Which hormone stimulates mammary glands to produce milk in nursing mothers?

Lactation

Lactation is relatively prolonged due to the immaturity of the neonate. Three phases of lactation are recognised, Stages I and II being the equivalent of lactogenesis stage I of Eutheria. There are dynamic changes in milk composition throughout the whole of lactation that correlate with changes in needs of the young and ultimately control its growth and development.

In early lactation the milk has a high protein, low fat composition, while later in lactation there is a high fat, low protein milk (Fig. 13). The particular proteins, amino acids, fats and carbohydrates are all precisely regulated, and in some of the continuously breeding kangaroos, adjacent mammary glands supporting a small new young and a large young at foot produce milk of different compositions, a phenomenon known as concurrent asynchronous lactation.

Studies in which young of various ages were cross-fostered to mothers at different stages of lactation have shown the critical importance of synchrony between developmental stage of the young and the milk composition it receives. Transferring a young to a mother at a later stage of lactation can accelerate both growth and development (Menzies et al., 2012; Hetz et al., 2015). Transfer to an earlier stage of lactation retards growth.

Milk contains many bioactive components including PDGF, IGFBP5, IGFBPL1 and EGFL6. Cross fostering studies have highlighted the importance of milk bioactives in development of organs including lungs and stomach.

Drug Use During Lactation

With current recommendations to breast-feed exclusively for 6 months, and maintain breast-feeding for 2 years if possible, it is likely that most infants will be exposed to maternal medications through breast milk. Women on average take four medications during lactation.147 Nursing mothers are understandably concerned about the transfer of drugs and chemicals to breast milk. Correct advice is important to prevent them from unnecessarily stopping breast-feeding or discontinuing appropriate drug treatment. Unfortunately, only about 5% of drugs have human data on breast-feeding.63 It can be difficult to decide which of the many, sometimes conflicting, sources of public information to trust.

Pharmaceutical information leaflets from manufacturers often discourage the use of drugs during breast-feeding simply as a general precaution. The most comprehensive up-to-date information is found in the Drugs and Lactation Database (LactMed) of the National Library of Medicine's Toxicology Data Network (TOXNET).148 The American Academy of Pediatrics (AAP) has published policy statements on the benefits of breast-feeding149 and the use of drugs during lactation.150 The Centers for Disease Control and Prevention (CDC) provides online information regarding breast-feeding and various toxins and infectious diseases.151

For the future, it is expected that the revised FDA Pregnancy and Lactation Labeling Rule (PLLR)70 will lead to better information on drugs and breast-feeding. Human data are used whenever possible, and animal data are purposefully omitted when human data are available. The lactation section has three parts that must be updated whenever new information is available. The risk summary outlines the drug absorption and transfer to milk, estimated infant exposure, effects on infant and possibly maternal milk production, and a risk/benefit statement including a statement that the drug is compatible with breast-feeding if human data are available to support that conclusion. The clinical considerations part gives advice on minimizing infant drug exposure and recommendations for monitoring possible drug effects. The data section gives more details about the available evidence to support the risk summary. Given the large knowledge gap, there are still many issues to resolve, such as the level of evidence required for the appropriate advice on the label, setting research priorities for the large number of older drugs still being used for which there is no information, and best research methods for human studies depending on the drug. These were discussed and summarized at a recent 2-day FDA meeting in June 2016.152

Only a few types of drugs such as cytotoxic and immunosuppressive drugs (e.g.,cyclophosphamide,methotrexate) and radioactive compounds are strongly contraindicated during breast-feeding.65 Mothers breast-feeding infants withglucose-6-phosphate-dehydrogenase (G6PD) deficiency should avoidfava beans and drugs such assulfonamides, including the combination ofsulfamethoxazole and trimethoprim, nitrofurantoin, primaquine, andphenazopyridine.

Initiation of Lactation

Although breastfeeding is a natural process in postpartum women, it is a learned skill, not a reflex. Because the incidence of breastfeeding in developed countries dropped to about 10% in the 1950s and 1960s, there are few experienced role models available to support, encourage, and assist new mothers in feeding their infants at the breast. In the late 1940s, Edith Jackson at Yale, in cooperation with Herbert Thoms, established the first rooming-in unit in the United States, introduced “child birth without fear,” and reestablished breastfeeding as the norm for mothers and infants at the Yale–New Haven Hospital.90 Obstetric and pediatric residents were well schooled in the practical aspects of breastfeeding and human lactation. Jackson and her pediatric colleagues published the classic article on the management of breastfeeding,91 on which decades of publications, both lay and professional, were based.

The obstetrician and pediatrician have become more involved in the decision to breastfeed and in the practical management of the mother-infant dyad. Medical schools are gradually adding breastfeeding and lactation to their curriculum. Although it is not the physician's role to put the infant to the breast, it is important to understand the process, to recognize problems, and to know how to solve them. Breastfeeding support is a team effort in which the physician works with many health care professionals, including nurses, midwives, doulas, and dietitians, to provide complete care to the perinatal patient. Lactation specialists may be nurses, dietitians, or nonmedical individuals with special training, or physicians with specialty designation. The physician should be sure that consultants are licensed and board certified by the International Board of Lactation Consultant Examiners, and that other physicians are recognized as a fellows of the Academy of Breastfeeding Medicine.

Except in extreme cases, breast size does not influence milk production. Augmentation mammoplasty does not interfere with lactation unless a periareolar incision was made and nerves were interrupted. If augmentation was done for cosmetic enhancement, the tissue should function well, but if there was little or no palpable breast tissue before surgery, lactation may be improbable.

Reduction mammoplasty is more invasive surgery, and lactation results depend on the technique used. If many ducts were severed and the nipple and areola transplanted, lactation is interfered with. However, if the nipple and areola remained intact on a pedicle of ducts, lactation could be successful. Other incisions (e.g., for lump removal) should be discussed but usually do not interfere with lactation.

During pregnancy, the obstetrician should document the changes in the breasts in response to pregnancy, when the nipple and areola should become more pigmented and enlarged and the breast should enlarge several cup sizes. Lack of breast changes should also be communicated to the pediatrician, because this represents a risk for early failure to thrive in the infant because of insufficient milk supply. A breast examination should be conducted late in the pregnancy to check for any new findings of masses, lumps, discharge, or pain. Berens92 described the role of the obstetrician throughout pregnancy in detail.

INDUCTION OF LACTATION

Induced lactation is defined as breast-feeding in the absence of a recent pregnancy. On occasion, adoptive mothers desire to breast-feed.41 In countries where access to formula is limited, induced lactation in a surrogate may be important if the biologic mother cannot continue to breast-feed.42 The key hormone involved in lactation is prolactin. Medications that raise prolactin levels can be used to help induce lactation. For example, metoclopramide, 10 mg three times daily, causes an increase in prolactin secretion.43 When metoclopramide is coupled with nipple stimulation every few hours using an electronic breast pump, lactation can be established in the majority of women. In many cases, the amount of milk produced may be insufficient to breast-feed the infant exclusively. Agents such as sulpiride and chlorpromazine can also be used to induce lactation, but these agents may be associated with drowsiness and extrapyramidal symptoms.44

Minerals and Calciotropic Hormones

Lactation-specific ranges in serum minerals and calciotropic hormones are not provided by laboratories; the typical mean changes that do occur are schematically depicted in Figure 63.1. Although ionized calcium and albumin-corrected serum calcium remain normal, in longitudinal studies of exclusively lactating women these values were modestly increased above pre-pregnancy or term values.1 The serum phosphorus may increase above the normal range; skeletal resorption of mineral likely overloads the renal capacity for excretion of phosphorus.

Modern intact and bio-intact assays have shown that PTH is normally low or undetectable during the first several months of exclusive lactation. As the baby is weaned, PTH increases and may exceed the normal range. Calcitriol levels promptly fall to normal during lactation, but may also increase during post-weaning. The decline in calcitriol to normal during lactation may occur because the factors that are thought to stimulate Cyp27b1 during pregnancy are lost at parturition (high concentrations of estradiol and placental lactogen). Also, although circulating PTHrP concentrations increase during lactation, it is a less potent stimulator of Cyp27b1 in comparison to PTH.24,25

The lactating breasts are functional “accessory parathyroids” in the sense that they produce substantial amounts of PTHrP. Human and cow’s milk contain PTHrP at 1000 to 10,000 times the blood level in patients with hypercalcemia of malignancy and normal human controls. Some PTHrP escapes into the maternal circulation, and higher levels are achieved after suckling.80,81 There are several lines of evidence that lactating mammary tissue is the source of PTHrP in the maternal circulation. In women, not only does circulating PTHrP increase with suckling,80 but total mastectomy during pregnancy corrects PTHrP-mediated hypercalcemia.82–84 In animal models, the PTHrP concentration is higher in venous outflow from mammary tissue as compared to the arterial inflow,85 while selective deletion of the PTHrP gene from mammary tissue significantly reduced the plasma PTHrP level in lactating mice.86

Mammary-derived PTHrP plays a central role during lactation to stimulate osteoclast-mediated bone resorption, osteocytic osteolysis, and renal tubular reabsorption of calcium (Figure 63.3). In women, higher plasma PTHrP correlates with greater loss of bone mineral density during lactation,87 higher serum calcium, and lower PTH.80,88 In hypoparathyroid women, as noted below, PTHrP is responsible for normalizing mineral homeostasis during lactation. In mice, ablation of the PTHrP gene from mammary tissue also reduces the magnitude of bone lost during lactation.86