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© 2007 American Society for Nutrition J. Nutr. 137:1390-1394, June 2007

Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Dietary Soy Protein Containing Isoflavonoids Does Not Adversely Affect the Reproductive Tract of Male Cynomolgus Macaques (Macaca fascicularis)1,2

Donna L. Perry3,*, Jennifer M. Spedick3, Thomas P. McCoy3, Michael R. Adams3, Adrian A. Franke4 and J. Mark Cline3

3 Wake Forest University School of Medicine, Winston-Salem, NC 27157 and 4 Cancer Research Center of Hawaii, Honolulu, HI 96813

* To whom correspondence should be addressed. E-mail: dlperry{at}wfubmc.edu.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Short-term dietary studies of soy-protein–derived isoflavonoids, using rodent and nonhuman primate models, have documented variable effects on the reproductive tract. Long-term effects of dietary soy and/or isoflavonoids on the reproductive tract of nonhuman primates have not been determined. The objective of this study was to assess the effects of long-term consumption of dietary soy isoflavonoids on histomorphology of the mammary glands and prostate gland, testis, and sperm counts in adult male cynomolgus macaques. Ninety-one adult male cynomolgus macaques (Macaca fascicularis) were fed diets for 3 y differing only in protein source: 1) a soy-free, casein-lactalbumin–based diet or 2) a low-soy isoflavonoid diet (~6 mg · kg–1 · d–1) or 3) a high-soy isoflavonoid diet (~12 mg · kg–1 · d–1). Serum isoflavonoids were measured by liquid chromatographic-photodiode array electrospray MS. Mammary gland, prostate gland, and testes were obtained at postmortem and evaluated histopathologically and histomorphometrically. Epididymal and testicular sperm counts were performed. Serum isoflavonoid concentrations at 4 h postfeeding differed among all groups (P < 0.001) and were (means ± SEM) 67 ± 23 (soy-free diet), 799 ± 44 (low-soy isoflavonoid diet), and 1458 ± 80 nmol · L–1 (high-soy isoflavonoid diet). Diet did not alter serum estradiol and testosterone concentrations or epididymal and testicular sperm counts. Organ weights and histologic indices did not differ among treatment groups. Mammary gland histopathologic and histomorphometric analysis revealed no abnormalities and no indication of gynecomastia. We found no evidence of an adverse effect of soy isoflavonoids at physiologically relevant doses within the reproductive organs of adult male macaques.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Men that consume a diet rich in soy-derived protein, typically in Asian countries, have a much lower prostate cancer incidence than men consuming a traditional Western diet (1–4). These isoflavonoid concentrations have been estimated to range from 25 to 50 mg/d (6–11 g soy protein) (5). This epidemiological observation prompted many to postulate that weakly estrogenic isoflavonoids present in soy proteins may have protective, i.e., antiproliferative and proapoptotic effects, in the prostate gland (6). Dietary studies evaluating the effects of soy-derived isoflavonoids in rodent models have reported results varying from no discernable negative effects to marked atrophy of the accessory sex glands (7–10). This variability of in vivo responses to dietary isoflavonoids may be due in part to differences in sensitivity of the various inbred laboratory rodent strains to these estrogen-like compounds (11,12). In vitro and in vivo studies evaluating effects of soy-derived isoflavonoids on sperm quality have also produced conflicting results (13,14). Several short-term pharmacokinetic studies evaluating the metabolism of soy isoflavonoids and several studies evaluating their effect on prostate-specific antigen have been performed in men. These studies demonstrated that the isoflavonoid metabolite, daidzein, concentrates in prostatic fluid, although the majority of studies demonstrate no effect on elevated or rising prostate-specific antigen levels (15–18). To our knowledge, long-term studies evaluating the effects of continuous dietary soy isoflavonoid consumption on reproductive tissues have not yet been attempted (18–21).

The purpose of this study was to evaluate the effects of long-term dietary isoflavonoid supplementation on the morphology of the reproductive tissues in the adult male cynomolgus macaque (Macaca fascicularis), an animal model sharing 97% genetic identity with humans (22).


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
Ninety-one adult male cynomolgus monkeys (Macaca fascicularis) were imported from Indonesia (Institut Pertanian Bogor) and lived in social groups composed of 4 individuals. Effects on the cardiovascular system and behavior have been reported previously (23,24). Age was estimated from dentition to range from 15 to 23 y at the study's end. Briefly, all monkeys were fed a moderately atherogenic diet, designed to mimic the diet consumed by most men in Western countries, and randomized into 3 groups differing only by the source of dietary protein. The control group (n = 30 monkeys, no-SP) was fed a soy-free and isoflavonoid-free, casein-lactalbumin based diet. The low isoflavonoid group (n = 30, low-SI) was fed a mixture of alcohol-washed (isoflavonoid-depleted) and unwashed soy-protein isolate containing 0.94 mg of isoflavonoids per gram of product or ~6 mg · kg–1 · d–1, approximating a human soy isoflavonoid dose of 75 mg · d–1. The high soy isoflavonoid treatment group (n = 31, high-SI) was fed a soy protein isolate containing 1.88 mg soy isoflavonoid per gram of product or ~12 mg · kg–1· d–1, approximating a human soy isoflavonoid dose of 150 mg · d–1. These diets were continuously fed over a 31-mo treatment period. The source of the diets and a detailed description of the components in each have been described previously (23). All procedures involving monkeys were approved by the Institutional Animal Care and Use Committee of Wake Forest University School of Medicine and adhered to the National Research Council's Guide for the Care and Use of Laboratory Animals.

Serum isoflavonoids

Serum was collected under ketamine sedation (10 mg · kg–1 intramuscular) by femoral vein venipuncture at 4 h after feeding. Serum isoflavonoids including genistein, dihydrogenistein, daidzein, dihydrodaidzein, glycitein, O-desmethylangolensin, and equol were measured using liquid chromatographic-photodiode array electrospray MS with isotopically labeled internal standards (7,23,25).

Serum hormones

Blood samples were collected in late morning to control for diurnal variation. Total testosterone, free testosterone, and androstenedione concentrations were determined on unextracted samples using solid phase radioimmunoassay with a commercially available kit (Coat-A-Count, Diagnostic Products). Estrogen was determined after ethyl ether extraction using a radioimmunoassay kit (DSL 4800, ultrasensitive estradiol, Diagnostics Systems Laboratory). CV for individual assays were: total testosterone 9.6%, free testosterone 6.8%, and estradiol 7.9%.

Necropsy and histomorphometry

The monkeys were humanely killed by pentobarbital overdose (30 mg · kg–1 intravenous) and a complete necropsy was performed immediately with collection, weighing, and 24 h fixation of all major organs in 4% paraformaldehyde. After paraffin embedding, 5 µm hematoxylin and eosin-stained sections of the testes, seminal vesicles, mammary glands, prostate, and adrenal glands were examined by a pathologist (DLP).

    Histomorphometry. Histomorphometry was done using a video image analysis system (Sony 3-chip color CCD camera, Pentium III computer, a Scion CG-7 video capture board, and Scion image public domain software). Measurements included prostatic glandular, luminal, and stromal areas (expressed as percentages), and prostatic glandular epithelial height.

Areas were measured at 200x magnification in 3 randomly chosen areas, by tracing the basement membrane and luminal epithelial border of each prostatic acinus followed by calculation of the percentage areas.

    Mammary gland. Glandular epithelial tissue was measured at 200x magnification within 5 randomly chosen fields by tracing the basement membrane surrounding each mammary epithelial structure. Mammary gland and nipple width were measured at 100x magnification from histologic sections.

    Sperm counts. The number of intact sperm heads in 0.25 g of homogenized testicular and epididymal tissues were counted using a Neubauer hemocytometer as previously described (26). Counts were repeated if there was a >20% variation in sperm head counts among hemocytometer chambers.

Statistics

The goal of the analysis was to test the effects of soy protein or isoflavonoid treatment on organ weight, gland morphometry, sperm counts, and hormone levels. Descriptive statistics were calculated to assess normality and equality of variances. Nonparametric Kruskal-Wallis tests were performed to test for differences in isoflavonoid levels because those data had unequal variances that were not corrected by transformation. ANCOVA was used to determine the effects of soy treatment on sex hormones and sperm counts. Multivariate analysis of covariance (MANCOVA, Wilks' Lambda test) was used to determine the effects of soy treatment on prostate gland morphometry, mammary gland morphometry, and organ weight.

Analyses were performed, with and without weighting, for covariates such as age, serum isoflavonoid concentrations, serum hormones at baseline and during treatment. Bonferroni corrections and weighting for covariates did not change outcomes. Analyses were performed using SAS, version 9.1.3 (SAS Institute) and Statistica, version 6.1 (Statsoft, 2004). Differences were considered significant at P < 0.05.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
Isoflavonoids

Serum isoflavonoid concentrations consistently reflected differences among groups in isoflavonoid consumption over the 31-mo treatment period (Kruskal-Wallis P < 0.001), indicating successful dietary delivery of the 2 different concentrations of soy isoflavonoids (Table 1).


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  		TABLE 1 Serum isoflavonoid concentrations, accessory and sex gland organ weights, and testicular and epididymal sperm counts in monkeys fed No-SP, Low-SI, or High-SI diet for 31 mo1

 
Organ weights and sperm counts

Neither testicular and prostate gland weights nor testicular and epididymal sperm counts differed among the 3 groups (Table 1). The weights of other major organs, also were not affected by the diets (data not shown).

Histology and histomorphometry

    Prostate gland. We did not detect differences in architecture (atrophy, hypertrophy, dysplasia) at the microscopic level within stromal and epithelial (glandular) compartments of the prostate gland among treatment groups. However, there were 5 monkeys with basal cell adenomas within the cranial lobe of the prostate gland. These basal cell adenomas were present in 1 monkey in the no-SP group, 2 monkeys in the low-SI group, and 2 monkeys in the high-SI group. Basal cell adenomas are considered incidental or background lesions in cynomolgus macaques and have been described previously (27,28). Histomorphometrically the percentage of stromal area compared with glandular (epithelial) area did not differ in the cranial and caudal prostate glands among the 3 groups (Table 2).


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  		TABLE 2 Prostate gland percent epithelial and stromal areas and mammary gland histomorphometry monkeys fed No-SP, Low-SI, or High-SI diet for 31 mo1

 
    Mammary gland. We observed no evidence of gynecomastia or abnormal glandular morphology or proliferation in the monkeys with the exception of one in the high-SI treatment group, which was diagnosed with an intraductal mammary gland adenocarcinoma and was published previously (29). The incidence of mammary gland carcinoma in male cynomolgus macaques is unknown at this time, although is thought to be rare. As such, it is impossible to determine whether this neoplasm was related to soy isoflavonoid treatment or within an expected incidence rate for this species of macaque. With respect to quantitative measures, the high-SI treatment group had the smallest mammary gland nipple width and this was significantly less than that of the control group (P < 0.025) (Table 2).

Serum hormones

Serum estradiol, testosterone, or androstenedione did not differ among the 3 groups at baseline or following the 31-mo dietary soy protein treatment period (Table 3).


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  		TABLE 3 Serum sex hormones in monkeys fed No-SP, Low-SI, or High-SI diet for 31 mo1

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
This 31-mo soy protein–derived isoflavonoid intervention study confirmed successful delivery of isoflavonoids through dietary consumption by measurement of serum isoflavonoid concentrations. Serum hormones, organ weights, prostate and mammary gland histomorphometry, and testicular and epididymal sperm counts were evaluated within a no-soy, a low-soy (~6 mg · kg–1 · d–1or 75 mg · person–1 · d–1), and a high-soy isoflavonoid (~12 mg · kg–1 · d–1 or 150 mg · person–1 · d–1) treatment group. We found no adverse effects of dietary isoflavonoids in the organs and variables evaluated.

These findings are in contrast to our previous dietary isoflavonoid metabolite treatment study demonstrating marked accessory sex gland atrophy by Cline et al. (7) in apolipoprotein E null C57BL/6J mice. In this study mice were fed soy isoflavonoid metabolites genistein (G) and daidzein (D) in ratios of 2G:1D, 10G:1D, and 1G:10D at a dose of 120 mg · 7536 kJ–1 · d–1 or 40 mg · kg–1 · d–1 from 6 to 22 wk of age. All mice receiving the isoflavonoid-enriched soy diet exhibited accessory sex gland atrophy. Spearow et al. (11) speculated that differences among murine strains in responses to isoflavonoids may be due to differences in liver and testicular sulfotransferase activity. The C57BL/6 mouse strain, used in the Cline et al. (7) study, was more sensitive to estrogenic compounds than the ICR strain of mice. In a study utilizing the ICR strain of mice fed genistein at lower concentrations of 2.5 mg · kg wt–1 · d–1 for 5 wk postweaning, no lesions within the testis, epididymis, or prostate gland occurred (10). Yet, in a different study using ICR mice fed genistein at 2.5 and 5 mg · kg wt–1 · d–1 for 5 wk postweaning, there were no changes in accessory sex gland weight, but Leydig cell hyperplasia occurred histopathologically (9).

Interestingly, hyperplasia of Leydig cells, estimated as an increase in Leydig cell numbers of 74%, was seen in newborn marmosets fed a commercially available soy-protein–based infant formula containing concentrations of soy isoflavonoids estimated to range from 18 to 41 mg aglycone · L–1. The testes of these marmosets were compared with those of their fraternal twin fed a control diet of commercially available cow's milk-based infant formula for 40 d (30). Upon evaluation of the co-twin marmosets at adulthood (120–138 wk of age), both groups proved fertile, being able to impregnate a female marmoset, although the testes of the soy-infant formula fed marmosets were 14% heavier than males fed a cow's milk-based infant formula. The testes of the soy infant-formula–fed monkeys had larger numbers of both germ cells (Sertoli cells) and Leydig cells (interstitial cells) with no evidence of a long-term adverse effect of soy isoflavonoids on reproductive function as a result of the soy isoflavonoids fed during development (31).

In a study by Svechnikov et al. (32), male Sprague-Dawley rats were fed genistein at a dose of 1 g · kg–1 of diet from 3 to 6 mo of age (21.1 mg genistein · d–1 or 46.2 mg · kg body wt–1 · d–1). The Leydig cells of these rats were isolated, and concentrations of testosterone were determined in culture following stimulation with human chorionic gonadotropin or butyryl cAMP. Although serum concentrations of testosterone did not differ in the genistein treated group when compared with untreated controls, the Leydig cells evaluated in culture did not respond to stimulation with human chorionic gonadotropin or butyryl cAMP, which the authors attributed to a reduction in mitochondrial p450 scc enzyme expression. These findings provide in vitro evidence of a negative effect of genistein administration on Leydig cell testosterone production; although an assessment of testicular morphology was not performed to determine whether increases in Leydig cell numbers were present, as previously observed in mice and marmosets. Further studies investigating the effects of soy isoflavonoids on Leydig cell density and function are warranted, although we are unaware of data demonstrating reduced fertility as a result of ingesting soy protein or isoflavonoids by nonhuman primates or humans.

In this study, no evidence of gynecomastia was seen within the low-SI and high-SI treatment groups. Fisher et al. (17) reported gynecomastia and breast tenderness in 3 of 20 men enrolled in a study evaluating the safety and pharmacokinetics of soy isoflavonoids over a 3-mo treatment period. However, these results may not apply to the general population. All 3 men were previously diagnosed with prostate cancer and were given a purified isoflavonoid extract at a high dose, i.e., 300–600 mg genistein · d–1 and 150–300 mg daidzein · d–1. One of the 3 men, reported to have gynecomastia, was being treated with the androgen receptor antagonist, Casodex, and had symptoms of gynecomastia at baseline and before the initiation of soy isoflavonoid treatment. Furthermore, these symptoms continued past discontinuation of isoflavonoid treatment. A second man also had gynecomastia at baseline, prior to the initiation of soy isoflavonoid treatment, that was attributed to use of PC-Spes, a diethylstilbestrol-contaminated herbal product with the recognized side effect of nipple tenderness and gynecomastia. This product has since been withdrawn from the marketplace. The third report of gynecomastia during the study was spontaneously resolved by the subsequent follow-up visit. Giampietro et al. (33) evaluated the effects of the use of soy-protein–based formula in children ranging from 7 to 96 mo of age and found no evidence of precocious puberty, gynecomastia, or altered bone metabolism. Although the study of neonatal soy-isoflavonoid formula-fed twin marmosets, performed by Sharpe et al. (30) and Tan et al. (31), might have shed some light on this question, the mammary glands from these monkeys were not evaluated.

Taken together, these studies demonstrate that concerns over the effect of soy-protein–derived isoflavonoids on the reproductive tract in male primates are not yet supported scientifically (34,35). Our study demonstrated no adverse effects of soy protein on the reproductive organs of adult male cynomolgus macaques. At this time demonstrable evidence does not exist to indicate that, when used in moderate doses, consumption of soy isoflavonoids reduces fertility or causes gynecomastia in men or nonhuman primates.

To our knowledge, this is the first study to evaluate the long-term effects of dietary soy-protein–derived isoflavonoid consumption in the adult male nonhuman primate. Future studies are necessary to explain the mechanism by which regular consumption of a diet rich in soy-derived isoflavonoids may lower the incidence of prostate cancer (1,2). These future studies should also address the effects of other soy components commonly consumed by human beings that act alone or in combination with isoflavonoids.


   ACKNOWLEDGMENTS
 
We thank Hermina Borgerink, Beth Phifer, Dianna Swaim, Lisa O'Donnell, Joseph Finley, Jean Gardin of the Wake Forest University School of Medicine and Laurie Custer of the Cancer Research Center of Hawaii for technical assistance.


   FOOTNOTES
 
1 Supported by grants from the NIH (P01 HL45666 to M.R.A.) and the National Center for Research Resources (T32 RR 07009 to D.L.P.). Soy products were kindly provided by the Solae Company, St. Louis, MO. Back

2 Author disclosures: D. L. Perry, J. M. Spedick, T. P. McCoy, M. R. Adams, A. A. Franke, and J. M. Cline, no conflicts of interest. Back

Manuscript received 27 September 2006. Initial review completed 27 November 2006. Revision accepted 4 April 2007.


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 

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