phytoestrogens and Infertility--Male

Exposure to toxicants present in the environment, especially the so-called endocrine-disrupting chemicals (EDCs), has been associated with decreased sperm quality and increased anomalies in male reproductive organs over the past decades. Both human and animal populations are continuously exposed to ubiquitous synthetic and natural-occurring EDCs through diet, dermal contact and/or inhalation, therefore potentially compromising male reproductive health. Although the effects of EDC are likely induced via multiple genomic-based pathways, their non-genomic effects may also be relevant. Furthermore, spermatozoa are transcriptionally inactive cells that can come in direct contact with EDCs in reproductive fluids and secretions and are therefore a good model to address non-genomic effects. This review thus focuses on the non-genomic effects of several important EDCs relevant to mammalian exposure. Notably, EDCs were found to interfere with pre-existing pathways inducing a panoply of deleterious effects to sperm function that included altered intracellular Ca(2) (+) oscillations, induction of oxidative stress, mitochondrial dysfunction, increased DNA damage and decreased sperm motility and viability, among others, potentially jeopardizing male fertility. Although many studies have used non-environmentally relevant concentrations of only one compound for mechanistic studies, it is important to remember that mammals are not exposed to one, but rather to a multitude of environmental EDCs, and synergistic effects may occur. Furthermore, some effects have been detected with single compounds at environmentally relevant concentrations.

Topics: Animals; Calcium; Dioxins; DNA Damage; Drug Synergism; Endocrine Disruptors; Environmental Exposure; Humans; Infertility, Male; Male; Mammals; Mitochondria; Mycotoxins; Oxidative Stress; Phytoestrogens; Polychlorinated Biphenyls; Polycyclic Aromatic Hydrocarbons; Reproduction; Sperm Count; Sperm Motility; Spermatozoa

A time-related negative trend in male reproductive function has been suggested. It has been hypothesized that this is due to exposure to chemicals interfering with the action of sex hormones. Also a negative effect of phytoestrogens on male fertility has been postulated. This review aimed to review the epidemiological evidence of deteriorating male reproductive function and summarize the most recent literature on exposure to endocrine disrupters and phytoestrogens in relation to male fertility and/or semen quality.. There is no doubt that the incidence of testicular cancer has increased through the past 50 years, a decline in sperm counts, if any, may have leveled off during the past decade. There are some reports indicating negative association between exposure to certain chemicals and sperm parameters such evidence has not been found for phytoestrogens. The majority of these studies have been limited to assessing postnatal exposure.. Although possible negative impact of industrial chemicals and male fertility is an important issue on the research agenda, so far, it has no clinical implications. The future research should focus on looking at the impact of low dose exposure to a mixture of chemicals, two generation studies and gene-environment interaction.

Topics: Endocrine Disruptors; Environmental Exposure; Environmental Pollutants; Estrogens; Fertility; Gene-Environment Interaction; Humans; Infertility, Male; Male; Phytoestrogens; Risk Assessment; Risk Factors; Spermatogenesis; Spermatozoa

There is growing interest in the possible health threat posed by the effects of endocrine disruptors on reproduction. Soy and soy-derived products contain isoflavones that mimic the actions of oestrogens and may exert adverse effects on male fertility. The purpose of this review was to examine the evidence regarding the potential detrimental effects of soy and phyto-oestrogens on male reproductive function and fertility in humans and animals. Overall, there are some indications that phyto-oestrogens, alone or in combination with other endocrine disruptors, may alter reproductive hormones, spermatogenesis, sperm capacitation and fertility. However, these results must be interpreted with care, as a result of the paucity of human studies and as numerous reports did not reveal any adverse effects on male reproductive physiology. Further investigation is needed before a firm conclusion can be drawn. In the meantime, caution would suggest that perinatal phyto-oestrogen exposure, such as that found in infants feeding on soy-based formula, should be avoided.

Topics: Animals; Endocrine Disruptors; Environmental Exposure; Humans; Infant; Infant Formula; Infertility, Male; Isoflavones; Male; Phytoestrogens; Reproduction; Risk Factors; Sexual Development; Soybean Proteins

In Europe, endocrine disruptors (EDs) have been defined as substances foreign to the body that have deleterious effects on the individuals or their descendants, due to changes in endocrine function. In the United States, EDs have been described as exogenous agents that interfere with the production, release, transport, metabolism, binding, action or elimination of the natural ligands responsible for maintaining homeostasis and regulating body development. These two definitions are complementary, but both indicate that the effects induced by EDs probably involve mechanisms relating in some way to hormonal homeostasis and action. EDs are generally described as substances with anti-oestrogenic, oestrogenic, anti-androgenic or androgenic effects. More recently, other targets have been evidenced such as the thyroid and immune system. Many different EDs are present in the various compartments of the environment (air, water and land) and in foods (of plant and animal origin). They may originate from food packaging, combustion products, plant health treatments, detergents and the chemical industry in general. In addition to the potential effects of these compounds on adults, the sensitivity of embryos and fetuses to many of the xenobiotic compounds likely to cross the placenta has raised considerable concern and led to major research efforts. With the exception of the clearly established links between diethylstilbestrol, reproductive health abnormalities and cancers, very little is known for certain about the effects of EDs on human health. Given the lack of available data, current concerns about the possible involvement of EDs in the increase in the incidence of breast cancer, and possibly of endometriosis and early puberty in girls, remain hypothetical. Conversely, the deterioration in male reproductive health is at the heart of preoccupations and progress in analyses of the relationship between EDs and human health. This literature review aims to describe the current state of knowledge about endocrine disruption, focusing in particular on the problem of food contaminants.

Topics: Abnormalities, Drug-Induced; Animals; Benzhydryl Compounds; Diethylstilbestrol; Endocrine Disruptors; Endocrine System Diseases; Environmental Health; Environmental Pollutants; Female; Fetus; Food Contamination; Gonadal Dysgenesis; Homeostasis; Humans; Industrial Waste; Infertility, Male; Male; Mammary Neoplasms, Experimental; Neoplasms; Pesticide Residues; Phenols; Phthalic Acids; Phytoestrogens; Plastics; Pregnancy; Prenatal Exposure Delayed Effects; Rats

Few potentially modifiable risk factors of male infertility have been identified, and while different diets and food groups have been associated with male infertility, evidence linking dietary factors including phytoestrogens and semen quality is limited and contradictory.. To study the associations between phytoestrogen intake and other dietary factors and semen quality.. High consumption of daidzein (≥13.74 μg/d), a phytoestrogen found in soy products, was a protective factor for MSC with an odds ratio (95%CI) of 0.58 (0.42-0.82) after adjustment for clustering and potential confounding. Dietary risk factors for PM after similar adjustment showed that drinking whole milk (OR 0.67, 95%CI 0.47-0.96) and eating red meat were protective with an OR 0.67 (0.46-0.99) for eating red meat >3 times/wk.. In this case-referent study of men attending an infertility clinic for fertility diagnosis, we have identified that low MSC is inversely associated with daidzein intake. In contrast, daidzein intake was not associated with PM but eating red milk and drinking whole milk were protective.. Dietary factors associated with semen quality were identified, suggesting that male fertility might be improved by dietary changes.

Topics: Case-Control Studies; Diet; Food Preferences; Humans; Infertility, Male; Isoflavones; Male; Meat; Phytoestrogens; Risk Factors; Semen Analysis; Soy Foods; Sperm Count; Spermatozoa; Surveys and Questionnaires

Phytoestrogens are plant-derived compounds that may interact with estrogen receptors and mimic estrogenic effects. It remains unclear whether the individual variability in metabolizing phytoestrogens contributes to phytoestrogens-induced beneficial or detrimental effects. Our aim was to determine whether there is any interaction between metabolic rates (MR) of phytoestrogens and genetic polymorphisms in related xenobiotic metabolizing enzyme genes. MR was used to assess phytoestrogen exposure and individual metabolic ability. The amount of phytoestrogens in urine was measured by ultra-high performance liquid chromatography-tandem mass spectrometry in 600 idiopathic infertile male patients and 401 controls. Polymorphisms were genotyped using the SNPstream platform combined with the Taqman method. Prototypes and metabolites of secoisolariciresinol (SEC) have inverse effects on male reproduction. It was found that low MR of SEC increased the risk of male infertility (OR 2.49, 95 % CI 1.78, 3.48, P trend = 8.00 × 10(-8)). Novel interactions were also observed between the MR of SEC and rs1042389 in CYP2B6, rs1048943 in CYP1A1, and rs1799931 in NAT2 on male infertility (P inter = 1.06 × 10(-4), 1.14 × 10(-3), 3.55 × 10(-3), respectively). By analyzing the relationships between urinary phytoestrogen concentrations, their metabolites and male infertility, we found that individual variability in metabolizing SEC contributed to the interpersonal differences in SEC's effects on male reproduction.

Topics: Adult; Arylamine N-Acetyltransferase; Asian People; Biotransformation; Butylene Glycols; Case-Control Studies; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP2B6; Humans; Infertility, Male; Lignans; Male; Phytoestrogens; Polymorphism, Single Nucleotide; Young Adult

Fetal exposure to environmental endocrine disruptors (EDs) is thought to contribute to reported idiopathic increases in adult male reproductive abnormalities. Although humans are exposed to myriad EDs from conception to adulthood, few studies have evaluated the effects of combined EDs on male reproduction. In the present study, we demonstrate that simultaneous gestational exposure to the phytoestrogen genistein and the antiandrogenic plasticizer di-(2-ethyhexyl) phthalate (DEHP) induces long-term alterations in testis development and function. Pregnant Sprague Dawley rats were gavaged from Gestational Day 14 to birth with corn oil, genistein, DEHP, or their mixture at 10 mg/kg/day, a dose selected from previous dose-response studies using single chemicals for its lack of long-term testicular effects. Hormonal and testicular end points were examined in adult male offspring. Serum testosterone levels were unchanged. However, significant increases were observed in testis weight and in the expression of mast cell markers in testes from adult rats exposed gestationally to combined compounds. The ED mixture also altered the mRNA expression of Sertoli cell makers Wt1 and Amh and germ cell markers cKit and Sox17, measured by quantitative real-time PCR (qPCR), suggesting long-term disruption in testis function and spermatogenesis. Alterations in germ cell markers might reflect direct effects on fetal gonocytes or indirect effects via primary targeting of somatic cells, as suggested by differentially regulated Leydig cell associated genes (Hsd3b, Anxa1, Foxa3, and Pdgfra), determined by gene expression array, qPCR, and protein analyses. The two chemicals, when given in combination, induced long-term reproductive toxicity at doses not previously reported to produce any conspicuous long-term effects. Our study therefore highlights a need for a more comprehensive evaluation of the effects of ED mixtures.

Topics: Animals; Biomarkers; Diethylhexyl Phthalate; Drug Synergism; Endocrine Disruptors; Female; Gene Expression Regulation, Developmental; Genistein; Infertility, Male; Leydig Cells; Male; Mast Cells; Nonsteroidal Anti-Androgens; Organ Size; Phytoestrogens; Pregnancy; Prenatal Exposure Delayed Effects; Rats, Sprague-Dawley; Sertoli Cells; Spermatogenesis; Testis; Testosterone

Phytoestrogens (PEs) are naturally occurring chemical constituents of certain plants. The internal PE exposures, mainly from diet, vary among different populations and in different regions due to various eating habits. To investigate the potential relationship between urinary PE levels and idiopathic male infertility and semen quality in Chinese adult males, 608 idiopathic infertile men and 469 fertile controls were recruited by eligibility screening procedures. Individual exposure to PEs was measured using UPLC-MS/MS as spot urinary concentrations of 6 PEs (daidzein, DAI; equol, EQU; genistein, GEN; naringenin, NAR; coumestrol, COU; and secoisolariciresinol, SEC), which were adjusted with urinary creatinine (CR). Semen quality was assessed by sperm concentration, number per ejaculum and motility. We found that exposures to DAI, GEN and SEC were significantly associated with idiopathic male infertility (P-value for trend=0.036; 0.002; and 0.0001, respectively), while these exposures had stronger association with infertile subjects with at least one abnormal semen parameter than those with all normal semen parameters. Exposures to DAI, GEN and SEC were also related to idiopathic male infertility with abnormal sperm concentration, number per ejaculum and motility (P-value for trend<0.05), while these exposures had stronger association with the infertile men with abnormal sperm number per ejaculum. These findings provide the evidence that PE exposures are related to male reproductive function and raise a public health concern because that exposure to PEs is ubiquitous in China.

Topics: Adult; Butylene Glycols; China; Diet; Feeding Behavior; Genistein; Humans; Infertility, Male; Isoflavones; Lignans; Male; Phytoestrogens; Semen; Semen Analysis; Sperm Count; Tandem Mass Spectrometry

Mice with mutations in the kisspeptin signaling pathway (Kiss1(-/-) or Gpr54(-/-)) have low gonadotrophic hormone levels, small testes, and impaired spermatogenesis. Between 2 and 7 months of age, however, the testes of the mutant mice increase in weight and in Gpr54(-/-) mice, the number of seminiferous tubules containing spermatids/spermatozoa increases from 17 to 78%. In contrast, the Kiss1(-/-) mice have a less severe defect in spermatogenesis and larger testes than Gpr54(-/-) mice at both 2 and 7 months of age. The reason for the improved spermatogenesis was investigated. Plasma testosterone and FSH levels did not increase with age in the mutant mice and remained much lower than in wild-type (WT) mice. In contrast, intratesticular testosterone levels were similar between mutant and WT mice. These data indicate that age-related spermatogenesis can be completed under conditions of low plasma testosterone and FSH and that intratesticular testosterone may contribute to this process. In addition, however, when the Gpr54(-/-) mice were fed a phytoestrogen-free diet, they showed no age-related increase in testes weight or improved spermatogenesis. Thus, both genetic and environmental factors are involved in the improved spermatogenesis in the mutant mice as they age although the mice still remain infertile. These data show that the possible impact of dietary phytoestrogens should be taken into account when studying the phenotype of mutant mice with defects in the reproductive axis.

Topics: Age Factors; Aging; Animals; Diet; Drug Evaluation, Preclinical; Fertility; Infertility, Male; Male; Mice; Mice, Knockout; Phytoestrogens; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Severity of Illness Index; Spermatogenesis; Testis

We describe the case of a 30-year-old man with severe oligospermia, caused by partial sperm maturation arrest at spermatidic stage, who was given phytoestrogens. The couple had been trying to conceive for 3 years. The woman was normal at the clinical and endocrinological examination. No other parameters except sperm count, motility and morphology were altered in the male subject. Semen analysis was performed at baseline and after 3 and 6 months of therapy, which consisted of phytoestrogens 80 mg/day for 6 months. An additional semen analysis was performed 6 months after the termination of therapy (wash-out period). During the third month semen parameters improved drastically; therefore a reproductive technique (intrauterine insemination) was performed. This treatment resulted in pregnancy, and a healthy baby weighing 3300 g was born. After 6 months of treatment, sperm parameters ameliorated further. Conversely, after the wash-out period, they returned to baseline values. The appealing results strongly suggest a therapeutic role for phytoestrogens in the treatment of oligospermia. However, it is evident that a validation stage and randomized, controlled studies are essential in order to confirm this observation and verify that phytoestrogens can play an important role in male infertility.

Topics: Adult; Female; Humans; Infant, Newborn; Infertility, Male; Isoflavones; Male; Oligospermia; Phytoestrogens; Pregnancy; Sperm Count; Sperm Maturation; Sperm Motility; Treatment Outcome

Topics: Abnormalities, Drug-Induced; Adult; Animals; Breast Neoplasms; DDT; Endocrine Disruptors; Environmental Exposure; Environmental Pollutants; Estradiol Congeners; Estrogens; Estrogens, Non-Steroidal; Female; Humans; Infant, Newborn; Infertility, Male; Male; Pesticides; Phytoestrogens; Pregnancy; Spain; Toxicology; Universities

Reports of increased incidences of male reproductive abnormalities and falling sperm counts have prompted interest into the nature of these threats to global fertility. Xenoestrogens have been flagged as major culprits but to date, little is known about the effects of dietary phytoestrogens on male reproductive health. These non-steroidal oestrogens of plant origin are potent endocrine disruptors that modulate normal physiological functions. Phytoestrogens have become a major component in the typical Western fast food diet over the last few decades. Soy formula milk is another common source of phytoestrogens, now used increasingly as an alternative to breast or cow's milk for infants with allergies. This use is of particular concern since the most vulnerable periods for oestrogenic insult are thought to be the pre- and neonatal periods when irreversible damage can be inflicted on the developing germinal epithelium. Studies into the safety of phytoestrogens are urgently needed either to allay fears or increase awareness of the effects of our modern diet on future fertility.

Topics: Animals; Diet; Diethylstilbestrol; Genital Diseases, Male; Humans; Infant Formula; Infertility, Male; Male; Phytoestrogens; Reproduction; Soy Milk

The aim of this study was to analyse the multigenerational effects of para-nonylphenol (NP) and resveratrol (RES) on the body weight, organ weight and reproductive fitness of outbred CD-1 mice. The data indicate that in male mice, NP had an effect on the weight of selected reproductive organs and the kidneys in the parental (P) generation males. Effects on selected reproductive organs, the liver and kidneys in the F1-generation males were also seen. In females, effects of NP on body weight and kidney weight were seen in the P generation, but no effects on any measured parameter were seen in the F1 generation. RES had no effect on body weight but did have some effect on selected male and female reproductive organs in the P generation. RES altered the spleen and liver weights of P-generation males and the kidney weight of F1-generation males. Acrosomal integrity (using a monoclonal antibody against intra-acrosomal sperm proteins) was assessed for both generations of NP- and RES-treated mice. A significant reduction in acrosomal integrity was seen in both generations of NP-treated, but not in RES-treated, mice. Fewer offspring were observed in the second litter of the F2 generation of mice treated with NP; no similar effect was seen in RES-treated mice. The litter sex ratio was not different from controls. Unlike RES, NP had a negative effect on spermatogenesis and sperm quality with a resultant impact on in vivo fertility.

Topics: Acrosome; Animals; Animals, Outbred Strains; Body Weight; Environmental Pollutants; Female; Fertility; Genitalia, Female; Genitalia, Male; Infertility, Male; Isoflavones; Kidney; Litter Size; Liver; Male; Mice; Organ Size; Ovarian Follicle; Phenols; Phytoestrogens; Plant Preparations; Pregnancy; Resveratrol; Sex Ratio; Spermatogenesis; Stilbenes

Topics: Aluminum; Alzheimer Disease; Breast Neoplasms; Child; Chronic Kidney Disease-Mineral and Bone Disorder; Estrogens, Non-Steroidal; Female; Food Contamination; Glycine max; Humans; Infertility, Male; Isoflavones; Male; Menarche; Phytoestrogens; Plant Preparations; Sperm Count