Medical Physiology, 3rd Edition

Lactation

The fundamental secretory unit of the breast (Fig. 56-11A) is the alveolus (see Fig. 56-11B, C), which is surrounded by contractile myoepithelial cells and adipose cells. These alveoli are organized into secretory lobules, each of which drains into a ductule. A group of 15 to 20 ductules drain into a lactiferous duct, which widens at the ampulla—a small reservoir. The lactiferous ducts carry the secretions to the outside.

image

FIGURE 56-11 Cross section of the breast and milk production. A, The breast consists of a series of secretory lobules, which empty into ductules. The ductules from 15 to 20 lobules combine into a duct, which widens at the ampulla—a small reservoir. The lactiferous duct carries the secretions to the outside. B, The lobule is made up of many alveoli, the fundamental secretory units. C, Each alveolus consists of secretory epithelial cells (alveolar cells) that actually secrete the milk, as well as contractile myoepithelial cells, which are in turn surrounded by adipose cells. D, The epithelial alveolar cell secretes the components of milk via five pathways.

Breast development at puberty depends on several hormones, but primarily on the estrogens and progesterone. During pregnancy, gradual increases in levels of PRL and hCS, as well as very high levels of estrogens and progesterone, lead to full development of the breasts.

As indicated in Table 56-6, hormones affecting the breast are mammogenic (promoting the proliferation of alveolar and duct cells), lactogenic (promoting initiation of milk production by alveolar cells), galactokinetic (promoting contraction of myoepithelial cells and thus milk ejection), or galactopoietic (maintaining milk production after it has been established).

TABLE 56-6

Hormones Affecting the Mammary Gland During Pregnancy and Breast-Feeding

Mammogenic Hormones (promote cell proliferation)

Lobuloalveolar Growth

Estrogen

GH (IGF-1)

Cortisol

Prolactin

Relaxin?

Ductal Growth

Estrogen

GH

Cortisol

Relaxin

Lactogenic Hormones (promote initiation of milk production by alveolar cells)

Prolactin

hCS (or hPL)

Cortisol

Insulin (IGF-1)

Thyroid hormones

GH?

Withdrawal of estrogens and progesterone

Galactokinetic Hormones (promote contraction of myoepithelial cells and thus milk ejection)

OT

AVP (1%–20% as powerful as OT)

Galactopoietic Hormones (maintain milk production after it has been established)

PRL (primary)

Cortisol and other metabolic hormones (permissive)

IGF-1, insulin-like growth factor 1.

The epithelial alveolar cells of the mammary gland secrete the complex mixture of sugars, proteins, lipids, and other substances that constitute milk

Milk is an emulsion of fats in an aqueous solution containing sugar (lactose), proteins (lactalbumin and casein), and several cations (K+, Ca2+, and Na+) and anions (Cl and phosphate). The composition of human milk differs from that of human colostrum (the thin, yellowish, milk-like substance secreted during the first several days after parturition) and cow's milk (Table 56-7). Cow's milk has more than three times more protein than human milk, almost exclusively a result of its much higher casein concentration. It also has a higher electrolyte content. The difference in composition between human milk and cow's milk is important because a newborn, with his or her delicate gastrointestinal tract, may not tolerate the more concentrated cow's milk.

TABLE 56-7

Composition of Human Colostrum, Human Milk, and Cow's Milk (per Deciliter of Fluid)

COMPONENT

HUMAN COLOSTRUM

HUMAN MILK

COW'S MILK

Total protein (g)

2.7

0.9

3.3

Casein (% of total protein)

44

44

82

Total fat (g)

2.9

4.5

3.7

Lactose (g)

5.7

7.1

4.8

Caloric content (kcal)

54

70

69

Calcium (mg)

31

33

125

Iron (µg)

10

50

50

Phosphorus (mg)

14

15

96

Cells (macrophages, neutrophils, and lymphocytes)

7–8 × 106

1–2 × 106

The epithelial cells in the alveoli of the mammary gland secrete the complex mixture of constituents that make up milk by five major routes (see Fig. 56-11D).

1. Secretory pathway. The milk proteins lactalbumin and casein are synthesized in the endoplasmic reticulum and sorted to the Golgi apparatus (see p. 21). Here alveolar cells add Ca2+ and phosphate to the lumen. Lactose synthetase in the lumen of the Golgi catalyzes synthesis of lactose, the major carbohydrate. Lactose synthetase has two components, a galactosyltransferase and lactalbumin, both made in the endoplasmic reticulum. Water enters the secretory vesicle by osmosis. Finally, exocytosis discharges the contents of the vesicle into the lumen of the alveolus.

2. Transcellular endocytosis and exocytosis. The basolateral membrane takes up maternal immunoglobulins by receptor-mediated endocytosis (see p. 42). Following transcellular transport of these vesicles to the apical membrane, the cell secretes these immunoglobulins (primarily immunoglobulin A) by exocytosis. The gastrointestinal tract of the infant takes up these immunoglobulins (see p. 922), which are important for conferring immunity before the infant's own immune system matures.

3. Lipid pathway. Epithelial cells synthesize short-chain fatty acids. However, the longer-chain fatty acids (>16 carbons) that predominate in milk originate primarily from the diet or from fat stores. The fatty acids form into lipid droplets and move to the apical membrane. As the apical membrane surrounds the droplets and pinches off, it secretes the milk lipids into the lumen in a membrane-bound sac.

4. Transcellular salt and water transport. Various transport processes at the apical and basolateral membranes move small electrolytes from the interstitial fluid into the lumen of the alveolus. Water follows an osmotic gradient generated primarily by lactose (present at a final concentration of ~200 mM) and, to a lesser extent, by the electrolytes.

5. Paracellular pathway. Salt and water can also move into the lumen of the alveolus via the tight junctions (see p. 137). In addition, cells, primarily leukocytes, also squeeze between cells and enter the milk.

PRL is essential for milk production, and suckling is a powerful stimulus for PRL secretion

PRL is a polypeptide hormone that is structurally related to GH, pvGH, and hCS1 and hCS2 (see Table 48-1). Like GH, PRL is made and released in the anterior pituitary; however, lactotrophs rather than somatotrophs are responsible for PRL synthesis. Another difference is that, whereas GH-releasing hormone stimulates somatotrophs to release GH, dopamine (DA) inhibits the release of PRL from lactotrophs. Thus, the removal of inhibition promotes PRL release.

The actions of PRL on the mammary glands (see Table 56-6) include promotion of mammary growth (mammogenic effect), initiation of milk secretion (lactogenic effect), and maintenance of milk production once it has been established (galactopoietic effect). Although the initiation of lactation requires the coordinated action of several hormones, PRL is the classic lactogenic hormone. Initiation of milk production also necessitates the abrupt fall in estrogens and progesterone that accompanies parturition. PRL is also the primary hormone responsible for maintaining milk production once it has been initiated.

PRL binds to a tyrosine kinase–associated receptor (see p. 70) in the same family of receptors as the GH receptor. PRL receptors, which have equal affinities for GH, are present in tissues such as breast, ovary, and liver. Presumably via pathways initiated by protein phosphorylation at tyrosine residues, PRL stimulates transcription of the genes that encode several milk proteins, including lactalbumin and casein.

Suckling is the most powerful physiological stimulus for PRL release. Nipple stimulation triggers PRL secretion via an afferent neural pathway through the spinal cord, thereby inhibiting dopaminergic neurons in the median eminence of the hypothalamus (Fig. 56-12). Because DA normally inhibits PRL release from the lactotrophs, it is called a PRL-inhibitory factor (PIF). Thus, because suckling decreases DA delivery via the portal vessels, it relieves the inhibition on the lactotrophs in the anterior pituitary and stimulates bursts of PRL release. Treating women with DA receptor agonists rapidly inhibits PRL secretion and milk production.

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FIGURE 56-12 Effect of suckling on the release of PRL, OT, and GnRH. Suckling has four effects. First, it stimulates sensory nerves, which carry the signal from the breast to the spinal cord, where these nerves synapse with neurons that carry the signal to the brain. Second, in the arcuate nucleus of the hypothalamus, the afferent input from the nipple inhibits neurons that release DA. DA normally travels via the hypothalamic-portal system to the anterior pituitary, where it inhibits PRL release by lactotrophs. Thus, inhibition of DA release leads to an increase in PRL release. Third, in the supraoptic and paraventricular nuclei of the hypothalamus, the afferent input from the nipple triggers the production and release of OT in the posterior pituitary. Fourth, in the preoptic area and arcuate nucleus, the afferent input from the nipple inhibits GnRH release. GnRH normally travels via the hypothalamic-portal system to the anterior pituitary, where it stimulates the synthesis and release of FSH and LH. Thus, inhibiting GnRH release inhibits FSH and LH release and thereby inhibits the ovarian cycle.

Several factors act as PRL-releasing factors (PRFs): thyrotropin-releasing hormone (TRH), angiotensin II, substance P, β endorphin, and AVP. In rats, suckling stimulates the release of TRH from the hypothalamus. In lactating women, TRH leads to increased milk production. Estradiol modulates PRL release in two ways. First, estradiol increases the sensitivity of the lactotroph to stimulation by TRH. Second, estradiol decreases the sensitivity of the lactotroph to inhibition by DA.

During the first 3 weeks of the neonatal period, maternal PRL levels remain tonically elevated. Thereafter, PRL levels decrease to a constant baseline level that is higher than that observed in women who are not pregnant. If the mother does not nurse her young, PRL levels generally fall to nonpregnancy levels after 1 to 2 weeks. If the mother does breast-feed, increased PRL secretion is maintained for as long as suckling continues. Suckling causes episodic increases in PRL secretion with each feeding, thus producing peaks in PRL levels superimposed on the elevated baseline PRL levels. After the infant completes a session of nursing, PRL levels return to their elevated baseline and remain there until the infant nurses again.

OT and psychic stimuli initiate milk ejection (“let-down”)

OT, which can promote uterine contraction, also enhances milk ejection by stimulating the contraction of the network of myoepithelial cells surrounding the alveoli and ducts of the breast (galactokinetic effect). Nursing can sometimes cause uterine cramps. During nursing, suckling stimulates nerve endings in the nipple and triggers rapid bursts of OT release (see Fig. 56-12). This neurogenic reflex is transmitted through the spinal cord, the midbrain, and the hypothalamus, where it stimulates neurons in the paraventricular and supraoptic nuclei that release OT from their nerve endings in the posterior pituitary. From the posterior pituitary, OT enters the systemic circulation and eventually reaches the myoepithelial cells that are arranged longitudinally on the lactiferous ducts and around the alveoli in the breast (see Fig. 56-11C, D). Activation of OTRs causes these cells to contract by mechanisms similar to those for the contraction of uterine smooth muscle (see p. 1146). The result is to promote the release of pre-existing milk after 40 to 60 seconds, a process known as the let-down reflex.

In addition to the suckling stimulus, many different psychic stimuli emanating from the infant, as well as neuroendocrine factors, promote OT release. The site or sound of an infant may trigger milk let-down, a phenomenon observed in many mammals. Thus, the posterior pituitary releases OT episodically even in anticipation of suckling. Fear, anger, or other stresses suppress this psychogenic reflex, thus inhibiting OT release and suppressing milk outflow.

Suckling inhibits the ovarian cycle

Lactation generally inhibits cyclic ovulatory function. Suckling likely reduces the release of gonadotropin-releasing hormone (GnRH) by neurons in the arcuate nucleus and the preoptic area of the hypothalamus (see Fig. 56-12). Normally, GnRH travels through the portal vessels to the gonadotrophs in the anterior pituitary. Thus, the decreased GnRH release induced by suckling reduces the secretion of follicle-stimulating hormone (FSH) and LH and has a negative effect on ovarian function. As a result, breast-feeding delays ovulation and normal menstrual cycles. However, if the mother continues to nurse her infant for a prolonged period, ovulatory cycles will eventually resume. Suckling intensity and frequency, which decrease with the introduction of supplementary foods to the infant, determine the duration of anovulation and amenorrhea in well-nourished women. In breast-feeding women in Bangladesh, the period of anovulation averages 18 to 24 months. If the mother does not nurse her child after delivery, ovulatory cycles resume, on average, 8 to 10 weeks after delivery, with a range of up to 18 weeks.

LESION

REFLEXOGENIC ERECTION

PSYCHOGENIC ERECTION

EFFECT ON EJACULATION

Upper motor neuron

Present

Absent

Significantly impaired

Lower motor neuron

Absent

Present

Less impaired