phytoestrogens and Infertility--Female

Estrogen is essential for folliculogenesis with independent roles attributed to each of the two estrogen receptors (ERs). ERβ, expressed predominantly by the ovarian granulosa cells, is required for antrum formation, preovulatory follicle maturation, expression of genes involved in ovarian differentiation (luteinizing hormone, aromatase, etc.), and follicle rupture during ovulation. Ovulatory dysfunction is associated with polymorphisms of the ERβ gene, and endocrine disruptors that selectively activate ERβ cause reproductive dysfunction and impairment fertility. ERβ may also exhibit antitumorigenic properties, with a decline in ERβ levels in epithelial ovarian cancers associated with more severe disease and poor prognosis. In this review, we examine the models that have been used to elucidate the roles ERβ plays in the ovary and consider the clinical consequences of altered ERβ expression or inappropriate activation of ERβ signaling.

Topics: Animals; Antineoplastic Agents, Hormonal; Estrogen Receptor beta; Estrogens; Female; Gene Expression Regulation; Granulosa Cells; Humans; Infertility, Female; Neoplasm Proteins; Ovarian Neoplasms; Ovary; Phytoestrogens; Protein Isoforms; Signal Transduction

Ewes exposed to phytoestrogens may display two forms of infertility, categorized as temporary or permanent. Temporary infertility results from actions of estrogen that are similar to the activational effects of estrogen in most species of mammals. The permanent infertility results from changes to the cervix which are analogous to the organizational effects of estrogen reported in other species treated during organogenesis. However, in the ewe these effects may be produced after organogenesis by prolonged treatment during adult life. It has recently become apparent that the level of nutrition and metabolic hormones influence the degree of uterus-like histological change in the cervix produced by prolonged treatment with estrogen. It is hypothesized that, under some nutritional conditions, the hormonal milieu in adult ewes may simulate hormonal patterns that are normally experienced by fetal lambs in utero, thereby allowing the cervix of the adult ewe to give an organizational response to estrogen.

Topics: Animals; Cervix Uteri; Estrogens, Non-Steroidal; Female; Infertility, Female; Isoflavones; Phytoestrogens; Plant Preparations; Sheep

When clover-infertile ewes are subsequently exposed to non-oestrogenic pasture, they have a reduced fertilization rate, due to an inability to store spermatozoa in the cervix, and the cervical mucus has a reduced spinnbarkeit, caused by a slower response to oestrogenic stimulation. Vaginal cell keratinization and oestrous behaviour occurred more slowly after treatment of affected ewes with oestrogen. Other changes in affected ewes suggest that phyto-oestrogens have permanent mild differentiating effects on adults. Sexual behaviour is masculinized, the cervix takes on a uterine-like appearance and the genital tract becomes permanently oestrogenized. The manner in which these changes relate to the altered responsiveness to oestrogen remains to be clarified.

Topics: Animals; Castration; Cervix Mucus; Cervix Uteri; Estrogens; Estrogens, Non-Steroidal; Estrus; Female; Infertility, Female; Isoflavones; Luteinizing Hormone; Male; Phytoestrogens; Plant Preparations; Plants; Pregnancy; Progesterone; Sexual Behavior, Animal; Sheep; Sheep Diseases; Sperm Transport

The anti-oestrogenic activity of clomiphene citrate (CC) on the cervical mucous and endometrium may be the reason for the relatively low pregnancy rates in CC induction cycles. Various follicular-phase supplements have been tried to improve cycle outcome in these patients. This study compared follicular-phase supplementation with either phytoestrogen (PE) or ethinyl oestradiol (EE) in CC induction cycles for the treatment of unexplained infertility. A total of 134 patients were randomly allocated to each treatment group (67 each). The PE group needed significantly fewer days for adequate follicular maturation, had a thicker endometrium and higher oestradiol concentration at the time of human chorionic gonadotrophin injection (all P < 0.001). The PE group had higher luteal-phase serum progesterone compared with the EE group. No significant difference was found regarding clinical pregnancy rates (14.0% versus 21.1%, respectively). In conclusion, the cycle characteristics in unexplained infertility women treated with clomiphene citrate induction and timed intercourse improved after follicular-phase supplementation with PE compared with EE supplementation. Further studies are needed to confirm the mechanism beyond these effects.

Topics: Adult; Cimicifuga; Clomiphene; Estradiol; Ethinyl Estradiol; Female; Fertility Agents, Female; Humans; Infertility, Female; Phytoestrogens; Plant Extracts; Pregnancy

To compare the effectiveness of clomiphene citrate (CC) alone or combined with phytoestrogens (PE) in ovulation induction in patients who had intrauterine insemination in a randomized, double-blind study.. A total of 134 women aged 25-35 years, who were infertile for at least 2 years and who had oligomenorrhea or amenorrhea associated with a positive menstrual response to the intramuscular progesterone-challenge test were enrolled. They were randomly treated with CC (100 mg daily for 5 days) and CC (100 mg daily for 5 days) in combination with PE (1500 mg daily for 10 days). We estimated the difference in uterine artery pulsatily index, number of preovulatory follicles, endometrial thickness, and pregnancy rate.. Both treatments increased follicle-stimulating hormone, luteinizing hormone, and 17beta-estradiol plasma concentrations, but the differences were not statistically significant. However, the differences in endometrial thickness of the two groups were statistically significant. No significant differences in the pulsatility index values and in the number of preovulatory follicles were noted.. A high dose of phytoestrogens can reverse the deleterious effects of clomiphene citrate on endometrial thickness and could contribute to higher pregnancy rates.

Topics: Abortion, Spontaneous; Adult; Amenorrhea; Clomiphene; Double-Blind Method; Endometrium; Estrogen Receptor Modulators; Female; Humans; Infertility, Female; Insemination, Artificial, Homologous; Phytoestrogens; Pregnancy; Pregnancy Outcome

To compare the effectiveness of i.m. P and i.m. P plus oral phytoestrogens for luteal phase support in patients undergoing IVF-ET cycles.. Prospective, controlled, randomized trial.. University Hospital, Perugia, Italy.. Two hundred thirteen infertile patients undergoing IVF-ET were included in the study. The inclusion criteria were use of a GnRH agonist for pituitary down-regulation and age <40 years. The total number of cycles performed was 274.. Patients were assigned to receive either i.m. P (50 mg daily) plus placebo or P (50 mg daily) plus phytoestrogen supplementation (1,500 mg daily) for luteal phase support starting from the evening of oocyte retrieval until either a serum pregnancy test result was negative or embryonic heartbeat was sonographically confirmed.. The outcomes of IVF-ET were evaluated in both study groups in terms of implantation rate, biochemical pregnancy rate (PR), clinical PR, spontaneous abortion rate, and ongoing pregnancy/delivered rate.. Statistically significant higher values for implantation rate, clinical PR, and ongoing pregnancy/delivered rate were recorded in the patients who received P plus phytoestrogens for luteal phase support in comparison with patients receiving P and placebo.. Although the results of this study encourage the use of phytoestrogens for luteal phase support in patients undergoing IVF-ET program, more studies are necessary to support the hypothesis that phytoestrogens have a beneficial effect in IVF cycles.

Topics: Adult; Delivery, Obstetric; Drug Therapy, Combination; Embryo Implantation; Embryo Transfer; Female; Fertilization in Vitro; Humans; Infertility, Female; Injections, Intramuscular; Luteal Phase; Phytoestrogens; Pregnancy; Pregnancy Rate; Progesterone; Prospective Studies; Tablets

Treatment of neonatal mice with the phytoestrogen genistein (50 mg/kg/day) results in complete female infertility caused in part by preimplantation embryo loss in the oviduct between Days 2 and 3 of pregnancy. We previously demonstrated that oviducts of genistein-treated mice are "posteriorized" as compared to control mouse oviducts because they express numerous genes normally restricted to posterior regions of the female reproductive tract (FRT), the cervix and vagina. We report here that neonatal genistein treatment resulted in substantial changes in oviduct expression of genes important for the FRT mucosal immune response, including immunoglobulins, antimicrobials, and chemokines. Some of the altered immune response genes were chronically altered beginning at the time of neonatal genistein treatment, indicating that these alterations were a result of the posteriorization phenotype. Other alterations in oviduct gene expression were observed only in early pregnancy, immediately after the FRT was exposed to inflammatory or antigenic stimuli from ovulation and mating. The oviduct changes affected development of the surviving embryos by increasing the rate of cleavage and decreasing the trophectoderm-to-inner cell mass cell ratio at the blastocyst stage. We conclude that both altered immune responses to pregnancy and deficits in oviduct support for preimplantation embryo development in the neonatal genistein model are likely to contribute to infertility phenotype.

Topics: Animals; Animals, Newborn; Embryonic Development; Female; Gene Expression Regulation, Developmental; Genes, MHC Class II; Genistein; Immunity, Mucosal; Infertility, Female; Inflammation Mediators; Male; Mice; Oviducts; Phytoestrogens; Pregnancy

Female mice treated neonatally with the phytoestrogen genistein (50 mg/kg/day) have multioocyte follicles, lack regular estrous cyclicity, and are infertile even after superovulation. To determine the cause of their infertility, we examined oocyte developmental competence and timing of embryo loss. Eggs obtained by superovulation of genistein-treated or control females were equally capable of being fertilized in vitro and cultured to the blastocyst stage. However, if eggs were fertilized in vivo, retrieved at the pronucleus stage, and cultured, there was a significant reduction in the percentage of embryos from genistein-treated females reaching the blastocyst stage. When these blastocysts were transferred to pseudopregnant recipients, the number of live pups produced was similar to that in controls. Preimplantation embryo development in vivo was examined by flushing embryos from the oviduct and/or uterus. Similar numbers of one-cell and two-cell embryos were obtained from genistein-treated and control females. However, significantly fewer embryos (<50%) were obtained from genistein-treated females on postcoital Days 3 and 4. To determine if neonatal genistein treatment altered the ability of the uterus to support implantation, blastocysts from control donors were transferred to control and genistein-treated pseudopregnant recipients. These experiments demonstrated that genistein-treated females are not capable of supporting normal implantation of control embryos. Taken together, these results suggest that oocytes from mice treated neonatally with genistein are developmentally competent; however, the oviductal environment and the uterus have abnormalities that contribute to the observed reproductive failure.

Topics: Animals; Cells, Cultured; Disease Models, Animal; Embryo Implantation; Embryo Transfer; Embryonic Development; Female; Fertilization; Genistein; Infertility, Female; Mice; Mice, Inbred ICR; Oocytes; Ovary; Oviducts; Phytoestrogens; Pregnancy; Prenatal Exposure Delayed Effects; Uterus

Phytoestrogens have been thought to have favorable effects on women's health and perhaps in offsetting cancers. The possible adverse effects of phytoestrogens have not been evaluated.. Abnormal uterine bleeding with endometrial pathology in three women was found to be related to a high intake of soy products. The first woman had postmenopausal bleeding with uterine polyp, proliferative endometrium and a growing leiomyoma. The second woman presented with severe dysmenorrhea, abnormal uterine bleeding, endometriosis and uterine leiomyoma not responding to treatment. The third woman with severe dysmenorrhea, abnormal uterine bleeding, endometriosis and uterine leiomyomata presented with secondary infertility. All three women improved after withdrawal of soy from their diet.. Additional information on phytoestrogens is necessary to ascertain their safety before they can be routinely used as supplements.

Topics: Adult; Diet; Dysmenorrhea; Endometrium; Female; Glycine max; Humans; Infertility, Female; Middle Aged; Phytoestrogens; Postmenopause; Uterine Hemorrhage

Populations of European hare (Lepus europaeus) are in decline in Europe, and populations in Australia remain at low densities. Populations are sensitive to size of the breeding stock, which is influenced by fertility in the females. From 1996 to 1999, a total of 272 adult female hares from three Australian populations were dissected and their reproductive systems examined for abnormalities. Cystic endometrial hyperplasia was relatively common and often accompanied by hydrosalpinx. Extrauterine fetuses, neoplasms, pseudopregnancies, and resorptions also were found. However, although pseudopregnancies and resorptions were found in young adults (<12 mo) as well as older hares, conditions possibly causing infertility were almost always in older hares with prevalences up to 46.2%. Only hares with access to known sources of estrogens exhibited pathologic conditions, but sympatric European rabbits (Oryctolagus cuniculus) did not, which is consistent with known difference in responses between the corpora lutea of the two species to exogenous estrogen. Infertility at such a high prevalence could compound and extend the impact of years of low juvenile survival on recruitment.

Topics: Abnormalities, Drug-Induced; Age Factors; Animals; Australia; Conservation of Natural Resources; Female; Genitalia, Female; Hares; Infertility, Female; Phytoestrogens; Population Density; Population Dynamics; Prevalence; Reproduction

In bovine oviduct cells 17beta-oestradiol can induce the synthesis of leukaemia inhibitory factor (LIF), a glycoprotein essential for embryo implantation. Therefore substances which are structurally similar to 17beta-oestradiol and possess oestrogenic activity may also modulate LIF synthesis and influence the reproductive process. We used primary cultures of bovine and human oviduct cells (epithelial cells:fibroblasts 1:1) to compare the effects of 17beta-oestradiol, phyto-oestrogens (genistein, biochanin A, daidzein, formononetin, and equol) and xeno-oestrogens [polychlorinated biphenyls (PCB): trichlorobiphenyl, 4-hydroxy-trichlorobiphenyl and 4-hydroxy-dichlorobiphenyl] on LIF synthesis. Immunoreactive LIF-enzyme-linked immunosorbent assay was used to determine the concentration of LIF in the culture medium. Similar to 17beta-oestradiol, genistein (0.02-2 micromol/l) induced LIF synthesis in bovine oviduct cells in a concentration-dependent manner. Equol, biochanin A and daidzein (2 micromol/l), 4-hydroxy-trichlorobiphenyl and 4-hydroxy-dichlorobiphenyl (0.01-10 micromol/l) but not formononetin (2 micromol/l) also induced LIF synthesis in bovine cells. Phyto-oestrogens and xeno-oestrogens also induced LIF synthesis in human oviduct cells (P < 0.05). The stimulatory effects of PCB, phyto-oestrogens and 17beta-oestradiol were blocked by ICI 182,780 (1 micromol/l). Moreover, 17beta-oestradiol, 4-hydroxy-trichlorobiphenyl, 4-hydroxy-dichlorobiphenyl, genistein, tamoxifen and ICI 182,780 displaced [(3)H]17beta-oestradiol from cytosolic oestrogen receptors in bovine oviduct cells. These results suggest that phyto-oestrogens and PCB mimic the effects of oestradiol in inducing LIF synthesis by bovine and human oviduct cells and that these stimulatory effects are oestrogen receptor-mediated. Environmental oestrogens act as endocrine modulators/disrupters and may induce deleterious effects on the reproductive process by influencing LIF synthesis in a non-cyclic fashion leading to tubal infertility.

Topics: Animals; Cattle; Cells, Cultured; Estradiol; Estrogen Antagonists; Estrogens, Non-Steroidal; Fallopian Tubes; Female; Fulvestrant; Genistein; Growth Inhibitors; Humans; Infertility, Female; Interleukin-6; Isoflavones; Leukemia Inhibitory Factor; Lymphokines; Phytoestrogens; Plant Preparations; Polychlorinated Biphenyls

Topics: Aging; Animal Feed; Animals; Australia; Estrogens, Non-Steroidal; Female; Fertility; Infertility, Female; Isoflavones; Phytoestrogens; Plant Poisoning; Plant Preparations; Poaceae; Random Allocation; Reproduction; Sheep; Sheep Diseases

The cheetah in the wild is "racing towards extinction" mostly due to habitat destruction. Its survival will probably depend on accelerated captive breeding. At this time, however, reproductive failure and liver disease threaten the future of the captive cheetah population. Histopathological evaluation of more than 100 cheetah livers identified venocclusive disease as the main hepatic lesion responsible for liver disease in this species. Analysis of the commercial feline diet by high-performance liquid chromatography and gas-liquid chromatography-mass spectrometry revealed large amounts of two phytoestrogens identified as daidzein and genistein. These compounds were found to be derived from a soybean product that was a component of the cheetah diet, and their concentrations both ranged from 18 to 35 micrograms/g diet. The adult cheetah consequently consumes approximately 50 mg/day of these weak estrogens. When extracts of the diet were tested for estrogenicity using a bioassay, a dose-related increase in uterine weight was observed. In 4 cheetahs studied, withdrawal of this feline diet by substitution with a chicken diet resulted in an improvement in conventional liver function tests and a normalization in the appearance of hepatic mitochondria. We conclude that the relatively high concentrations of phytoestrogens from soybean protein present in the commercial diet fed to captive cheetahs in North American zoos may be one of the major factors in the decline of fertility and in the etiology of liver disease in this species. The survival of the captive cheetah population could depend upon a simple change of diet by excluding exogenous estrogen.

Topics: Acinonyx; Animal Feed; Animals; Biological Assay; Carnivora; Cat Diseases; Cats; Chromatography, High Pressure Liquid; Estrogens; Estrogens, Non-Steroidal; Female; Gas Chromatography-Mass Spectrometry; Glycine max; Hepatic Veno-Occlusive Disease; Infertility, Female; Isoflavones; Liver; Liver Diseases; Liver Function Tests; Male; Mice; Phytoestrogens; Plant Preparations; Rats

Ovariectomized ewes, 14 with permanent clover disease infertility (affected ewes) and 14 controls, were injected daily with 40 micrograms oestradiol benzoate for 12 days, and run with 2 rams fitted with marking crayons. The control ewes were mated sooner (P less than 0.05) but both groups became refractory at a similar rate. In a second experiment, 20 similar affected ewes and 19 controls were injected daily with 5 mg testosterone propionate for 31 days and observed daily for 50 min with rams. Affected ewes again were slower to show female behaviour (P less than 0.05) but faster (P less than 0.05) to show aggression against the rams and other ewes. Over the 31 days, the incidence of female sexual behaviour declined at a similar rate in affected and control ewes. When examined in individual pen tests with oestrous ewes on Day 28, affected ewes showed more male-like courting behaviour than did controls (P less than 0.05). The changes in behaviour are too slight to account for the infertility but they do support the hypothesis that phyto-oestrogens can act on the ewe by some of the pathways of sexual differentiation, even after puberty.

Topics: Animals; Castration; Estradiol; Estrogens; Estrogens, Non-Steroidal; Female; Infertility, Female; Isoflavones; Phytoestrogens; Plant Preparations; Plants; Sexual Behavior, Animal; Sheep; Sheep Diseases; Testosterone

Characteristics of the uterus anc cervix after ovariectomy of ewes with permanent phytooestrogen infertility (PPI) were compared with controls. Ewes with PPI had more oestrogen-binding sites in the cervix, but not in the uterus. There was no difference between the two groups of ewes in the binding affinity constant of receptors from the uterus or cervix. There were more keratinized cells in the vaginal epithelium of ewes with PPI, and the rates of protein and glycoprotein synthesis in the uterus and cervix were higher in ewes with PPI. These results offer further evidence that PPI in adult ewes is similar to the "persistent oestrus' syndrome in rodents oestrogenized neonatally.

Topics: Animals; Castration; Cervix Uteri; DNA; Estrogens; Estrogens, Non-Steroidal; Female; Infertility, Female; Isoflavones; Phytoestrogens; Plant Preparations; Protein Biosynthesis; Receptors, Estrogen; Sheep; Sheep Diseases; Uterus