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Endocrine Modulators


Endocrine Modulators

Piglets suckling a sow.

NOTE: This section is identical to the Endocrine Modulators section that you used in the Mammary Development Resources Module.

There are many substances found in our environment that may result in altered physiology of an animal if the substance is ingested. Many of these substances either have activities that give them hormone-like properties or they may affect normal endocrine-based mechanisms in the body. These types of substanses are considered as endocrine modulators. In terms of mammary gland growth and function, we would focus primarily on those that may have activities of estrogens or progesterones, or those that may alter endogenous prolactin secretion. Some of these endocrine modulators and related physioogical mechanisms are discussed below.

Estrogens have a powerful role in the mammary gland, especially in growth and development. These effects may occur at all phases of mammary gland development, including a) during development of the rudimentary mammary structures when the animal is an early fetus, b) during the enhanced growth rate occurring between birth and puberty, c) during the cyclic bursts of mammary growth and regression associated with estrous cycles, and d) during the explosive mammary gland growth occurring during pregnancy. In spite of the powerful role that estrogen plays in most aspects of mammary growth throughout the life of the animal, an appreciation for the complexity and multiple levels of estrogen's actions on mammary gland growth has only recently been developed. Estrogen affects mammary growth indirectly by effects on systemic mammogenic factors (prolactin, growth hormone), and directly at the mammary tissue by effects on stromal components required for development and direct effects on mammary epithelial cells. Potential estrogenic or antiestrogenic actions of dietary phytoestrogens, or environmental substances with estrogenic activity, could alter the normal role of physiological estrogen at any of these points.


Phytoestrogens

Plants compounds with estrogenic activity are one type of endocrine modulator. Many plants with estrogenic activity have been identified (see the Table below). Phytoestrogens are a broad group of plant-derived compounds that are structurally and functionally similar to estrogen and have a range of estrogenic activity in animals.   Soybean phytoestrogens include several isoflavones, as well as a range of nonisoflavone compounds with estrogenic activity.   Isoflavones are prevalent in soybeans, a primary livestock feed ingredient, as well as an ingredient in human diets. The only way to determine the value and utility of phytoestrogens in manipulating reproductive function in livestock is to directly test the compounds in the animal.   Information about the effects of phytoestrogens in livestock species is limiting progress in this field, and information in the pig is particularly lacking. This project will establish fundamental information on the in vivo effects of administration of the soybean phytoestrogen, genistein, on reproductive tissues in female swine.

A partial list of plants which contain estrogenic compounds:

Alfalfa

Anise

Grapefruit

Rape

Ladino clover

Apple

Green beans

Red beans

Red clover

Black tea

Green tea

Red wine

Sorghum

Cabbage

Hops

Rice

Soybeans

Carrot

Kudzu root

Rye

Subterranean clover

Cherry

Liquorice

Sage

Coffee

Marijuana

Sesame

Barley

Date palm

Palmetto grass

Soya sprouts

Blue grass

Fennel

Parsley

Strawberry

Oats

Flax seed

Peas

Sunflower seed

Orchard grass

French beans

Pomegranate

Tomato

Wheat

Garlic

Potato

Estrogens are strong effectors in reproductive and other tissues, having significant control of reproduction in females, as well as having effects on male reproductive systems. For example, estrogens have dramatic effects on uterine hypertrophy and hyperplasia, on cervical development and extensibility, particularly in conjunction with other hormones in late pregnancy, and on mammary gland growth and development. Estrogen administration to ovariectomized gilts also stimulates mammary gland growth and cervical softening.   There is considerable evidence that phytoestrogens, and particularly the soybean isoflavones, affect many aspects of reproductive function in mammals, as well. These effects vary depending upon the developmental stage of the animal, length of exposure, and the species studied.

Reproductive tissues are particularly sensitive to exposure to phytoestrogens.   Exposure of immature rats to coumestrol, a potent phytoestrogen, either by parenteral injection or in the diet, results in significant increases in uterine wet and dry weights. Ovariectomized postpubertal rats consuming dietary genistein have a dose-dependent increase in uterine development. Cervical histology and cervical mucus characteristics are affected in sheep grazing pastures of highly estrogenic subterranean clover. In swine, extended exposure of prepubertal gilts to soybean meal, vs. a nonsoybean diet, results in increased vulval size, although those results are not conclusive of an estrogenic effect on vulval development.   Exposure of porcine granulosa cells to phytoestrogens in vitro decreases cell death. Early embryonic mortality can result in substantial losses and may also be affected by phytoestrogens. Further information on phytoestrogenic effects on reproductive tissues in swine is limited.

Some evidence for an effect of phytoestrogen on mammary tissue comes from studies related to mammary cancers in rats. Oral administration of coumestrol to postpubertal rats with mammary tumors had no estrogenic nor antiestrogenic effect on the tumors, although coumestrol injected subcutaneously seemed to support tumor growth. Indeed, genistein injected into prepubertal female rats had a protective effect against postpubertal development of mammary tumors.  

            Prepubertal injection of genistein enhanced mammary development during the prepubertal period, but this effect was lost by the time the animal underwent puberty. Mammary tissue was able to respond to the estrogenic effects of genistein in the relative absence of endogenous estrogen prior to puberty, but was less responsive after puberty.   This resulted in a protective effect in terms of formation of estrogen-induced tumors, but reduced the normal mammary development which occurs during estrous cycling. These studies did not further characterize the prepubertal effects of genistein or the later consequences in terms of mammary gland development during pregnancy or subsequent initiation of lactation (lactogenesis).

            Other studies indicate that injection of genistein into postpubertal rats will stimulate mammary cell proliferation. Furthermore, oral genistein administration to ovariectomized postpubertal rats slows mammary gland regression and increases plasma prolactin over control ovariectomized rats. Similar estrogenic effects on mammary proliferation in ovariectomized mice have been observed for another phytoestrogen, formononetin, although a 40,000 fold higher dose was required to elicit a comparable response to estradiol administration.   The latter study also observed elevated mammary tissue estrogen receptor and plasma prolactin concentrations in formononetin treated mice vs. control mice.

            Exposure of adult nonpregnant ewes to dietary phytoestrogen by grazing subterranean clover resulted in significant estrogenic-like changes in the reproductive tract and in the mammary glands. The effect on mammary glands included production of a small amount of a milky substance from the gland, suggesting an estrogenic effect on mammary development, although the secretion appeared to derive from the ducts and alveolar buds rather than from developed alveoli. Ovariectomized ewes consuming red clover have increased teat size and accumulation of small amounts of fluid in the mammary glands. In contrast, genistein has been found to inhibit prolactin stimulation of milk component synthesis in cultured mouse mammary tissue.   This effect probably occurs as a result of the highly specific tyrosine kinase inhibiting activity of genistein.

There is substantial species variability in the metabolism of isoflavones and in tissue responses to the plant estrogenic compounds.   It is difficult to extrapolate the positive or negative effects of phytoestrogens on reproductive tissues of rodents to reproductive function in other mammals.


Mycotoxins

Fungi produce a wide range of substances that may affect other organisms. Some fungi may produce alkaloid compounds that have strong estrogenic activity. The fungi that causes moldy corn (Fusarium spp.) produces zearalanone and derivatives of that alkaloid. Zearalanone is a potent estrogen and has dramatic effects on primary and secondary reproductive structures that are estrogen responsive.

Beyond this estrogenic effect, many fungi secrete antibacterial compounds that help the fungus compete for survival in an environment where a major competitor may be certain types of bacteria. This property has led to the discovery, development and use of many antibiotics by man, penicillin being just one obvious example.

Some fungi also produce compounds that may impact the normal physiology of animals.   Some of these compounds can have a dramatic effect on the reproduction and lactation of mammals. For example, fungal species that produce ergot alkaloids infest various grasses, particularly cereal grains. Under optimal environmental conditions (rain, heat, humidity, etc), the fungi infesting the seed heads of grain plants may produce several ergot alkaloids (moldy grain). These have two important properties for mammals. First, many of the ergot alkaloids have vasoconstrictive properties. That is they are chemically similar to the same neurotransmitter that cause vasoconstriction in the animal. As a result of ingesting the grain infested with the ergot-producing fungi, the animal's vascular system is generally constricted, especially the extremities. Animals consuming these ergot alkaloids in cold weather will experience significant blood flow problems in the limbs and tail, even leading to sloughing of the hooves or tail in extreme cases. Vascular problems also can occur in humans, called ergotism. This property of some of the ergot alkaloids has led to development of man-made ergot derivatives that are used in medical applications. For example, people with migraine headaches are sometimes prescribed ergotamine or some form of ergotamine. This causes vasoconstriction of the dilated facial blood vessels, a major contributor to the pain associated with migraines. The second property of some ergot alkaloids is that their similarity to some neurotransmitters result in altering hormone secretion, specifically secretion of prolactin from the pituitary. Regulation of secretion of prolactin from the pituitary is a bit different from other pituitary hormones. The primary regulator of prolactin secretion is by an inhibitor, called L-DOPA (dopamine), secreted by the hypothalamus. Ergot alkaloids are chemically similar to dopamine. An animal consuming ergot alkaloids will have prolactin secretion significantly reduced. Bromocryptine (also called CB-154; a synthetic ergocryptine) and cabergoline (a synthetic ergoline) are both chemically synthesized compounds used experimentally to reduce prolactin secretion or medically to treat conditions of hyperprolactinemea (elevated blood prolactin). Many of the earlier experiments with animals that demonstrate a role for prolactin in mammary gland growth or milk secretion employed CB-154 to demonstrate the effects of very low prolactin concentrations in the blood on mammary function.

Other fungi can infest other grasses, such as tall fescue or perennial ryegrass. Fescue infected with these fungi (termed endophyte-infected fescue; the fungi actually resides within the plant tissue, integrated between the plant's cells) can cause fescue toxicosis in animals that ingest the fescue. This can cause symptoms very similar to ergotism. Secretion of prolactin also is substantially inhibited. This can have dramatic inhibitory effects on lactation in some species, especially in mares fed endophyte-infected fescue grass or hay prepartum.


Environmental estrogenic substances

Environmental contaminants are substances that are man-made and either do not normally exist in the environment or are found in the environment at elevated levels as a result of man's activities. A wide range of man-made substances have estrogenic activity, including some pesticides, dioxin and other related compounds, and many other synthetic compounds. Many of these substances have been demonstrated to have estrogenic effects in cell culture systems and in studies where animals are administered purified compound under very controlled experimental conditions. In nature, mostly the studies have been efforts to correlate abnormalities in a species (amphibians, for example) to the level of a contaminant in the animals' environment. Although mammary epithelial cells have been shown to respond to many of these compounds in vitro, I am unaware of any direct evidence that environmental exposure to the compounds will enhance or inhibit mammary development or function. But, the jury is still out on that issue.


Plants with potential progesterone activity (Phytoprogestins)

Some plants contain substances that bind to progesterone receptors. I am unaware of any relationship between the potential progesterone activity of these plants and mammary development, however, such a relationship may exist.

A partial list of plants with progesterone receptor-binding components:

Red clover

Damiana

Thyme

Fennel

Pennyroyal

Calamus root

Camomille

Bloodroot

Verbena

Goldenseal

Cloves

Ocotillo

Nutmeg

Licorice

Mandrake

Tumeric

Mistletoe

Oregano

Yucca

Cumin


Stimulating Prolactin Secretion

Reserpine is a compound that is known to increase milk yield. Reserpine is extracted from the root of the Rauwolfia serpentina plant, also called Snakeroot. Reserpine blocks dopamine effects on the pituitary cells that secrete prolactin (mammotrophs). Remember that dopamine is the inhibitor of prolactin secretion secreted by the hypothalamus. It acts to inhibit prolactin secretion by binding to dopamine receptors on the pituitary. Reserpine acts by blocking the intraneuronal storage of dopamine, serotonin, and norepinephrine, both centrally and peripherally, resulting in depletion of these neurotransmitters. So, reserpine would block the inhibitory effects of dopamine and allow prolactin secretion. Reserpine has been used in efforts to induce lactation in nonlactating cows. It also has been shown to enhance milk yield in lactating sheep. Snakeroot is one of the herbs that has been implicated as a galactagogue in lactating women.

The medical use of reserpine is considered relatively safe and it has low toxicity in pharmaceutical terms. However, it may have several side effects. The mechanism by which reserpine increases prolactin secretion also results in a sedative effect on the central nervous system. Depletion of intraneuronal storage of norepinephrine and serotonin underlies the ability of reserpine to produce mental depression. Psychosis disorders like schizophrenia seem to reflect excess dopamine activity in human cases. So, the depletion of dopamine storage provides the mechanism for reserpine's antipsychotic action.

Suckling Induced Prolactin Secretion

There is a milking-induced or nursing-induced release of PRL (see graph below; adapted from Tucker 1994). his surge of PRL (green line in the graph) is small compared with the peripartum surge of PRL associated with lactogenesis; about a 3-fold increase over non-stimulated PRL concentrations (blue hatched line). However, the milking-induced PRL surge is a direct link between the act of nursing or milk removal and the galactopoietic hormones involved in maintaining lactation. The surge occurs over a period of about a half of an hour after milking or nursing. This compares with the oxytocin surge which only lasts about 5 to 10 minutes (red stippled box in the figure). Part of the galactopoietic response to nursing intensity (litter size) in pigs or rodents may involve the amount of PRL released at nursing. This suckling-induced prolactin also has been observed in lactating women and other species.

Graph of blood prolactin concentrations after teat stimulation.

Suckling or milking probably works by decreasing prolactin inhibiting factor (PIF; that is, dopamine) from the hypothalamus, and therefore increasing PRL levels. It may also act to increase the response of the pituitary to prolactin releasing factors (Samson et al., 1989, Endocrinology 124:812). The effect of suckling on PRL declines with advancing lactation, even if nursing stimulus is kept equivalent throughout lactation.


 
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