kronenberg F. Hot flashes: phenomenology, quality of life, and search for treatment options.  Exp Gerontol.  1994;29:319-336.

12. Finck G, Barton DL, Loprinzi CL, et al. Definitions of hot flashes in breast cancer survivors. J Pain Symptom Manage.  1998;16:327-333.

13. Chandler RF. Herbal medicine: ginseng—an aphrodisiac? Can Pharm J.  1988;121:36-38.

14. Punnonen R, Lukola A. Oestrogen-like effect of ginseng. BMJ.  1980;281:1110.

15. Duda RB, Taback B, Kessel B, et al. pS2 expression induced by American ginseng in MCF-7 breast cancer cells. Ann Surg Oncol.  1996;3:515-520.

16. Elghamry MI, Hansel R. Activity and isolated phytoestrogen of shrub palmetto fruits (Serenoa repens Small), a new estrogenic plant. Experimenta.  1969;25:828-829.

17. Schubert W, Cullberg G, Edgar B, et al. Inhibition of 17 beta-estradiol metabolism by grapefruit juice in ovariectomized women. Maturitas.  1994;20:155-163.

18. Miksicek R. Commonly occurring plant flavonoids have estrogenic activity. Mol Pharmacol.  1993;44:37-43.

19. Chenoy R, Hussain S, Tayob Y, et al. Effect of oral gamolenic acid from evening primrose oil on menopausal flushing. BMJ.  1994;308:501-503.

20. Einer-Jensen N, Ahao J, Andersen KP, et al. Cimicifuga and Melbrosia lack oestrogenic effects in mice and rats. Maturitas.  1996;25:149-153.

21. Cahill DJ, Fox R, Wardle PG, et al. Multiple follicular development associated with herbal medicine. Hum Reprod.  1994;9:1469-1470.

22. Hiruta JD, Swierz LM, Zell B, et al. Does dong quai have estrogenic effects in postmenopausal women? A double-blind, placebo-controlled trial. Fertil Steril.  1997;68:981-986.

23. Price KR, Fenwick GR. Naturally occurring oestrogens in foods-a review. Food Addit Contam.  1985;2:73-106.

24. Salvador RL. Hops. Can Pharm J.  1994;127: 203-204.

25. Zava DT, Dollbaum CM, Blen M. Estrogen and progestin bioactivity of foods, herbs, and spices. Proc Soc Exper Biol Med.  1998;217:369-378.

26. DiPaola RS, Zhang H, Lambert GH, et al. Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. N Engl J Med.  1998;339:785-791.

27. Stephens FO. Phytoestrogens and prostate cancer: possible preventive role. Med J Aust.  1997;167: 138-140.

28. Briggs CJ. Herbal medicine: dioscorea. Can Pharm J.  1990;123:413-415.

29. Quella SK, Loprinzi CL, Barton D, et al. Evaluation of soy phytoestrogens for treatment of hot flashes in breast cancer survivors. Am Soc Clin Oncol.  1999;18:591a (abstract 2285).

30. Wang H, Murphy PA. Isoflavone composition of American and Japanese soybeans in Iowa: effects of variety, crop year, and location. J Agric Food Chem.  1994;42:1674-1677.

31. Wang H, Murphy PA. Isoflavone content in commercial soybean foods. J Agric Food Chem.  1994;42:1666-1673.

32. Dwyer JT, Goldin BR, Saul N, et al. Tofu and soy drinks contain phytoestrogens. J Am Diet Assoc.  1994;94:739-743.

33. Petrakis NL, Barnes S, King EB, et al. Stimulatory influence of soy protein isolate on breast secretion in pre- and post-menopausal women. Cancer Epidemiol Biomarkers Prev.  1996;5:785-794.

34. Byar DP, Corle DK. Hormone therapy for prostate cancer: results of The Veterans Administration Cooperative Urological Research Group Studies. NCI Monogr.  1988;7:165-170.

35. Adlercreutz H, Mazur W. Phyto-oestrogens and western diseases. Ann Med.  1997;29:95-120.

36. Peterson G, Barnes S. Genistein and biochanin A inhibit the growth of human prostate cancer cells but not epidermal growth factor receptor autophosphorylation. Prostate.  1993;22:335-345.

37. Pollard M, Luckert PH. Influence of isoflavones in soy protein isolates on development of induced prostate-related cancers in L-W rats. Nutr Cancer.  1997;28:41-45.

38. Baum JA, Teng H, Erdman JW Jr, et al. Long-term intake of soy protein improves blood lipid profiles and increases mononuclear cell low-density-lipoprotein receptor messenger RNA in hypercholesterolemic, postmenopausal women. Am J Clin Nutr.  1998;68: 545-551.

39. Moyad MA, Brumfield SK, Pienta KJ. Gamma-tocopherol (natural vitamin E) demonstrates greater inhibition of growth on a human prostate cancer cell line than alpha-tocopherol (synthetic vitamin E). J Urol.  1999;161:52 (abstract 192).

40. Meydani SN, Meydani M, Blumberg JB, et al. Assessment of the safety of supplementation with different amounts of vitamin E in healthy older adults. Am J Clin Nutr.  1998;68:311-318.

41. Sigounas G, Anagnostou A, Steiner M. dl-alpha-Tocopherol induces apoptosis in erythroleukemia, prostate, and breast cancer cells. Nutr Cancer.  1997;28:30-35.

42. Fleshner N, Fair WR, Huryk R, et al. Vitamin E inhibits the high-fat diet promoted growth of established human prostate LNCaP tumors in nude mice. J Urol.  1999;161:1651-1654.

43. Heinonen OP, Albanes D, Virtamo J, et al. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst.  1998;90:440-446.

44. Brown KM, Morrice PC, Duthie GG. Erythrocyte vitamin E and plasma ascorbate concentrations in relation to erythrocyte peroxidation in smokers and nonsmokers: dose response to vitamin E supplementation. Am J Clin Nutr.  1997;65:496-502.

45. Ginsburg ES. Hot flashes-physiology, hormonal therapy, and alternative therapies. Obstet Gynecol Clin North Am.  1994;21:381-390.

46. Miller KL. Alternatives to estrogen for menopausal symptoms. Clin Obstet Gynecol.  1992;35:884-893.

47. Armanini D, Bonnani G, Palermo M. Reduction of serum testosterone in men by licorice. N Engl J Med.  1999;341:1158.

48. Hammar M, Frisk J, Grimas O, et al. Acupuncture treatment of vasomotor symptoms in men with prostatic carcinoma: a pilot study. J Urol.  1999;161:853-856.