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Lactogenic Complex of Hormones


Lactogenic
Complex

Piglets suckling a sow.

Lactogenic Complex of Hormones

There is considerable species variability in how specific hormones control lactogenesis. Actually, with few exceptions we are really referring to a lactogenic complex of hormones rather than a single hormone that "does it all." Much of what we know comes from in vitro studies where lactogenesis or some phase of lactogenesis is induced in tissue from mid-pregnant primiparous animals (mostly rats and mice). From all of that work we can conclude that:

In vitro, the lactogenic complex consists of insulin, glucocorticoids and prolactin.

Insulin

Insulin is required in vitro to cause a lactogenic-like response in mammary tissue. Insulin causes the nonsecretory epithelia to undergo one cell division. This cell division seems to be necessary for lactogenesis to occur.

The role of insulin in lactogenesis in vivo is unknown. However, it is known that mammary cells in vivo undergo a large burst of cell division in late pregnancy.

In vivo, IGF-1 may be the primary mitogen involved in this cell division leading up to lactogenesis, with insulin playing a minor role in this function.

Both insulin and the IGFs may be involved in glucose uptake by the mammary cells. This glucose uptake is of critical importance for lactose synthesis. Insulin also may be directly involved in expression of milk protein genes.


Glucocorticoids

Glucocorticoids are required in vitro for full initiation of milk secretion. There may be several roles of glucocorticoids in lactogenesis. They seem to be involved in development of the RER and other ultrastructural changes required for massive protein synthesis. They also may be directly involved in transcription of the casein and a-lactalbumin genes.

In vivo:

Adrenalectomy blocks casein synthesis and casein mRNA synthesis. Mammary glucocorticoid receptors increase 3 fold in the second half of pregnancy in mice. Adrenal corticoids, especially the glucocorticoids, synergize with PRL to initiate lactation and are essential in most species for PRL to have an optimal effect in its role in initiating lactation. The effects of administration of ACTH (adrenocorticotropic hormone from the pituitary gland) are mediated by its stimulation of glucocorticoid secretion from the adrenal.

Glucocorticoid concentrations in blood are fairly low during most of pregnancy, but increase markedly during the last few days prepartum. Another consideration when evaluating the effective concentration of glucocorticoids in blood is the concentration of corticoid-binding globulin (CBG), a blood protein that binds to corticoids and prevents them from having their actions on cells. Concentrations of CBG decrease in the prepartum period, thereby increasing available free hormone. Increased uptake of glucocorticoid by the mammary tissue coincides with lactogenesis, although a precise association with the first or second stage of lactogenesis has not been established. Glucocorticoid receptors in the mammary cells increase in numbers in late pregnancy. Both cortisol and PRL are required to maintain glucocorticoid receptor numbers.


Prolactin (PRL)

In vitro , PRL added to cultures containing insulin and glucocorticoids causes transcription of casein and a-lactalbumin genes, translation of milk protein mRNAs, swelling of Golgi membranes, and milk protein secretion, as well as synthesis of lactose and milk fat.

From in vitro studies on mid-pregnant mouse and rat mammary tissue culture we can generalize that:

Insulin alone in the medium causes cells to divide, but there are no cytological changes.
Insulin + glucocorticoid in the medium results in development of RER and Golgi, and the cells can synthesize structural proteins, but there is minimal milk protein or lactose synthesis.
Insulin + PRL in the medium results in transcription of milk protein genes, but minimal translation or milk protein synthesis.
Insulin + glucocorticoid, followed by Insulin + PRL or Insulin plus glucocortcoid plus PRL in the medium results in all of the cytological and enzymatic changes, and milk components are produced.

As an example of this type of in vitro study, the lactogenic complex of hormones are seen in in vitro culture of bovine mammary tissue (explant tissue culture of mammary tissue from late pregnant cows; Collier et l., 1977. Endocrinology 100:1192). Hormones are added to culture medium as: O = no homones added; I = insulin only; IC = insulin plus glucocorticoid (hydrocortisone); IPrl = insulin plus prolactin; and ICPrl = insulin plus glucocorticoid plus prolactin. Tissue explants are inculbated for up to 72 hours. Incorporation of radiolabeled acetate into fatty acids (de novo fatty acid synthesis) was determined by adding radiolabeled acetate to the medium for the final 2 hours of incubation. Only the ICPrl combination was effective in maximizing fatty acid synthesis (an indicator of lactogenesis) for an extended period.

Again, the specific hormonal requirments for lactogenesis in vitro varies between species. For, example, while the above combination of insulin, glucocorticoid and prolactin are required in many species, PRL alone can stimulate synthesis of casein and a-lactalbumin in rabbit mammary tissue explants. However, addition of insulin, glucocorticoid and PRL significantly enhances milk protein synthesis over PRL alone, in the rabbit. In contrast, apparently the wallaby (a kangaroo, specifically the Macropus eugenii) requires only PRL to induce milk protein synthesis during lactogenesis, because addition of insulin and glucocorticoid in vitro does not further enhance the response to PRL (see Nicholas 1988 Ch. 6 In: The Developing Marsupial, Models fror Biomedical Research, Springer-Verlag, Berlin, pp. 68-85). Interestingly, progesterone does not seem to be inhibitory to lactogenesis in the wallaby, although it is necessary for mammary growth and development during pregnancy. Remember that the joey is born very immature after a short gestation. The joey attaches to a nipple and continues to nurse that same nipple. The structural and functional development of the mammary gland during lactation in the wallaby is closely linked to the development of the joey.

What do we know about the role of prolactin from studies In Vivo ?

Hypophysectomy during pregnancy completely suppresses subsequent lactation after delivery (that is, in those species that do not abort after hypox. during pregnancy). In ovariectomized - adrenalectomized - hyphophysectomized rats the minimal hormone requirement to induce lactogenesis is PRL plus glucocorticoid. However, in most species PRL levels are low during pregnancy and only increase prepartum around the time of the second stage of lactogenesis.

In nonruminants, suppression of endogenous PRL by administration of ergot alkaloids (such as bromocriptine) during late gestation completely suppresses lactogenesis. However, interpretation of this response is complicated by the fact that suckling by the newborn is prevented. The suckling stimulus has a lactogenic activity and is important in maintaining lactation once initiated.

In lactating goats, hypophysectomy results in an immediate decline in milk production. Administration of PRL with thyroxine and glucocorticoid to these goats reinitiates milk production, which can then be maintained with growth hormone [Cowie et al., 1964, J. Endocrinol. 28:253 and 28:267; also see Cowie, 1969, p. 157, In Lactogenesis: The Initiation of Milk Secretion at Parturition, Eds. Reynolds and Folley, Univ. Penn. Press, Philadelphia.]

In cattle (where milk removal can be controlled by mechanical milking), CB-154 (2-Br-alpha-ergokryptin; also known as bromocriptine; it is a synthetic ergot alkaloid) completely blocks the peripartum surge of PRl, as well as the milking-induced surges of PRL, and decreases basal PRL by 80 %. CB-154 administered to dairy cows from 12 days prepartum through 10 days postpartum reduced milk yield 45 % during the first 10 days of lactation (see Akers et al. 1981 Endocrinology 109:23). Milk yield did increase as lactation progressed, despite continued suppression of endogenous PRL.

In most species, PRL binding sites (receptors) in the mammary gland are low during pregnancy and increase coincident with the secretion of milk during the second stage of lactogenesis. So, both the availability of PRL (blood hormone concentrations) and the responsiveness of the mammary epithelial cells to PRL (receptors for PRL) increase about the time of the switch-over from the first to the second stage of lactogenesis (start of copious milk secretion).


 
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