Estrogenism and Vulvovaginitis
Fusarium spp molds are extremely common and often contaminate growing plants and stored feeds. Corn (maize), wheat, and barley are commonly contaminated. In moderate climates under humid weather conditions, F graminearum may produce zearalenone, one of the resorcyclic acid lactones (RALs). Zearalenone (formerly called F2 toxin) is a potent nonsteroidal estrogen and is the only known mycotoxin with primarily estrogenic effects. Often, zearalenone is produced concurrently with deoxynivalenol. Depending on the ratio of these two mycotoxins, signs of reduced feed intake or reproductive dysfunction may predominate, but presence of deoxynivalenol may limit exposure to zearalenone, thus reducing its practical effect.
Zearalenone binds to receptors for 17β-estradiol, and this complex binds to estradiol sites on DNA. Specific RNA synthesis leads to signs of estrogenism. Zearalenone is a weak estrogen with potency 2–4 times less than estradiol. Under controlled administration, zearalanol, a closely related RAL, is widely used in cattle as an anabolic agent.
Estrogenism due to zearalenone was first clinically recognized as vulvovaginitis in prepubertal gilts fed moldy corn (maize), but zearalenone is occasionally reported as a suspected disease-causing agent for sporadic outbreaks in dairy cattle, sheep, chickens, and turkeys. High dietary concentrations (>20–30 ppm) are required to produce infertility in cattle and sheep, and extremely high dosages are required to affect poultry.
Zearalenone has been detected in corn, oats, barley, wheat, and sorghum (both fresh and stored); in rations compounded for cattle and pigs; in corn ensiled at the green stage; and very rarely in hay. It has been detected occasionally in samples from pastures in temperate climates at levels believed sufficient to cause reproductive failure of grazing herbivores.
Clinical effects cannot be distinguished from excessive estrogen administration. Physical and behavioral signs of estrus are induced in young gilts by as little as 1 ppm dietary zearalenone. In pigs, zearalenone primarily affects weaned and prepubertal gilts, causing hyperemia and enlargement of the vulva (known as vulvovaginitis). There is hypertrophy of the mammary glands and uterus, and abdominal straining results in prolapse of the uterus in severe cases. Removal of affected grain results in return to normal in ~1 wk.
Zearalenone causes reproductive toxicosis in sexually mature sows by inhibiting secretion and release of follicle-stimulating hormone (FSH), resulting in arrest of preovulatory ovarian follicle maturation. Reproductive effects in sexually mature sows depend on time of consumption. Zearalenone fed at 3–10 ppm on days 12–14 of the estrous cycle in open gilts results in retention of corpora lutea and prolonged anestrus (pseudopregnancy) for up to 40–60 days. Zearalenone fed at ≥30 ppm in early gestation (7–10 days after breeding) may prevent implantation and cause early embryonic death. Zearalenone metabolites can be excreted in milk of exposed sows, resulting in hyperestrogenic effects in their nursing piglets.
In cattle, dietary concentrations >10 ppm may cause reproductive dysfunction in dairy heifers, although mature cows may tolerate up to 20 ppm.
Young males, both swine and cattle, may become infertile, with atrophy of the testes. However, mature boars appear unaffected by as much as 200 ppm dietary zearalenone.
Ewes may show reduced reproductive performance (reduced ovulation rates and numbers of fertilized ova, and markedly increased duration of estrus) and abortion or premature live births.
Lesions in pigs include ovarian atrophy and follicular atresia, uterine edema, cellular hypertrophy in all layers of the uterus, and a cystic appearance in degenerative endometrial glands. The mammary glands show ductal hyperplasia and epithelial proliferation. Squamous metaplasia is seen in the cervix and vagina. Sexually mature sows will have retained corpora lutea for 40–70 days after exposure, consistent with signs of pseudopregnancy.
Diagnosis is based on reproductive performance in the herd or flock, clinical signs, history of diet-related occurrence, and excluding other known causes of infertility. Chemical analysis of suspect feed for zearalenone and careful examination of reproductive organs at necropsy are required. As a bioassay, virgin prepubertal mice fed diets or extracts of zearalenone-contaminated feed demonstrate enlarged uteri and vaginal cornification typical of estrogens.
Differential diagnoses include reproductive tract infections and other causes of impaired fertility such as diethylstilbestrol in the diet of housed stock. In grazing herbivores, especially sheep, the plant estrogens (eg, isoflavones associated with some varieties of subterranean and red clovers, and coumestans in certain fodders [eg, alfalfa]) should be considered.
Unless stock are severely or chronically affected, usually reproductive functions recover and signs regress 1–4 wk after intake of zearalenone stops. However, multiparous sows may remain anestrous up to 8–10 wk.
Management of swine with hyperestrogenism should include changing the grain immediately. Signs should stop within 1 wk. Animals should be treated symptomatically for vaginal or rectal prolapse and physical damage to external genitalia. For sexually mature sows with anestrus, one 10-mg dose of prostaglandin F2α, or two 5-mg doses on successive days, has corrected anestrus caused by retained corpora. Alfalfa and alfalfa meal fed to swine at 25% of the ration may reduce absorption and increase fecal excretion of zearalenone, but this is often not considered practical. Feeding activated charcoal, cholestyramine, or alfalfa meal may reduce zearalenone absorption and retention, but the high concentrations needed generally render this impractical.