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Appendix K
Prototype Focused Monograph: Review of Antiandrogenic Risks of Saw Palmetto Ingestion by Women1

I. DESCRIPTION OF THE INGREDIENT

A. Saw Palmetto as a Dietary Supplement Ingredient

Saw palmetto refers to Serenoa repens (W. Bartram) Small (Family: Arecaceae). An alternative name for the Arecaceae family is Palmae or Palmaceae. This plant is also known as (1) Serenoa serrulatum Schultes, (2) Serenoa serrulata (Michaux) Nichols, and (3) Sabal serrulata (Michaux) Nutall ex Schultes.

The medicinal part of saw palmetto is the fruit, which is about the size of a berry and is sometimes referred to as a “saw palmetto berry,” although it is a single seed drupe. The fruit is rich in carbohydrates and lipid components. The dried ripe fruit is typically the part of the plant used for dietary supplements.

1  

This is a focused monograph, prepared for the purpose of illustrating how a safety review of a dietary supplement ingredient might be prepared following the format for focused monographs 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.



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Dietary Supplements: A Framework for Evaluating Safety Appendix K Prototype Focused Monograph: Review of Antiandrogenic Risks of Saw Palmetto Ingestion by Women1 I. DESCRIPTION OF THE INGREDIENT A. Saw Palmetto as a Dietary Supplement Ingredient Saw palmetto refers to Serenoa repens (W. Bartram) Small (Family: Arecaceae). An alternative name for the Arecaceae family is Palmae or Palmaceae. This plant is also known as (1) Serenoa serrulatum Schultes, (2) Serenoa serrulata (Michaux) Nichols, and (3) Sabal serrulata (Michaux) Nutall ex Schultes. The medicinal part of saw palmetto is the fruit, which is about the size of a berry and is sometimes referred to as a “saw palmetto berry,” although it is a single seed drupe. The fruit is rich in carbohydrates and lipid components. The dried ripe fruit is typically the part of the plant used for dietary supplements. 1   This is a focused monograph, prepared for the purpose of illustrating how a safety review of a dietary supplement ingredient might be prepared following the format for focused monographs 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.

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Dietary Supplements: A Framework for Evaluating Safety B. Individual Components Table A contains a list of the known components in extracts of saw palmetto fruit. Some components are common in many other plants and are widespread in the human diet. The components of extracts of saw palmetto fruit are commonly categorized as hexane extractable (i.e., phytosterols, phenolic components, free fatty acids, ethyl esters of fatty acids, and other lipid components), ethanol extractable (i.e., polyprenoids, flavonoid components, phenolic glycosides, and fatty alcohols), or water soluble (i.e., commonly found sugars and unique high-molecular-weight acidic polysaccharides). A hexane extract of saw palmetto fruit is the preparation that has been used most commonly in clinical trials. The hexane extract of saw palmetto fruit is unusual for a plant extract in that is has a very high content of medium-chain fatty acids and a high proportion of fatty acids present as ethyl esters. C. Description of Dietary Supplement Preparations and Amounts Ingested in Ordinary Use Saw palmetto is sold in several forms with lipid/sterol and “oily” extracts of the dried fruit being the most common forms on the market. A lipid/sterol extract of saw palmetto fruit (LESP) can be prepared by extraction with n hexane (100 percent), extraction with ethanol (70–95 percent, w/w), or by supercritical fluid extraction with liquid carbon dioxide. LESPs are somewhat quantifiable or standardized by total fatty acid content (usually 70–95 percent, w/w) or other components (USP, 2000). LESPs are commonly sold as capsules or tablets of a dried powder of the extract and in blended preparations where the powdered extract is combined with other ingredients, typically other powdered botanical extracts. Other forms of saw palmetto that may be available include powdered dried fruit (usually available in capsule or tablet form), dried whole fruit or preparations of the fruit (used in making a tea or water extract), tinctures (extracts made with aqueous ethanol as the solvent), and other liquid extracts. In numerous clinical trials, the typical dose of saw palmetto for a subject with symptomatic benign prostatic hyperplasia (BPH)2 was 320 mg 2   BPH is a nonmalignant enlargement of the prostate from excessive proliferation, which causes nodules of the prostate gland to enlarge around the urethra, eventually limiting urinary flow from the bladder. Throughout life, dihydrotestosterone (DHT) directly stimulates the growth of the epithelial and stromal cells of the prostate. In aging men, the prostate is more responsive to androgen stimulation and the gland increases in size, causing urinary symptoms. Symptoms include difficulty in starting or stopping urine flow, a need to urinate frequently (especially at night), and a feeling of urgency-to-urinate. Urinary tract infections and urinary obstruction are common.

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Dietary Supplements: A Framework for Evaluating Safety of LESP per day in 1 to 3 divided doses taken orally (or rectally in a few trials). The duration of ingestion of LESP varied from several weeks to several years. II. SAFETY INFORMATION A. Human Safety Data 1. Historical use Historical use of saw palmetto for symptoms of BPH has been common in Asia and in native cultures in North America for centuries (Lowe, 2001; Wilt et al., 1998). Of the 30 plants known to have been used historically in phytotherapy for symptoms of BPH, saw palmetto has been the most widely used (Wilt et al., 1998). Historical uses were limited to saw palmetto in the form of the whole fruit, teas, aqueous extracts, and tinctures. They did not include lipid/sterol extracts of saw palmetto fruit such as those available in the current market. In American Indian cultures, specifically in Florida, saw palmetto fruit was considered useful as a diuretic, sedative, aphrodisiac, nutritional tonic (due to the high oil content of the fruit), and to create a soothing vapor used as an expectorant. As American and European cultures learned about American Indian phytotherapy, the saw palmetto fruit came to be used to improve sexual vigor; to increase sperm production; as a mild diuretic; to relieve urinary difficulty, such as urgency-to-urinate and nocturnal enuresis in both men and women; and to improve urogenital disorders in women, such as ovarian enlargement and dysmenorrhea (Gennaro, 2000; Wilt et al., 1998). Typically, the dried, ripe fruit is used for medicinal purposes. At times, the fresh fruit may be used; the safety of this practice has not been evaluated. 2. Adverse effects Clinical trials: The clinical data for saw palmetto is primarily generated on male subjects. The one trial in women is in Table B, but there is no indication that pregnant women were included in this trial. Spontaneous adverse event reports: Spontaneous reports related to possible effects in utero did not exist.

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Dietary Supplements: A Framework for Evaluating Safety 3. Interactions Not applicable to the focus of this monograph. B. Animal Studies Animal studies: Only minimal classical animal toxicity data are available (Barsanti et al., 2000). These studies did not assess possible effects in utero or in offspring. Table E summarizes information available from animal experiments related to antiandrogenic activity. In summary, in some model systems, antiandrogenic activity (specifically inhibition of hormonally or chemically induced prostate hyperplasia) can be demonstrated for extracts of saw palmetto fruit. In other model systems, no antiandrogenic activity was demonstrated. C. In Vitro Studies In vitro studies: Table F summarizes relevant information from in vitro experiments with saw palmetto. Inhibition of androgen-dependent proliferation and cellular stimulation have been demonstrated for extracts of saw palmetto fruit. In vitro inhibition of testosterone metabolism through inhibition of steroid 5-α-reductase and 3-α-hydroxysteroid dehydrogenase was demonstrated. Inhibition of androgen binding was demonstrated in some model systems. Classical in vitro toxicity data available are minimal (Degenring et al., 2001; Ondrizek et al., 1999a, 1999b) and do not address antiandrogenic concerns in females. D. Related Substances Table G contains information relevant to antiandrogenic safety issues for substances related to saw palmetto. Information about substances that are functionally related because they inhibit steroid 5-α-reductase is included. In summary, several of the substances functionally related to saw palmetto extract are contraindicated for use in women because of potential deleterious effects on the external genitalia and internal reproductive organs of the male fetus.

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Dietary Supplements: A Framework for Evaluating Safety III. OTHER RELEVANT INFORMATION A. Sources The saw palmetto is one of the “fan palms”; it is also called the American dwarf palm tree or cabbage palm. The plant is sometimes called sabal and the fruit is called sabal fructus. This can be confusing because the saw palmetto is not a member of the genus Sabal; it is a distinct plant that can be confused with the Sabal palmetto. Other names for saw palmetto include shrub palmetto, juzhong, and palmier nain. Botanical descriptions of saw palmetto can be found in the literature (Leung and Foster, 1996). Saw palmetto is an evergreen shrub, usually 2 to 10 feet tall. It is indigenous to undeveloped areas of the southern costal regions of the United States, especially Florida and Georgia, and is also abundant in Cuba and the Bahamas. Most saw palmetto fruit used in dietary supplements is harvested in Florida. It grows rapidly in sandy soil (either acidic or alkaline) and forms prominent colonies in sandy dunes, hammocks, or costal prairies. In the Northern Hemisphere, the plant blooms from April to early June and the fruit ripens in September and October. Analytical issues: Saw palmetto was defined in the U.S. Pharmacopeia (USP) formulary in the early 1990s, but was eventually dropped. The 2002 National Formulary describes saw palmetto and powdered saw palmetto as preparations of partially dried, ripe fruit (USP, 2002). The USP requirements are voluntary, but must be met for any product bearing the USP designation. The USP formulary contains general tests for quality assurance3 and specific tests for saw palmetto or powdered saw palmetto4 (USP, 2000). Because these tests are voluntary, consumers have little assurance of product quality; variability in products is high (Feifer et al., 2002). B. Relevant Conditions of Use Suggested or Recommended in Labeling or in Other Marketing Material Occasionally, saw palmetto is marketed to women for urinary function, milk production during lactation, and, rarely, breast enlargement. 3   General USP tests for quality assurance are (i) foreign organic matter, (ii) loss on drying, (iii) total ash, (iv) acid-insoluble, (v) pesticide residues, (vi) heavy metals, and (vii) microbial limits. 4   Specific USP tests for saw palmetto or powdered saw palmetto are (i) botanic characteristics, macroscopic and microscopic (not applicable for powdered saw palmetto), (ii) identification, (iii) volatile oil content, (iv) content of lipophilic extract, and (v) content of fatty acids. The latter test includes identification of 11 USP methyl fatty acid RS standards (C6:0 through C18:3).

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Dietary Supplements: A Framework for Evaluating Safety C. Cautions About Use Cautions provided in labeling5 or other marketing material: A review of saw palmetto product labels and Internet marketing materials indicated that many (but not all) provide cautions to consumers to seek advice from health care providers before using the products if they have had prostate disorders or hormone-dependent cancers or are taking prescription medication, are pregnant, or are nursing. Some products carry warnings to discontinue use two weeks prior to surgery. D. Usage Patterns Total usage patterns and usage by men have been studied, but very little information is available about usage by women. Saw palmetto has been used extensively in Europe and Asia. European sales figures for 1997 were $4 billion (Levy, 1998). In the United States, sales data reported by the Natural Marketing Institute ranked saw palmetto as the thirteenth best selling dietary supplement (Marra, 2002); however, sales growth has decreased 11 percent since 2001 (Marra, 2002). Sales for the U.S. market for saw palmetto supplements have been reported as $18 million in 1997 (Levy, 1998), $140 million in 1999 (Anon, 2000b), and $640 million in 2000 (Anon, 2000a). In a survey that examined the prevalence of use of herbal products among 752 randomly selected adults in Minnesota, saw palmetto was reportedly used by 4.3 percent of 376 respondents within the past 12 months to treat or prevent enlarged prostate, and to a lesser extent to promote general health and well-being and stimulate the immune system (Harnack et al., 2001). It is estimated that 50 percent of men over the age of 50 have some symptoms of BPH (Berry et al., 1984). The incidence of BPH is 80 percent in men over the age of 80 (Berry et al., 1984). Urinary symptoms due to BPH result in 300,000 prostatectomies in the United States each year (Pinn, 2001). In a survey of patients in a U.S. urology clinic, 20 percent were combining conventional and botanical therapies, and 15 percent were using botanical dietary supplements alone (Bales et al., 1999). Over 30 percent of men with prostate problems have ingested saw palmetto for some period of time (Anon, 2000a). 5   As defined in the Federal Food, Drug, and Cometic Act (FDCA) as currently amended, “The term ‘labeling’ means all labels and other written, printed, or graphic matter (1) upon any article or any of its containers or wrappers, or (2) accompanying such article.” The term “label” is not being used; label means “a display of written, printed, or graphic matter upon the immediate container of any article” (FDCA, 21U.S.C. § 201(k) and (m)).

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Dietary Supplements: A Framework for Evaluating Safety E. Information on Regulation and Regulatory Actions Foreign regulatory status: Saw palmetto is approved as a drug with prescription status in Austria, Italy, and Poland (Vallancien and Pariente, 2001). It is approved as a drug with over-the-counter drug (OTC) status for use in various urinary problems associated with BPH in Switzerland, Sweden, and Denmark. In Spain, standardized lipid/sterol extracts are approved as a drug with prescription status, and nonstandardized extracts are approved as dietary supplements. In France, saw palmetto has OTC status but is primarily prescribed by physicians. In Germany, the Commission E has evaluated saw palmetto as safe and effective for urination problems in mild to moderate BPH; extracts of saw palmetto fruit have OTC status but are primarily prescribed by physicians (Blumenthal, 1998). In Canada, saw palmetto is authorized for sale as a traditional herbal medicine with the indication of increasing the flow of urine. F. Available Information on Physiological and Biochemical Aspects Very little is known about the digestion, absorption, distribution, metabolism, and excretion of some components of saw palmetto fruit (i.e., phenolic components, phytosterols, flavonoids, and polyprenoids). Other components have been well characterized (i.e., sugars, fatty acids, and other hydrocarbons). Distribution: In a study of rats given a radioactive n-hexane LESP, tissue concentrations of radioactive labeled isolates of lauric acid, oleic acid, and β-sitosterol were highest in abdominal fat tissue, prostate, and skin. Lower concentrations were distributed to the liver and urinary bladder (Chevalier et al., 1997). No other studies reporting on the distribution of components of saw palmetto fruit were identified. Saw palmetto components were not clearly identified in any reports found in the literature. G. Supplementary Information Rectal administration: Extract of saw palmetto fruit was administered rectally (De Bernardi di Valserra and Tripodi, 1994) to show that the bioavailability and pharmacokinetic profile was quite similar to oral administration. Tmax occurred about 1 hour after administration and a component was still detectable in plasma after 8 hours. Topical use: A lotion containing cystine and saw palmetto extract is of possible use in alopecia (Morganti et al., 1998).

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Dietary Supplements: A Framework for Evaluating Safety IV. TABLES ON SAW PALMETTO6 Table A Individual Components of Saw Palmetto Fruit Table B Saw Palmetto: Summary of Adverse Effects in Clinical Trials Table C Saw Palmetto: Summary of a Clinical Case Reports (no relevant data available) Table D Saw Palmetto: Summary of Adverse Event Reports (no relevant data available) Table E Saw Palmetto: Summary of Animal Studies Table F Saw Palmetto: Summary of In Vitro Studies Table G Saw Palmetto: Related Substances that Might Suggest Risk V. SUMMARY AND CONCLUSIONS A. Summary Saw palmetto is being widely used by men for prostate-related conditions, most notably benign prostate hyperplasia. Descriptions of saw palmetto are appearing in pharmacology texts for use in cystitis and for its antiedematous and antiandrogenic properties (Gennaro, 2000). There is a concern that these antiandrogenic properties pose a risk to males in utero because of the potential for deleterious effects on male genitalia. Several pieces of evidence integrated together demonstrate that while there have not been documented cases of saw palmetto-induced birth defects in male offspring of humans or animals, there is a risk associated with saw palmetto ingestion by women. It is well understood that testosterone, an androgen, or male sex hormone, is required for developing and maintaining masculine sexual characteristics. Testosterone is converted to the most active androgen DHT by 5-α-reductase, which then exerts the androgen action via androgen receptors. In vitro data consistently demonstrate that saw palmetto extracts inhibit the testosterone conversion to DHT, including by inhibiting the 5-α-reductase enzyme. They also inhibit binding of DHT to androgenic receptors. Both of these actions would inhibit the androgen pathway if they occurred in vivo. Animal data indicate that orally consumed saw palmetto preparations are antiandrogenic in vivo. Several animal studies were completed with oral administration of saw palmetto extracts following androgen stimulation of prostate hyperplasia. Studies indicate that saw palmetto extract at 50 to 6   Tables appear at the end of this appendix.

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Dietary Supplements: A Framework for Evaluating Safety 300 mg/kg/day inhibit the androgen-stimulated hyperplasia in what appears to be a dose-dependent manner within studies. The 50 mg/kg/day is higher than the ~5 mg/kg/day ingested by humans (assuming 320 mg/day of LESP and 70-kg weight), but not high enough to mitigate concern for such serious effects as teratogenicity. Inhibitors of 5-α-reductase are known to cause adverse effects and are thus contraindicated in women who may become pregnant (Table G). They are classified as pregnancy category X, the category indicating the greatest concern for pregnant women. As described in Table G, the pregnancy category X of these drugs results from teratogenicity studies in animals. These studies have shown that male offspring of animals (including monkeys) that consumed 5-α-reductase inhibitors exhibit abnormal male genitalia development. Finally, the presumed mechanism for effectiveness of saw palmetto in prostate disorders is inhibition of androgen-sensitive pathways. This is partly because the prostate problems being investigated are generally treated by steroid 5-α-reductase inhibitors (Thomson PDR, 2004). Along these lines, the effect of saw palmetto on androgen pathways has also specifically been examined in humans. In a clinical study of healthy young males, no change in serum DHT was observed from ingesting the extract of saw palmetto fruit (320 mg/d, two divided doses, for 1 week) (Strauch et al., 1994). However, it was shown that activity of 5-α-reductase was decreased in prostate tissue and the content of DHT was markedly decreased in prostate tissue (mainly in the periurethral zone) in patients with benign prostatic hyperplasia who had ingested extract of saw palmetto fruit for 3 months. The historical use of saw palmetto does not mitigate any concern about safety for pregnant women for several reasons. Most obvious is that saw palmetto has been predominantly used by men, and there is no indication that it has been safely used by pregnant women. 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 scientific evidence suggests that consumption of saw palmetto poses a risk to unborn male fetuses. This overall public health concern is mitigated somewhat by the much lower popularity of saw palmetto with women, but as noted previously, saw palmetto use is not limited to men. In summary, unless information becomes available to suggest that the antiandrogenic activity in humans is not high enough to cause birth defects in male offspring, a concern exists.

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Dietary Supplements: A Framework for Evaluating Safety VI. LITERATURE CITED Anon. 2000a. Herbal Rx for prostate problems. Consum Rep 65(9):60–62. Anon. 2000b. The mainstreaming of alternative medicine. Consum Rep 65(5):17–25. Bales GT, Christiano AP, Kirsh EJ, Gerber GS. 1999. Phytotherapeutic agents in the treatment of lower urinary tract symptoms: A demographic analysis of awareness and use at the University of Chicago. Urology 54:86–89. Barsanti JA, Finco DR, Mahaffey MM, Fayrer-Hosken RA, Crowell WA, Thompson FN Jr, Shotts EB. 2000. Effects of an extract of Serenoa repens on dogs with hyperplasia of the prostate gland. Am J Vet Res 61:880–885. Bayne CW, Donnelly F, Ross M, Habib FK. 1999. Serenoa repens (Permixon®): A 5α-reductase types I and II inhibitor-new evidence in a co-culture model of BPH. Prostate 40:232–241. Berry SJ, Coffey DS, Walsh PC, Ewing LL. 1984. The development of human benign prostatic hyperplasia with age. J Urol 132:474–479. Blumenthal M, ed. 1998. The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. Austin, TX: American Botanical Council. Bombardelli E, Morazzoni P. 1997. Serenoa repens (Bartram) J.K. Small. Fitoterapia 68:99–113. Breu W, Hagenlocher M, Redl K, Tittel G, Stadler F, Wagner H. 1992. Anti-inflammatory activity of Sabal fruit extracts prepared with supercritical carbon dioxide. In vitro antagonists of cyclooxygenase and 5-lipoxygenase metabolism. Arzneimittelforschung 42:547–551. California Department of Health Services. 2002. State Health Director Warns Consumers about Prescription Drugs in Herbal Products. Online. Available at http://www.applications.dhs.ca.gov/pressreleases/store/pressreleases/02-03.html. Accessed January 8, 2003. Carilla E, Briley M, Fauran F, Sultan C, Duvilliers C. 1984. Binding of Permixon®, a new treatment for prostatic benign hyperplasia, to the cytosolic androgen receptor in the rat prostate. J Steroid Biochem 20:521–523. Chevalier G, Benard P, Cousse H, Bengone T. 1997. Distribution study of radioactivity in rats after oral administration of the lipido/sterolic extract of Serenoa repens (Permixon®) supplemented with [1-14C]-lauric acid, [1-14C]-oleic acid or [4-14C]-beta-sitosterol. Eur J Drug Metab Pharmacokinet 22:73–83. Cristoni A, Morazzoni P, Bombardelli E. 1997. Chemical and pharmacological study on hypercritical CO2 extracts of Serenoa repens fruits. Fitoterapia 68:355–358. De Bernardi di Valserra M, Tripodi AS. 1994. Rectal bioavailability and pharmacokinetics in healthy volunteers of Serenoa repens new formulation. Arch Med Interna 46:77–86. Degenring FH, Sokolowski A, Suter A, Weber M. 2001. Salmonella typhimurium reverse mutation assay with the Serenoa repens extract Prostasan®. Online. The European Phytojournal Vol. 2. Accessed December 12, 2002. De Swaef SI, Vlietinck AJ. 1996. Simultaneous quantitation of lauric acid and ethyl laureate in Sabal serrulata by capillary gas chromatography and derivatisation with trimethyl sulphoniumhydroxide. J Chromatogr A 719:479–482. De Swaef SI, Kleibohmer W, Vlietinck AJ. 1996. Supercritical fluid chromatography of free fatty acids and ethyl esters in ethanolic extracts of Sabal serrulata. Phytochem Anal 7:223–227. Délos S, Iehlé C, Martin PM, Raynaud JP. 1994. Inhibition of the activity of “basic” 5α-reductase (type 1) detected in DU 145 cells and expressed in insect cells. J Steroid Biochem Mol Biol 48:347–352.

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Dietary Supplements: A Framework for Evaluating Safety Délos S, Carsol JL, Ghazarossian E, Raynaud JP, Martin PM. 1995. Testosterone metabolism in primary cultures of human prostate epithelial cells and fibroblasts. J Steroid Biochem Mol Biol 55:375–383. Düker EM, Kopanski L, Schweikert HU. 1989. Inhibition of 5α-reductase activity by extracts from Sabal serrulata. Planta Med 55(Supplement):587. Elghamry MI, Hansel R. 1969. Activity and isolated phytoestrogen of shrub palmetto fruits (Serenoa repens Small), a new estrogenic plant. Experientia 25:828–829. El-Sheikh MM, Dakkak MR, Saddique A. 1988. The effect of Permixon® on androgen receptors. Acta Obstet Gynecol Scand 67:397–399. Fang S, Wang X, inventors. International Medical Research I, assignee. 1995. Composition of Herbal Extracts. U.S. Patent 5,417,979. Feifer AH, Fleshner NE, Klotz L. 2002. Analytical accuracy and reliability of commonly used nutritional supplements in prostate disease. J Urol 168:150–154. Gennaro AR, ed. 2000. Remington: The Science and Practice of Pharmacy. 20th ed. Baltimore, MD: Lippincott, Williams and Wilkins. GlaxoSmithKline. 2001. Approval Package. Duagen (Dutasteride) Soft gel Capsules. Pharmacology Review(s). Online. Available at http://www.fda.gov/cder/foi/nda/2001/21319_Duagen.htm. Accessed January 8, 2003. Griebel C, Bames E. 1916. Über eine zur aromatisierung des kognaks dienende palm-frucht. [German]. Zeitschrift Für Untersuchung Der Nahrung-Und Genussmittel, Sowie Der Gegrauchsgegenstände 31:282-290. Harnack LJ, Rydell SA, Stang J. 2001. Prevalence of use of herbal products by adults in the Minneapolis/St Paul, Minn, metropolitan area. Mayo Clin Proc 76:688–694. Harnischfeger G, Stolze H. 1989. Portrait of a medicinal plant Serenoa repens. Saw palmetto. Zeitschrift Für Phytotherapie 10:71–76. Hatinguais P, Belle R, Basso Y, Ribet JP, Bauer M, et al. 1981. Composition of the hexane extract from Serenoa repens Bartram fruits. Trav Soc Pharm Montp 41:253–262. Hiermann A. 1989. About contents of sabal fruits and their anti-inflammatory effect. Arch Pharm (Weinheim) 322:111–114. Hiipakka RA, Zhang HZ, Dai W, Dai Q, Liao S. 2002. Structure-activity relationships for inhibition of human 5α-reductases by polyphenols. Biochem Pharmacol 63:1165–1176. Iehlé C, Délos S, Guirou O, Tate R, Raynaud JP, Martin PM. 1995. Human prostatic steroid 5α-reductase isoforms. A comparative study of selective inhibitors. J Steroid Biochem Mol Biol 54:273–279. Jommi G, Verotta L, Gariboldi P, Gabetta B. 1988. Constituents of the lipophilic extract of the fruits of Serenoa repens (Bart.) small. Gazz Chim Ital 118:823–826. Kloss P. 1966. Steam vaporizable constituents of pressed juice of Sabal serrulatum (Roem et Schult). Arzneimittelforschung 16:95–96. Kokkalou E, Souleles C. 1988. Flavonoid constituents of Pelargonium × asperum Enrh. ex Willd. Geraniaceae. Plant Med Phytother 22:247–253. Leung AY, Foster S. 1996. Saw palmetto. Encyclopedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics. 2nd ed. New York: John Wiley & Sons. Pp. 467–469 . Levy MA, Brandt M, Sheedy KM, Dinh JT, Holt DA, Garrison LM, Bergsma DJ, Metcalf BW. 1994. Epristeride is a selective and specific uncompetitive inhibitor of human steroid 5α-reductase isoform 2. J Steroid Biochem Mol Biol 48:197–206. Levy S. 1998. Can saw palmetto be used to treat benign prostatic hypertrophy? Drug Top 142:53. Lowe FC. 2001. Phytotherapy in the management of benign prostatic hyperplasia. Urology 58:71–76.

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Dietary Supplements: A Framework for Evaluating Safety TABLE C Saw Palmetto: Summary of a Clinical Case Reports (no relevant data available) No relevant clinical case reports TABLE D Saw Palmetto: Summary of Adverse Event Reports (no relevant data available) No relevant adverse event reports

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Dietary Supplements: A Framework for Evaluating Safety TABLE E Saw Palmetto: Summary of Animal Studies Study Design Results and Conclusions Studies with rats (oral administration) Male Wistars Extract of saw palmetto fruit (several hypercritical CO2 extracts) Rat model of prostate hyperplasia due to androgen stimulation: in castrated prepubescent rats, administration of testosterone (15 μg/d, subcutaneously, for 10 d) stimulated prostate hyperplasia Oral administration of an extract of saw palmetto fruit inhibited testosterone-induced increase in prostate weight by 38% (150 mg extract/d) or 76% (300 mg extract/d); two other extracts were less effective (Cristoni et al., 1997) Male Wistars Extract of saw palmetto fruit (50 mg/kg body weight/d, oral gavage, for 90 d; control was 2.5% ethanol vehicle) Castrated on day 0, hormone implants (estradiol implanted on day 7; testosterone implanted on day 21) Rat model of prostate hyperplasia due to androgen stimulation: in castrated rats, administration of estradiol plus testosterone (over 3 mo following castration) stimulated prostate hyperplasia (maximal effect at 30 d) Oral administration of extract of saw palmetto fruit (50 mg/kg body weight/d) inhibited hormone-induced increase in prostate weight (maximal effect at 60 d and 90 d for the dorsal and lateral regions of the rat prostate; maximal effect at 30 d and 60 d for ventral region) (Paubert-Braquet et al., 1998) Males Extract of saw palmetto fruit Rat model of prostate hyperplasia due to androgen stimulation: in castrated rats, administration of testosterone stimulated prostate hyperplasia Oral administration of an extract of saw palmetto fruit (200 mg/d, for 6 d) inhibited hormone-induced increase in prostate weight (Plosker and Brogden, 1996; Stenger et al., 1982) Immature males Extract of saw palmetto fruit (180 or 1,800 mg/d, in methyl cellulose in water, by gavage, BID), finasteride (0.1 or 10 mg/d, oral, BID) or cottonseed oil (2 ml, 5% ethanol, by gavage, control) Castrated; treatment was started on the day following castration and continued for 7 d: testosterone propionate (10 μg/d, subcutaneously), dihydrotestosterone (DHT) propionate (20 μg/d, subcutaneously), or Rat model of prostate hyperplasia due to androgen stimulation: in castrated rats, administration of testosterone or DHT stimulated prostate hyperplasia; coadministration of finasteride inhibited testosterone-stimulated prostate growth Coadministration of an extract of saw palmetto fruit did not inhibit testosterone-stimulated prostate growth Coadministration of finasteride or extracts of saw palmetto fruit did not inhibit DHT-stimulated prostate growth (Rhodes et al., 1993)

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Dietary Supplements: A Framework for Evaluating Safety Study Design Results and Conclusions cottonseed oil (0.2 mL/d, subcutaneously, control); prostate was removed and weighed   Mature male Wistars Sulpiride (40 mg/kg/d, ip); extract of saw palmetto fruit (100, 320, or 640 mg/kg/d, in 2.5% ethanol, by gavage), finasteride (5 mg/kg/d, in 2.5% ethanol, by gavage), or vehicle (2.5% ethanol, by gavage); treatments conducted for 30 days Control, castrated, sham-castrated, castrated/testosterone-implanted (resulting in subnormal testosterone level), castrated/DHT-implanted; castrated/adrenalectomized rats also mentioned (data not shown) Rat model of prostate hyperplasia due to androgen stimulation: in castrated rats, administration of testosterone or DHT stimulated prostate hyperplasia Administration of extract of saw palmetto fruit (at 100 or 320 mg/kg/d) did not alter weight of the lateral lobe of the prostate in castrated, castrated/testosterone-treated, or castrated/ DHT-treated rats; only at 640 mg/kg/d did the extract decrease (by 59%) the weight of the lateral lobe in castrated/ testosterone-treated rats For comparison, finasteride (5 mg/kg/d) decreased (by 67%) the weight of the lateral lobe in castrated/testosterone-implanted rats (but not in castrated/DHT-implanted rats) (Van Coppenolle et al., 2000) Studies with mice (oral administration) Males Extract of saw palmetto fruit Murine model of prostate hyperplasia due to androgen stimulation: in castrated mice administration of testosterone stimulated prostate hyperplasia Oral administration of an extract of saw palmetto fruit (300 mg/d, for 12 days) inhibited hormone-induced increase in prostate weight (Plosker and Brogden, 1996; Stenger et al., 1982) Studies with dogs (oral administration) 20 males with moderate-severe prostate enlargement, but without clinical signs of prostatic hyperplasia, > 4 yr, 25–30 kg body weight) Extract of saw palmetto fruit Group A: 8 dogs, 1,500 mg/d, TID, orally, five 100-mg capsules per treatment, ~10 mg/kg/d, for 91 days Group B: 6 dogs, 300 mg/d, TID, orally, one 100-mg capsule per treatment, ~10 mg/kg/d, for 91 days Benign prostatic hypertrophy model in dogs (the only domestic animal that commonly develops prostatic hyperplasia in aging)

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Dietary Supplements: A Framework for Evaluating Safety Study Design Results and Conclusions Group C: 6 dogs, vehicle alone   Vehicle was a meatball of canned dog food   NOTE: BID = twice per day (amount listed is the total amount administered per day), TID = three times per day (amount listed is the total amount administered per day). Other animal toxicity studies in rats, mice, and dogs have been reported in a review article (Bombardelli and Morazzoni, 1997); however, primary publications of these studies were not available.

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Dietary Supplements: A Framework for Evaluating Safety TABLE F Saw Palmetto: Summary of In Vitro Studies Substance Study Design Results and Conclusions Alteration of cells Saw palmetto, extract of fruit (Permixon) Cells in culture: PC3 cells cotransfected with androgen receptor (wild-type) and CAT reporter genes (under control of androgen response element) Addition of extract (25–50 μg/mL) inhibited CAT transcription induced by androgen (methyltrienolone) stimulation. No effect was observed in the absence of androgen-stimulation or in mock-transfected cells (Ravenna et al., 1996). Saw palmetto, extract of fruit (Permixon), 10 μg/mL for 24 hours In situ studies in human prostate biopsy samples: Normal tissue donors: 10 donors; 9 were ages 20–29 y, 1 was age 51 y BPH biopsy tissue samples: 10 from subjects without medical treatment, ages 62–83 y; 10 from subjects ingesting extract of saw palmetto fruit for previous 3 mo, 320 mg/d, BID Model of proliferation/ apoptotic balance in prostate tissue samples: in epithelial tissue from subjects with BPH who had ingested extract, apoptotic index was increased (as assessed by TUNEL) compared with samples from subjects with untreated BPH. A small increase in the apoptotic index was observed in stromal tissue. In epithelial and stromal tissue from subjects with BPH who had ingested extract, proliferative index was decreased (as assessed by a MIB-1 immunohisto-chemical stain for Ki-67 proliferation antigen) compared to samples from subjects with untreated BPH (Vacherot et al., 2000). (The proliferative index is increased in untreated BPH tissues as compared with normal tissues. Ingestion of extract returned the proliferative index to the level found in normal tissue.)

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Dietary Supplements: A Framework for Evaluating Safety Substance Study Design Results and Conclusions Inhibition of enzymes Saw palmetto, extract of fruit 5-α-reductase from human prostate (obtained from patients undergoing surgery for BPH) Addition of any of 4 extracts inhibited 5-α-reductase. IC50 values: 5.6 μg/mL (Permixon), 7.0 μg/mL (Talso, presumed to be the same as Talso uno), 31 μg/mL (Strogen forte), 40 μg/mL (Prostagutt, presumed to be the same as Prostagutt uno) For comparison, IC50 for finasteride: 1 μg/mL (Rhodes et al., 1993). Saw palmetto, extract of fruit (Permixon) Cells in culture: human foreskin fibroblasts (from healthy infants or adults) Addition of extract inhibited steroid 5-α-reductase (conversion of testosterone to DHT) and 3-α-hydroxysteroid dehydrogenase (conversion of DHT to androstanediol) in assays using intact cells. Addition of extract inhibited binding of [3H]-DHT to androgen receptor(s) in cytosolic, nuclear, and whole cell fractions. Addition of extract inhibited binding of [3H]-methyltrienolone (R1881) to cytosolic components of rat prostate (Sultan et al., 1984). Extract of fruit (Permixon) Cells in primary culture: Human prostate epithelial cells: from subjects with PBH (IC50 = 40 μg/mL); from subjects with prostate adenocarcinoma (IC50 = 90 μg/mL) Human prostate fibroblasts: from subjects with PBH (IC50 = 200 μg/mL); from subjects with prostate adenocarcinoma (IC50 = 70 μg/mL) Addition of extract inhibited metabolism of [3H]-testosterone (0.1 μM) to all metabolites (DHT, androst-4-ene-3,17-dione, 5-α-androstane-3,17-dione). By comparison, finasteride inhibited metabolism of [3H]-testosterone (0.1 μM) to DHT and 5-α-androstane-3,17-dione (IC50 = 20–40 ηM for fibroblasts; IC50 = > 100 ηM for epithelial cells),

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Dietary Supplements: A Framework for Evaluating Safety Substance Study Design Results and Conclusions     but not androst-4-ene-3,17-dione (∆4-A) (Délos et al., 1995). Extract of fruit (Permixon), 10 μg/mL Cells in coculture: human prostate fibroblasts and epithelial cells Addition of extract inhibited type I and type II steroid 5-α-reductase activity (Bayne et al., 1999). Extract of fruit (Permixon) Cells in culture: human prostatic carcinoma cell line (DU 145) Addition of extract inhibited metabolism of [3H]-testosterone (0.1 μM, 1–6 h) by intact cells in culture (Délos et al., 1994). Extract of fruit (Permixon) Human steroid 5-αreductase, type 1 and 2 isoforms expressed in insect cells (fall armyworm, Spodoptera frugiperda Sf9) transfected with baculovirus DNA (Autographa californica nuclear polyhedrosis virus, AcNPV) Addition of extract inhibited baculovirus DNA steroid 5-α-reductase activity in cell homogenates of transfected cells (using 5 mM NADPH; 1 μM [3H]-testosterone for IC50 assays; 0.1–10 μM [3H]-testosterone for Ki assays). Type 1 isoform: noncompetitive inhibition; IC50 = 4 μg/mL, Ki = 7–8 μg/mL (Délos et al., 1995; Iehlé et al., 1995). Type 2 isoform: uncompetitive inhibition; IC50 = 7 μg/mL, Ki = 5 μg/mL (Iehlé et al., 1995). For comparison, finasteride was found to be a competitive inhibitor of 5α-reductase type 1 (IC50 = 0.5 μM, Ki = 0.3 μM) and type 2 (IC50 = 11 ηM, Ki = 7 ηM). Addition of extract inhibited activity of partially purified, expressed type 1 steroid 5-α-reductase (liposome entrapped to preserve activity of this nuclear membrane-associated enzyme) (Iehlé et al., 1995).

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Dietary Supplements: A Framework for Evaluating Safety Substance Study Design Results and Conclusions Extract of fruit (Palmae, prepared by supercritical CO2 extraction) Homogenate of human prostatic tissue (obtained during suprapubic prostatectomy) Addition of extract (0.5 mg/ mL) inhibited steroid 5-α-reductase activity in prostate epithelium and stroma (Weisser et al., 1996) Alcoholic extract of fruit (Remigeron, alcoholic extract) Cells in culture: human genital skin fibroblasts Addition of alcoholic extract inhibited steroid 5-α-reductase in homogenate of fibroblasts (IC50 0.005% solution of the dried extract) and in intact fibroblasts (IC50 0.01% solution of the dried extract). Binding to the androgen receptor could not be demonstrated (Düker et al., 1989). Petroleum ether extract of fruit Cells in culture: human genital skin fibroblasts Addition of pet ether extract inhibited steroid 5-α-reductase of fibroblasts. The inhibitory activity was enriched in the pet ether extract vs. an alcoholic extract (Remigeron) (Düker et al., 1989). Other Extract of fruit (Permixon), 10 μg/mL for 4 d Cells in coculture: human prostate fibroblasts and epithelial cells Addition of extract did not inhibit secretion of PSA (Bayne et al., 1999). Extract of fruit (Permixon) Cytosolic androgen (DHT) receptor binding assay in rat prostate Addition of extract inhibited binding of [3H]-methyltrienolone (R1881). IC50 was 0.4 μg/mL (Carilla et al., 1984). Extract of fruit (Permixon) Cytosolic androgen receptor (DHT) binding assay in human tissues: uterus (1 specimen, 42-year-old female); vaginal skin (2-, 30- and 33-year-old females) Abdominal wall (2-, 30-, and 32-year-old females) Foreskin (6, newborn males) Addition of extract inhibited binding of radiolabeled DHT and testosterone (El-Sheikh et al., 1988).

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Dietary Supplements: A Framework for Evaluating Safety Substance Study Design Results and Conclusions Extract of fruit Rat prostate androgen (DHT) receptor binding assay Binding of DHT was not inhibited by the extract (data not shown) (Rhodes et al., 1993). NOTE: 3-α-hydroxysteroid dehydrogenase is also called 3-ketosteroid reductase. CAT = chloramphenicol acetyltransferase, BPH = benign prostatic hypertrophy, TUNEL = terminal deoxynucleotidyl transferase dUTP nick end labeling, BID = twice a day, MIB-1 = a monoclonal antibody used to detect Ki-67 antigen, Ki-67, a proliferation antigen, a cellular protein which is not present during G0 phase of cell cycle, IC50 = concentration at which response has decreased 50 percent of the original response, DHT = dihydrotestosterone, PBH = prostate benign hyperplasia, PSA = prostate-specific antigen.

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Dietary Supplements: A Framework for Evaluating Safety TABLE G Saw Palmetto: Related Substances That Might Suggest Risk Related Substance Safety Issues Functionally related therapeutic substancesabc Steroid 5-α-reductase inhibitorsd Pregnancy category X: Dutasteride is contraindicated for use in women (GlaxoSmithKline, 2001). Finasteride is contraindicated in pregnancy or in women who may become pregnant (Medical Economics Co., 2003) and is classified as not intended for use by women (Medsafe, 2001). Possible adverse effect: low plasma level of DHT caused by exposure of women to dutasteride may inhibit fetal development of male external genitalia and internal reproductive organs (GlaxoSmithKline, 2001). Animal studies Mice – the maximum tolerated dose of finasteride was 250 mg/kg/d. Rats, teratogenicity studies – finasteride was not teratogenic in rats (320 mg/kg/d, 24 mo). Rats, developmental studies – in pregnant rats treated with finasteride (0.1–100 μg/kg/d), male offspring developed hypospadias (penile defect, urethral opening is displaced to the under surface) in a dose-dependent manner (3.6% incidence at 0.1 μg/kg/d; 100% incidence at 100 μg/kg/d). In pregnant rats treated with finasteride (≥ 30 μg/kg/d), male offspring were observed to have smaller prostate, smaller seminal vesicles, delayed preputial/foreskin separation, and transient nipple development as compared to control animals. In pregnant rats treated with finasteride (≥ 3 μg/kg/d), male offspring displayed a decreased anogenital distance. The critical period is day 16 to day 17 during gestation (a total of 21 d in the rat) for male offspring exposed in utero to manifest the effects already described. No developmental effects were observed in female offspring exposed in utero to finasteride at any dose studied. Rabbits, developmental studies – no developmental defects were observed in rabbit pups exposed to finasteride (up to 100 mg/kg/d) in utero (days 6–18 of gestation). Monkeys, developmental studies – finasteride (0.8 μg/d, i.v.) was administered to pregnant rhesus monkeys (days 20–100 of gestation); no developmental abnormalities were observed in the male fetuses. In other studies, finasteride (2 mg/kg/d) administered orally to pregnant rhesus monkeys resulted in defects in the formation of the external genitalia of male fetuses; female fetuses were not affected.

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Dietary Supplements: A Framework for Evaluating Safety a To construct this table, substances were considered that are structurally, taxonomically, and functionally related to saw palmetto fruit, extracts saw palmetto fruit, or their constituents (see Table A). Only the substances considered to be relevant to the risk of saw palmetto as a dietary supplement are included in the table. “Functionally related” substances may exhibit an activity that saw palmetto exhibits, based on in vitro or other data; they are not listed here because they have a similar chemical composition b Botanical ingredients in dietary supplements with uses similar to extracts of saw palmetto fruit were considered. No data suggestive of toxicity are available and thus these substances were omitted from this table. The following substances were considered: extract of African palm tree bark (Pygeum africanum); extract of bark or leaves of aspen trees (Populi tremula); goathead vine (Tribulus terrestris); pumpkin seed (Cucurbita pepo; whole seeds, coarsely ground seeds or extract of seeds); extract of rhizomes/root purple coneflower (Echinacea purpurea); extract of stinging nettle root (Urtica dioica) (should be avoided by pregnant women) (Peirce, 1999). c SPES® (Botanic Labs, Brea CA), a blend of 15 botanical ingredients, was also considered but was not included in this table because it is not related to saw palmetto. Three of the ingredients of SPES are also in PC SPES® (a saw palmetto-containing blend of 8 botanicals); however, SPES does not contain saw palmetto. Additionally, SPES is used for cancer, not BPH. PC SPES is used in prostate cancer and BPH. The ingredients of PC SPES are described in a footnote to Table B-2. The ingredients of SPES are as follows: licorice (rhizome/root of Glycyrrhiza glabra Fisch/Glycyrrhiza uralensis Fisch, gan-zao), blushred rabdosia (leaf of Rabdosia rubescens Hara, dong-ling-cao), ginseng (root of Panax pseudoginseng Wall, jensheng), reishi mushroom (stem of Ganoderma japonicum, ling-zhi), desert ginseng (Cistanche deserticola, cheng-min chou), pear-leaf wintergreen (Pyrola rotundifolia L., lu-ti-cao), hairy agrimony (Agrimonia pilosa Lebed/Agrimonia japonica, xian-he-cao), yenhusuo/yan-hu-so (Corydalis yanhusuo/Corydalis bulbosa), higanbana/red spider lily (Lycoris radiata, shi-suan), mou-hui tou (Patrinia heterophylla), di-bu-long (Stephania delavayi Diels), runan/shan-wugui (Stephania sinica Diels, hua-jian-jiu-teng), golden cow in the soil/prickly-ash (Zanthoxylum nitidum, liang-mian-zhen), rokujo (Cervus nippon Temminck, lu-jung), and pollen (huafeng) (Fang and Wang, 1995). SPES may also contain soy milk. During analysis of specific lots of SPES substantial amounts of a synthetic drug (alprazolam, Xanax®) were identified (California Department of Health Services, 2002). SPES is no longer available on the market in the United States. d Steroid 5-α-reductase inhibitors include: finasteride (Proscar®, MK-906; competitive inhibitor, selective inhibitor of human type 2 steroid 5-α-reductase, 50-fold selectivity), dutaseride (Duagen, GI-198745; inhibitor of human type 1 and type 2 steroid 5-α-reductase), epristeride (SKF 105657, a 3-androstene-3-carboxylic acid; uncompetitive inhibitor; selective inhibitor of human type 2 steroid 5-α-reductase, 400-fold selectivity), izonsteride (LY320236, a benzoquinolinone; competitive inhibitor of human type 1 steroid 5-α-reductase; noncompetitive inhibitor of type 2 steroid 5-α-reductase), and 4MA (N,N-diethyl-4-methyl-3-oxo-4-aza-5-α-androstane-17-β-carboxamide, a 3-oxo-4-aza steroid; potent inhibitor of type 1 and type 2 steroid 5-α-reductase; potent inhibitor of 3β-hydroxysteroid dehydrogenase). Type 2 steroid 5-α-reductase is the predominant activity in human prostate; rat prostate contains equal activity of type 1 and type 2 (Levy et al., 1994). DHT = dihydrotestosterone.