phytoestrogens and Infertility

Sex steroid hormones, most notably estradiol, play a pivotal role in the sex-specific organization and function of the kisspeptin system. Endocrine--disrupting compounds are anthropogenic or naturally occurring compounds that interact with steroid hormone signaling. Thus, these compounds have the potential to disrupt the sexually dimorphic ontogeny and function of kisspeptin signaling pathways, resulting in adverse effects on neuroendocrine physiology. This chapter reviews the small but growing body of evidence for endocrine disruption of the kisspeptin system by the exogenous estrogenic compounds bisphenol A, polychlorinated biphenyl mixtures, and the phytoestrogen genistein. Disruption is region, sex, and compound specific, and associated with shifts in the timing of pubertal onset, irregular estrous cycles, and altered sociosexual behavior. These effects highlight that disruption of kisspeptin signaling pathways could have wide ranging effects across multiple organ systems, and potentially underlies a suite of adverse human health trends including precocious female puberty, idiopathic infertility, and metabolic syndrome.

Topics: Animals; Benzhydryl Compounds; Estradiol; Female; Genistein; Humans; Infertility; Kisspeptins; Menstrual Cycle; Metabolic Syndrome; Neurosecretory Systems; Phenols; Phytoestrogens; Puberty, Precocious; Sexual Behavior; Signal Transduction

During the 20th century, there has been an increased risk from environmental by-products that may be harmful to reproductive function in humans. Therefore, as the 21st century begins, it is appropriate to evaluate future directions within the field of reproductive toxicology. This commentary identifies several approaches and developing technologies that would help research continue in a meaningful direction. Four areas for development are suggested, and selected examples of research involved in those areas are discussed: (1) Translational applications: workplace exposures thought to cause infertility in men (1,2-dibromo-3-chloropropane, DBCP) and menstrual disturbances in women (2-bromopropane, 2BP) are given as examples of human effects that have prompted animal studies. (2) Exposure paradigms: extrapolating dosing in animals to exposures in humans becomes complex. Two examples of surprising findings using lower doses are cited: ovotoxicity caused by polycyclic aromatic hydrocarbons (PAHs), and disrupted sexual differentiation caused by the fungicide vinclozolin. (3) Gender differences: predicting variable risk between women and men requires investigation of the effects of reproductive toxicants in both genders. The phthalates provide a good example for this comparison. Whereas di-(2-ethylhexyl)phthalate (DEHP) is a reproductive toxicant working by similar mechanisms in males and females, di-n-butyl phthalate (DBP) produces developmental effects in males and reproductive tract effects in females. (4) Endocrine disruptors: recent research has identified environmental chemicals that disrupt reproductive processes by altering the actions of endogenous steroid hormones. The endocrine disruptor issue is discussed in terms of evaluation of the actual risk these chemicals may pose in humans.

Topics: Animals; Endocrine System; Environmental Exposure; Estrogens, Non-Steroidal; Female; Humans; Hydrocarbons, Brominated; Infertility; Insecticides; Isoflavones; Male; Phthalic Acids; Phytoestrogens; Plant Preparations; Propane; Reproduction; Sex Factors

Cows and ewes fed estrogenic forage may suffer impaired ovarian function, often accompanied by reduced conception rates and increased embryonic loss. Males are relatively unaffected, but the mammary glands in females and castrate males may undergo hypertrophy of the duct epithelium, accompanied by secretion of clear or milky fluid. In cows, clinical signs resemble those associated with cystic ovaries. The infertility is temporary, normally resolving within 1 mo after removal from the estrogenic feed. However, ewes exposed to estrogen for prolonged periods may suffer a second form of infertility that is permanent, caused by developmental actions of estrogen during adult life. The cervix becomes defeminized and loses its ability to store spermatozoa, so conception rates are reduced, although ovarian function remains normal. Importantly, both temporary and permanent infertility in ewes often occur without observable signs and can be detected only by measurement of phytoestrogens in the diet, or measurement of their effects on the animal. Low background concentrations of dietary phytoestrogens are suggested to play an important role in prevention of disease in humans and laboratory rats, but subclinical effects of phytoestrogens in cattle have not yet been described. Effects of low concentrations of phytoestrogens on reproductive function in ruminants are likely to receive increasing attention.

Topics: Animals; Cattle; Cattle Diseases; Cervix Uteri; Estrogens, Non-Steroidal; Fabaceae; Female; Hypertrophy; Infertility; Isoflavones; Male; Mammary Glands, Animal; Ovary; Phytoestrogens; Plant Preparations; Plants, Medicinal; Sheep; Sheep Diseases

Phytoestrogens exist in plants that are present in forages fed to horses. They may compete with 17-β estradiol and influence the estrous cycle. Therefore, the objective was to determine whether coumestrol from clover-mixed pastures is present in mare's plasma after their ingestion (experiment I), and when this phytoestrogen was present in mare's plasma after ingestion (experiment II). The effect of a long-term ingestion of phytoestrogens on estrous cycle disruption was assessed (experiment III; clinical case). Experiment I was carried out in nonpregnant anestrous and cyclic Lusitano mares (n = 14) kept on clover and grass-mixed pastures, and supplemented with concentrate and hay or cereal straw. Blood and feedstuff were obtained from November to March. In experiment II, stabled cyclic Lusitano mares (n = 6) were fed for 14 days with increasing amounts of alfalfa pellets (250 g to 1 kg/day). Sequential blood samples were obtained for 8 hours after feed intake on Day 0 (control) and on Days 13 and 14 (1 kg/day alfalfa pellets). Experiment III mares were fed with a mixture of alfalfa and clover haylage for 5 months (group 1; n = 4) or for 9 months (group 2; n = 12). Estrous cycle was determined on the basis of plasma estradiol (E2), progesterone (P4), and ultrasound (experiment III). Concentrations of phytoestrogen coumestrol and its metabolite methoxycoumestrol were determined by high-performance liquid chromatography coupled with mass spectrometry. Phytoestrogens decreased in pasture from November until March (P < 0.01) (experiment I), but were always detected in mares' plasma. In experiment II, plasma-conjugated forms of coumestrol and methoxycoumestrol were higher on Days 13 and 14 than in control (P < 0.05). The highest concentrations of conjugated form of coumestrol were at 1.5 and 4 hours (P < 0.001), whereas its free forms peaked at 1 and at 3.5 hours after ingestion (P < 0.05). Methoxycoumestrol-conjugated form concentration was the highest at 1.5 and 5 hours (P < 0.001), whereas its free form peaked at 1 hour (P < 0.05) and at 1.5 hours (P < 0.001). Long-term intake of coumestrol caused lack of ovulation, uterine edema, and uterine fluid accumulation (experiment III). Coumestrol and methoxycoumestrol in both forms were higher in group 2 (while still ingesting haylage) than in group 1, after haylage withdrawal (P < 0.001). These data show that in the mare, coumestrol and its metabolite increase in blood after ingestion of estrogenic plants and can i

Topics: Animal Feed; Animals; Coumestrol; Eating; Endocrine Disruptors; Estrous Cycle; Female; Horses; Infertility; Ovulation; Phytoestrogens; Plants

This study investigated the role of oral phytoestrogens in improving pregnancy rate and cycle outcomes with clomiphene citrate. Patients with unexplained infertility and recurrent clomiphene citrate induction failure, were randomly divided into two groups: group I (n = 60) and group II (n = 59). Both groups received clomiphene citrate 150 mg per day (days 3 to 7). Group I received additional oral phytoestrogen (Cimicifuga racemosa) 120 mg/day from days 1 to 12. Human chorionic gonadotrophin (HCG) injection (10,000 IU i.m.) was given and timed intercourse was recommended when a leading follicle reached >17 mm and serum oestradiol exceeded 200 (pg/ml). There was a non-significant shortening of induction cycles in group I. Oestradiol and LH concentrations were higher in group I compared with group II. Endometrial thickness, serum progesterone and clinical pregnancy rate were significantly higher in group I (8.9 +/- 1.4 mm versus 7.5 +/- 1.3 mm, P < 0.001; 13.3 +/- 3.1 ng/ml versus 9.3 +/- 2.0 ng/ml, P < 0.01; 36.7% versus 13.6%, P < 0.01, respectively). It is concluded that adding C. racemosa rhizome dry extract to clomiphene citrate induction can improve the pregnancy rate and cycle outcomes in these couples.

Topics: Adult; Algorithms; Cimicifuga; Clomiphene; Female; Fertility Agents, Female; Follicular Phase; Humans; Infertility; Male; Phytoestrogens; Phytotherapy; Plant Extracts; Pregnancy; Pregnancy Rate; Treatment Outcome

With recent poaching of southern white rhinoceros (SWR [

Topics: Animals; Animals, Zoo; Cluster Analysis; DNA, Ribosomal; Feces; Gastrointestinal Microbiome; Infertility; Mass Spectrometry; Perissodactyla; Phylogeny; Phytoestrogens; RNA, Ribosomal, 16S; Sequence Analysis, DNA

Preimplantation embryo loss during oviduct transit has been observed in adult mice after a 5-day neonatal exposure to the phytoestrogen genistein (Gen; 50 mg/kg/day).. We investigated the mechanisms underlying the contribution of the oviduct to infertility.. Female mice were treated on postnatal days 1-5 with corn oil or Gen (50 mg/kg/day). We compared morphology, gene expression, and protein expression in different regions of the reproductive tracts of Gen-treated mice with those of control littermates at several time points.. Neonatal Gen treatment resulted in substantial changes in expression of genes that modulate neonatal oviduct morphogenesis, including Hoxa (homeobox A cluster), Wnt (wingless-related MMTV integration site), and hedgehog signaling genes. An estrogen receptor antagonist blocked these effects, indicating that they were induced by the estrogenic activity of Gen. Oviducts of adults treated neonatally with Gen had abnormal morphology and were stably "posteriorized," as indicated by altered Hoxa gene patterning during the time of treatment and dramatic, permanent up-regulation of homeobox genes (e.g., Pitx1, Six1) normally expressed only in the cervix and vagina.. Neonatal exposure to estrogenic environmental chemicals permanently disrupts oviduct morphogenesis and adult gene expression patterns, and these changes likely contribute to the infertility phenotype.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Female; Gene Expression Regulation; Genistein; Immunoblotting; Infertility; Mice; Microarray Analysis; Morphogenesis; Oviducts; Phytoestrogens; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors