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Appendix H
Saw Palmetto: Prototype Monograph Summary1

V. SUMMARY AND CONCLUSIONS

A. Summary

Saw palmetto is a dietary supplement with a long history of human use. Currently, it appears to be used primarily by men. The plant part typically used in dietary supplements is the fruit. A primary form of saw palmetto currently marketed is an n-hexane extract of the fruit, which is rich in lipids. Other forms include ethanol extracts of the fruit and powdered dried, ripe fruit. In addition to lipids, other known chemical components of

1  

This is a summary of a prototype monograph, prepared for the purpose of illustrating how a safety review of a dietary supplement ingredient might be prepared following the format described in this report. While it was prepared as a prototype using the processes described in the report, it was not conducted under the auspices of the Food and Drug Administration utilizing all the resources available to the agency. Thus some pertinent information not available to the Committee could be of importance in evaluating safety to determine if use of this dietary supplement ingredient would present an unreasonable risk of illness or injury. Also, the development and review of this prototype was conducted by individuals whose backgrounds are in general aspects of evaluating science and whose expertise is not necessarily focused specifically on this dietary ingredient, although significant additional assistance was provided by consultants with relevant expertise. Therefore, this prototype monograph, while extensive, does not represent an authoritative statement regarding the safety of this dietary supplement ingredient. The full prototype monograph and its data tables on saw palmetto may be accessed at http://www.iom.edu/fnb.



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Dietary Supplements: A Framework for Evaluating Safety Appendix H Saw Palmetto: Prototype Monograph Summary1 V. SUMMARY AND CONCLUSIONS A. Summary Saw palmetto is a dietary supplement with a long history of human use. Currently, it appears to be used primarily by men. The plant part typically used in dietary supplements is the fruit. A primary form of saw palmetto currently marketed is an n-hexane extract of the fruit, which is rich in lipids. Other forms include ethanol extracts of the fruit and powdered dried, ripe fruit. In addition to lipids, other known chemical components of 1   This is a summary of a prototype monograph, prepared for the purpose of illustrating how a safety review of a dietary supplement ingredient might be prepared following the format described in this report. While it was prepared as a prototype using the processes described in the report, it was not conducted under the auspices of the Food and Drug Administration utilizing all the resources available to the agency. Thus some pertinent information not available to the Committee could be of importance in evaluating safety to determine if use of this dietary supplement ingredient would present an unreasonable risk of illness or injury. Also, the development and review of this prototype was conducted by individuals whose backgrounds are in general aspects of evaluating science and whose expertise is not necessarily focused specifically on this dietary ingredient, although significant additional assistance was provided by consultants with relevant expertise. Therefore, this prototype monograph, while extensive, does not represent an authoritative statement regarding the safety of this dietary supplement ingredient. The full prototype monograph and its data tables on saw palmetto may be accessed at http://www.iom.edu/fnb.

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Dietary Supplements: A Framework for Evaluating Safety saw palmetto fruit include flavonoids, polyisoprenoids, and saccharides. The identity of the biologically active constituents has not been firmly established. Preparations of saw palmetto powdered fruit and saw palmetto extracts are typically analyzed for fatty acid content. Currently, the majority of saw palmetto is obtained from the southern coastal United States. It should be noted that the chemical profile of any plant may vary substantially if it is collected from a significantly different environment. The typical daily amount ingested (usually by men with benign prostatic hyperplasia) is 320 mg of lipid/sterol extract of saw palmetto (LESP). The historical use of the plant was limited to whole fruit and teas; however, current widespread usage is primarily as the LESP. There are also blended products that include saw palmetto as one ingredient in a sometimes complex mixture of botanical or other ingredients. One such blend, PC-SPES, was found to be contaminated with the drug warfarin and was voluntarily withdrawn from the market in 2002. The safety/toxicity of blended products is not addressed in this prototype monograph, although the information about such combinations was considered to determine if it was relevant to the safety of saw palmetto. The evidence regarding the safety of saw palmetto extracts was derived from nine randomized, double-blind, placebo-controlled clinical trials and three reference-controlled human clinical trials. It should be pointed out that these studies used a variety of preparations of saw palmetto fruit extracts. Numerous other studies have been conducted, but their usefulness was limited by publication in foreign languages, deficiencies in experimental design, or deficiencies in the published record. There has been one clinical case report of a serious adverse effect (hemorrhage during an operative procedure) possibly associated with saw palmetto consumption; however, the specific preparation or product and dosage were not reported and the symptoms could be consistent with a contaminated blended product, such as contamination by the anticoagulant warfarin. Although there have been four Special Nutrition/Adverse Event Monitoring System reports, there was no indication of clear causal relationships with saw palmetto. To date, there have been no reports of studies on drug interactions. Some animal studies showed antiandrogenic effects on hyperplasia. These effects themselves were not considered to have serious implications to the safety of saw palmetto in older men, but they are consistent with saw palmetto being bioavailable and bioactive following oral ingestion and are consistent with saw palmetto’s purported beneficial antiandrogenic effects in humans. Also consistent are in vitro studies demonstrating some biological effects such as inhibition of steroid 5-α-reductase and antagonism of α1-adrenergic receptors. Of the chemical constituents known to be present in saw palmetto fruit,

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Dietary Supplements: A Framework for Evaluating Safety none are recognized as toxic substances. Likewise, the plant family, Arecaceae, is not generally regarded as a toxic plant family. Based on the limited in vitro studies to date, functionally related substances might include drugs that are inhibitors of steroid 5-α-reductase or antagonists of α1-adrenergic receptors. In general, these drugs are contraindicated for women and children (GlaxoSmithKline, 2001; Thomson PDR, 2004). Pregnant women are even cautioned not to touch broken tablets containing inhibitors of steroid 5-α-reductase (GlaxoSmithKline, 2001; Thomson PDR, 2004). Concern with these drugs are that in utero effects of inhibiting testosterone synthesis or action can deleteriously affect the external genitalia and internal reproductive organs of a male fetus (Bowman et al., 2003; Clark et al., 1990, 1993; GlaxoSmithKline, 2001). B. Conclusions and Recommendations About the Safety of the Ingredient Based on the Strength of the Scientific Evidence At the present time, the weight of the scientific evidence does not suggest that the consumption of saw palmetto powdered fruit or fruit extracts poses a safety risk when consumed by men at the currently recommended doses. These conclusions are germane only to the fruit and fruit extracts presently used; introduction of new products involving different plant parts would warrant further scrutiny. However, unlike for men, the reported adverse side effects for drugs that inhibit steroid 5-α-reductase or antagonize α1-adrenergic receptors raise concern about women who may become pregnant while using saw palmetto. This concern is mitigated somewhat by the apparent popularity of saw palmetto with men rather than women, but as noted, saw palmetto use is not limited to men. It is not evident that the testosterone pathway effects raise concerns about the safe use of saw palmetto fruit or fruit extracts in men. C. Unresolved Issues and Uncertainties in the Available Data Additional phytochemical analyses of the fruit and, especially, of the various fruit extracts (in which minor components would be expected to be concentrated) are needed in order to determine the presence of biologically active chemical components. In vitro reports of cytotoxicity in prostate cancer cell lines have not been extended to other cell types in order to ascertain whether there is broader cytotoxicity.

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Dietary Supplements: A Framework for Evaluating Safety D. Data Gaps and Future Research Recommended Additional phytochemical analyses to identify the biologically active components should be a high priority. Once biologically active components are identified, further biological evaluation should be conducted. Safety concerns should be revisited upon identification of additional components. There is a need to establish the mechanism of action of saw palmetto preparations. There are insufficient data to conclude that there are no drug interactions between saw palmetto preparations and conventional prescription drugs. Studies to establish the effects of saw palmetto products on bleeding times could shed additional light on the possible causal relationship of saw palmetto to the single clinical case report of excessive bleeding during surgery. Studies could shed light on the possibility of detrimental effects on the fetus. REFERENCES Bowman CJ, Barlow NJ, Turner KJ, Wallace DG, Foster PMD. 2003. Effects of in utero exposure to finasteride on androgen-dependent reproductive development in the male rat. Toxicol Sci 74:393–406. Clark RL, Antonello JM, Grossman SJ, Wise LD, Anderson C, Bagdon WJ, Prahalada S, MacDonald JS, Robertson RT. 1990. External genitalia abnormalities in male rats exposed in utero to finasteride, a 5 alpha-reductase inhibitor. Teratology 42:91–100. Clark RL, Anderson CA, Prahalada S, Robertson RT, Lochry EA, Leonard YM, Stevens JL, Hoberman AM. 1993. Critical developmental periods for effects on male rat genitalia induced by finasteride, a 5 alpha-reductase inhibitor. Toxicol Appl Pharmacol 119:34–40. GlaxoSmithKline. 2001. Approval Package. Duagen (Dutasteride) Soft Gel Capsules. Pharmacology Reviews. Online. Available at http://www.fda.gov/cder/foi/nda/2001/21319_Duagen.htm. Accessed January 8, 2003. Thomson PDR. 2004. Physicians’ Desk Reference. 58th ed. Montvale, NJ: Thomson PDR.