Mammary Glands Hormonal Regulation

Ronald S. Kensinger

Pennsylvania State University, University Park, Pennsylvania, U.S.A.

INTRODUCTION

The mammary glands are fascinating organs that are designed to provide nutrients and immunological protection to the young. These glands are a microcosm of the organism in that they have a life cycle (Fig. 1), which proceeds with each subsequent pregnancy, parturition, and lactation. The first phase of the life cycle is mammogenesis or growth and development of the mammary gland. This includes the growth and proliferation of mammary epithelial cells that comprise ducts and alveoli; myoepithelial cells required for milk ejection; fat cells, fibroblasts, and extracellular matrix components; the complex system of blood vessels found in the developed mammary gland, sensory, and motor fibers to innervate the glands; and also cells of the lymphatic and immune systems to defend the mammary glands when necessary. At the end of pregnancy, the mammary glands prepare for birth of the young by undergoing biochemical differentiation and the onset of milk synthesis, also known as lacto-genesis (Fig. 1). In most mammals, the process of lac-togenesis occurs over a period of days (in rodents) to weeks (in large animals) as the mammary cells acquire the ability to secrete copious amounts of milk. Once lactation is established, the mammary gland moves into a galactopoietic state for the maintenance of milk secretion. The duration of lactation is quite variable among species of mammals, but is generally proportional to metabolic body size. When it is time for the young to be weaned, the mammary glands involute to a quiescent state, but are able to begin another round of development in the event of another pregnancy (Fig. 1).

The mammary life cycle described above has been a useful classification to study and understand the mammary glands, but in reality there is dynamic movement from one phase to the next, and periods when there is evidence that the gland is in two states simultaneously. An example of this is found in litter bearing animals like the sow. The sow in early lactation may have glands that are undergoing continued mammary growth and lactogenesis at the same time. In addition, she may have other glands that are not being suckled and are undergoing involution. The concept that mammary cell proliferation is balanced by apoptosis of epithelial cells in the mammary gland was recently discussed by Capuco et al.[1] and illustrates the complexity of mammary gland biology.

The topic of hormonal regulation of mammary glands was recently reviewed in depth by Tucker[2] and Brisken.[3] The reader is referred to these papers for more detailed coverage, which is not given here for brevity reasons.

HORMONAL CONTROL OF MAMMOGENESIS

Studies of rodents that utilized a combination of endocrine gland removal, followed by gland or hormone replacement were foundation experiments to demonstrate hormonal regulation of mammary devel-opment.[4'5] These studies showed very clearly that removal of the ovaries or the pituitary glands had very significant and negative effects on mammary gland development. It is now realized that both estrogen and progesterone from the ovaries, as well as prolactin and growth hormone from the anterior pituitary gland, are essential for normal mammogenesis in most mammals. Placental lactogen, a member of the growth hormone/prolactin family, can at least partially replace prolactin and growth hormone in their ability to induce mammary proliferation, but this hormone is not secreted from the placenta of all mammals.[6,7] It is likely that the combination of circulating hormones delivered to the mammary glands from blood, in turn, stimulates the local production of mammary growth factors, such as insulinlike growth factors (IGFs), which stimulate cellular proliferation.[7,8] There may be important differences among species with respect to the growth factors required for mammary growth, but IGF-I and -II are consistently found in mammary tissues of many species. The ability of IGFs to stimulate cell division is affected by the presence of a family of binding proteins.[8] Regardless of the complexity of this interaction among various hormones and growth factors, the deletion of the receptors for either estrogen,[9] progesterone, or prolactin[3] from mammary cells leads to significantly impaired mammary development. Furthermore, the administration of estrogen and progesterone into intact animals at doses that simulate normal term pregnancy leads to significant mammary development,[10] demonstrating that the ovarian steroid hormones are critical to

Involution Lactogenesis ^SSSSss--Galactopoiesis

Fig. 1 The mammary gland life cycle.

mammary growth. It is also important to note that variable combinations of estrogen, progesterone, and placental lactogen (or another member of the prolac-tin/growth hormone family) are secreted from the placenta in all mammals. Thus, optimal mammary development as occurs during pregnancy is associated with placental secretions into the maternal bloodstream.

HORMONAL CONTROL OF LACTOGENESIS

In order for the epithelial cells in alveoli of the mammary glands to initiate milk synthesis and produce significant amounts of milk, it is necessary to have a well-developed lobulo-alveolar system.[2] It is also important to note that the process of lactogenesis usually occurs at the end of pregnancy and is coincidental with parturition. Parturition in mammals is generally characterized by high circulating concentrations of estrogen, cortisol, and prolactin, and decreasing concentrations of progesterone. Since progesterone is required to maintain pregnancy, the reduction in progesterone secretion is a seminal event in the induction of parturition and is associated with lactogenesis. This physiological change thus reduces the inhibitory effect of progesterone to lactogenesis.[2,6,7]

Various studies both in vivo and in vitro have demonstrated that mammary tissue in most, if not all, mammals responds to the lactogenic complex of insulin, cortisol, and prolactin to initiate milk secre-tion.[2,6,7] Prolactin is very important to this process as stimulation of the prolactin receptor initiates transcription of the casein genes; a critical step in onset of lactation.[11] The presence of insulin and cortisol is also required to attain high levels of casein gene expression in vitro, but there is little evidence that these hormones limit the volume of milk produced in large animals at the time of parturition. There are also many other hormones, such as growth hormone, which induce metabolic effects that support high levels of milk synthesis.

HORMONAL CONTROL OF GALACTOPOIESIS

Once the mammary glands are well developed and have undergone structural and biochemical differentiation, there remain a number of requirements to maintain a high level of milk secretion. The first is frequent milk removal, as the accumulation of milk components and increased intramammary pressure will eventually lead to a reduction in additional milk secretion. In addition, an adequate supply of substrates delivered to the mammary system is required for continued milk secretion. Oxytocin is secreted from the posterior pituitary gland in response to the milking stimulus and must be maintained for galactopoiesis. In addition, normal concentrations of insulin and IGFs in the circulation are needed for normal metabolism. In addition to these needs, continued lactation in all mammals requires continued stimulation by the prolactin/growth hormone family of hormones. Milk synthesis in nonruminant mammals is dependent upon continued secretion of prolactin and the transcription factor STAT5, as it has been shown that drugs that significantly reduce prolactin secretion lead to a reduction in milk synthesis. Ruminant animals may be more dependent upon growth hormone for galactopoiesis as studies in sheep, goats, and cows consistently show an increased milk volume associated with growth hormone treatment of lactating animals.[2,6,7] Growth hormone stimulates hepatic secretion of IGF-I, enhances hepatic gluconeogenesis, and attenuates lipogenesis in adipose tissue;[12] all factors that may favor milk synthesis in the mammary glands.

CONCLUSIONS

Numerous studies in many species of mammals demonstrate that secretions from the ovaries, the pituitary glands, and the placenta play a significant role in mammogenesis, lactogenesis, or galactopoiesis. There is also abundant evidence that locally produced growth factors in the mammary gland, as well as pancreatic insulin, adrenal cortisol, and perhaps other hormones affect mammary metabolism as well. It is generally understood that estrogen, progesterone, prolactin, growth hormone (or placental lactogen), and locally produced growth factors are essential for normal mammary development. Lactogenesis requires stimulation of mammary cells by insulin, cortisol, and prolactin, along with a reduction in progesterone influence on mammary cells. The maintenance of lactation requires oxytocin, prolactin, and growth hormone, IGF-I, as well as a normal complement of other metabolic hormones. There is less understanding to date of hormonal influences on mammary cell apoptosis and involution, but recent evidence suggests that prolactin and/or growth hormone may be involved.

ACKNOWLEDGMENTS

The author would like to acknowledge helpful suggestions from Ann Magliaro and Dana Pape.

REFERENCES

1. Capuco, A.V.; Ellis, S.E.; Hale, S.A.; Long, E.; Erdman, R.A.; Zhao, X.; Paape, M.J. Lactation persistency: insights from mammary cell proliferation studies. J. Anim. Sci. 2003,81 (Suppl. 3), 18 31.

2. Tucker, H.A. Hormones, mammary growth, and lactation: a 41-year perspective. J. Dairy Sci. 2000, 83, 874 884.

3. Brisken, C. Hormonal control of alveolar development and its implications for breast carcinogenesis. J. Mammary Gland Biol. Neopla-sia 2002, 7, 39 49.

4. Nandi, S. Endocrine control of mammary gland development and function in the C3H/HeCrgl mouse. J. Natl. Cancer Inst. 1958, 21, 1039 1063.

5. Lyons, W.R. Hormonal synergism in mammary growth. Proc. R. Lond. Ser. B 1958,149, 303 325.

6. Cowie, A.T.; Forsyth, I.A.; Hart, I.C. In Hormonal Control of Lactation; Springer-Verlag: New York, NY, 1980.

7. Akers, R.M. In Lactation and the Mammary Glands; Iowa State Press: Ames, Iowa, 2002; 129 199.

8. Cohick, W.S. Role of the insulin-like growth factors and their binding proteins in lactation. J. Dairy Sci. 1998, 81, 1769 1777.

9. Korach, K.S. Insights from the study of animals lacking functional estrogen receptor. Science 1994, 266, 1524 1527.

10. Kensinger, R.S.; Magliaro, A.L. Induced lactation. In Encyclopedia of Dairy Sciences; Roginski, H., Fuquay, J., Fox, P., Eds.; Academic Press: New York, 2003; Vol. 3, 1447 1452.

11. Lesueur, L.; Edery, M.; Ali, S.; Paly, J.; Kelly, P.A.; Djiane, J. Comparison of long and short forms of the prolactin receptor on prolactin induced milk protein gene expression. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 824 828.

12. Etherton, T.D.; Bauman, D.E. Biology of soma-totropin in growth and lactation. Physiol. Rev. 1998, 78, 745 761.

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  • Zula
    Which hormone is involved in development of mammry gland?
    16 hours ago

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