Lactation and Galactorrhea

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Chapter 17 Lactation and Galactorrhea

Elizabeth Ann Kennard, Elizabeth M. Hurd

INTRODUCTION

Lactation is one of the most important physiologic processes necessary for the survival of mammalian offspring in the absence of human intervention. Breast milk contains species-specific nutrients and immune factors that allow for the appropriate growth and development of newborns. For breastfeeding to be successful, the mammary glands must develop and transform into milk-producing organs by a hormone-driven process referred to as lactogenesis. An understanding of this process has taken on increasing importance as the tremendous benefits of breastfeeding have become widely known in the past two decades.

Galactorrhea, in its broadest sense, refers to the spontaneous flow of milk from the nipple at any time other than during breastfeeding. Derived from the Greek, galactorrhea literally means “milk flow.” Physiologic galactorrhea is experienced by many pregnant women late in gestation, as well as during the first few weeks or months after delivery when not breastfeeding or after cessation of breastfeeding.

Clinically, the term galactorrhea is used to refer to abnormal or inappropriate secretion of breast milk or a milklike fluid. This term often applies to milk secretion that occurs more than 6 months after either cessation of breastfeeding or delivery when not breastfeeding or in a woman who has never been pregnant. However, it is important to be aware that nonphysiologic galactorrhea has no universally agreed-upon definition.

Nonphysiologic galactorrhea can span the continuum from an incidental finding on examination to a significant social problem for the patient. The discharge may be unilateral or bilateral and it may occur spontaneously or only with nipple stimulation. Galactorrhea must be differentiated from a nipple discharge other than milk. The etiology can be idiopathic or related to any of a number of potentially serious underlying or iatrogenic causes.

This chapter begins with a review of the normal physiology of the breast and lactation. The various etiologies of pathologic galactorrhea are discussed, followed by a discussion of evaluation, treatment, and long-term prognosis for women with this problem.

PROLACTIN

A thorough comprehension of prolactin is required to understand both lactation and galactorrhea. Prolactin is responsible for the primary endocrine control of breast secretions, although multiple other hormones also influence breast milk production.

Prolactin is a 198-amino acid polypeptide hormone secreted in pulsatile fashion from the anterior pituitary (adenohypophysis) by specific cells referred to as lactotrophs.1 These cells have a common origin with the growth hormone-secreting cells (i.e., somatotrophs). Both prolactin and growth hormone are classified as somatomammotropic hormones based on their structural similarities. Due to its structural similarity to growth hormone, prolactin was the last pituitary hormone to be isolated.

Prolactin has a short half-life of only 20 minutes and exists in heterogeneous forms, including big prolactin, a dimeric glycosylated form, and big big prolactin.2,3 Secretion has a circadian rhythm, with a higher average level of serum prolactin during sleep, especially during the rapid eye movement phase.

The prolactin receptor is a member of the cytokine receptor family. It is a single transmembrane polypeptide found in multiple tissues in addition to the mammary glands, including the liver, adrenal glands, lungs, testes, and ovaries.4 The effects of prolactin in many of these tissues remains unknown.5

Neuroendocrinology of Prolactin Secretion

The control of prolactin secretion by the anterior pituitary lies within the hypothalamus and is predominantly inhibitory. However, the hypothalamus releases both prolactin-inhibiting factors (PIF) and prolactin-releasing factors (PRF) that modulate the secretion of prolactin.6

Prolactin-inhibiting factors are released by the hypothalamus into the hypothalamo-hypophyseal portal system. Although other compounds have been shown to have inhibitory activity, dopamine appears to be the most important PIF.7 Interruption of the tuberoinfundibular tract and blocking dopamine receptors with “gene knockout” techniques both result in high prolactin levels.8 Gonadotropin-associated peptide and γ-aminobutyric acid are also PIFs.9

Prolactin secretion is regulated by a negative feedback loop wherein prolactin, acting via prolactin receptors in the median eminence, stimulates dopamine secretion.10 Dopamine acts via the adenylyl cyclase pathway to reduce prolactin secretion from the pituitary lactotrophs. The predominant dopamine receptor in the adenohypophysis is D2 (DRD2). Binding of dopamine to this receptor decreases cellular adenylyl cyclase activity and cyclic adenosine monophosphate.

Although the major control mechanism for prolactin is inhibitory, the hypothalamus also releases PRFs, which stimulate lactotrophs to secrete prolactin (Table 17-1). The primary physiologic PRF appears to be vasoactive intestinal peptide. However, there appear to be two more clinically relevant PRFs.11,12 The ability of thyrotropin-releasing hormone (TRH) to act as a PRF is believed to be the basis of the association between hypothyroidism and hyperprolactinemia, a condition that resolves with thyroid hormone replacement. Serotonin appears to be another PRF; use of any of the various selective serotonin reuptake inhibitors (SSRIs) is commonly associated with hyperprolactinemia.

Table 17-1 Prolactin Releasing Factors

Thyrotropin-releasing hormone
Serotonin
Vasoactive intestinal peptide
Opioids
Growth hormone-releasing hormone
Gonadotropin-releasing hormone

LACTATION

The process of lactation requires normal breast development followed by appropriate hormonal and mechanical stimulation of the breast.

Breast Development

Prenatal

Normal development in utero requires fetal exposure to many hormones, including estrogens, progesterone, prolactin, insulin, cortisol, thyroxine, and growth hormone (Table 17-2). The endocrine system is essential for the proper development and function of the mammary glands.13,14 Gene knockout studies have demonstrated the importance of each of these hormones in fetal mammary gland development.15. These hormones work through normal hormone–receptor interactions using local growth factors in many cases.16,17

Table 17-2 Hormones Required for Normal Mammary Development

Estrogen
Progesterone
Prolactin
Cortisol
Insulin
Thyroxine
Growth hormone

Puberty

At puberty, estradiol is the major influence on breast development, and the breast contains both α and β estrogen receptors. However, multiple hormones are necessary for normal development, including all the hormones necessary for normal in utero development (see Table 17-2).

Under the influence of rising estradiol levels at puberty, the breast increases in size and the areola gains pigmentation.18 Most breast development at puberty is adipocyte differentiation under the influence of estrogens. Estrogens stimulate the lactiferous ducts to branch extensively. The terminal alveoli unit, however, is rudimentary.

The Mature Breast

Anatomy

The breasts consist of glands, fat, and connective tissue. The basic glandular unit consists of ducts and secretory lobules (Fig. 17-1). Twenty or more lactiferous ducts converge on the nipple. Each large duct is connected to smaller branching ducts and eventually lobules. The ducts are lined by a cuboidal or columnar epithelium, at the base of which are myoepithelial cells. Each lobule contains alveoli, milk glands lined by epithelium.19,20 In a nonactive state, the ductules often have only rudimentary terminal alveoli that secrete milk.

image

Figure 17-1 The breast and nipple–areolar complex. Distal ducts are lined by epithelial and myoephithelial cells. The breast lobules empty into lactiferous ducts, which terminate at the nipple. The glands of Montgomery are associated with sebaceous glands and terminate on the areola.

(From Powell DE: The normal breast: Structure, function and epidemiology. In Powell DB, Stelling CB. The Diagnosis and Detection of Breast Disease. Mosby, 1995,)

Cyclic Changes During the Menstrual Cycle

Breast changes occur with the different phases of the menstrual cycle. In the luteal phase, breast stromal water content and density increases under the influence of increased levels of circulating estrogen and progesterone. Clinically, the breasts become larger and fuller. On mammogram, breast tissue becomes more fibrous and dense, and thus more opaque. The “cloudy” mammography images make it difficult to detect small abnormalities in premenopausal women. Cell proliferation is also increased in the late luteal phase.

Pregnancy

Breast development and lactogenesis during pregnancy occurs under the influence of multiple hormones, most notably prolactin, estrogen, and progesterone. Prolactin is secreted in large amounts by the decidua, and levels will be 5 to 10 times normal by the end of the first trimester.21 Under the influence of increased estrogen, the pituitary lactotrophs undergo hyperplasia. After delivery, prolactin declines to a normal baseline by 6 weeks postpartum and then pulses with breastfeeding.

Lactogenesis

Final differentiation of the breast into a lactating organ occurs during pregnancy. Lactogenesis is a three-stage process whereby mammary glands develop the ability to produce and secrete milk.22 Starting in early pregnancy and ending within a week of parturition, the mammary glands are hormonally transformed from an undifferentiated state to a fully differentiated state with an established supply of mature milk.

Stage I Lactogenesis

During this stage, mammary glands become competent to secrete milk. This stage begins early in gestation and is nearly complete by midpregnancy. As a result of rising levels of estrogen, progesterone, prolactin, and human placental lactogen, the terminal duct lobular units expand and secretory cells begin to differentiate. Prolactin induces the transcription of β-casein and lactalbumin genes.23

Mammary cells start accumulating large numbers of fat droplets. The character of secreted glandular fluid changes, with increases in lactose, total protein, and immunoglobulin concentrations and decreases in sodium and chloride concentrations. The mammary glands remain quiescent as a result of elevated estrogen and progesterone levels, but are prepared to initiate milk production around parturition.

Stage II Lactogenesis

This stage begins at the time of birth and ends with the establishment of an appropriate milk supply. Delivery of the placenta results in a sudden drop in circulating progesterone levels. At the same time, both glucocorticoid and prolactin levels increase. This leads to increased synthesis of lactose. Lactose draws water by osmosis into the secretory vesicles. At the same time, synthesis of other milk components (e.g., nutrients and minerals) is increased under the influence of maternal insulin, growth hormone, cortisol, and parathyroid hormone. Secretion of the alveolar cells first leads to colostrum formation. Within the next 2 to 3 days, there is a relatively rapid onset of mature milk production.24

Stage III Lactogenesis

The last phase of lactogenesis, also referred to as galactopoiesis or simply lactation, is defined as secretion and continued production of mature milk by the mammary glands once lactation has been established. Lactation occurs in response to sensory signals from suckling transmitted to the paraventricular and supraoptic nuclei in the brain. This results in release of oxytocin from the posterior pituitary. Oxytocin causes mammary myoepithelial cell contraction, resulting in milk letdown. As long as prolactin and oxytocin secretion are maintained and milk is removed from the mammary glands, milk production will be maintained. Milk production appears to require the presence of other hormones as well, including insulin and glucocorticoids.

Suckling by the nursing young is the best-known physiologic stimulus of prolactin secretion. The mechanism of this classic neuroendocrine reflex appears to be decreased release of dopamine (a PIF) into portal blood.25

Breastfeeding

In nature, species-specific breast milk is necessary for survival of the neonate, because it is the only bioavailable source for the neonate of water, organic nutrients, and minerals. For human infants, breast milk gives the best opportunity for ideal growth and development because it contains a species-specific assortment of important nutrients and bioactive substances. These elements are critical during early developmental periods, especially for the brain, immune system, and intestinal tract. Colostrum, the first milk produced after parturition, is lower in fat than mature milk, but is higher in carbohydrates, protein, and antibodies. Mature milk is higher in calories as a result of higher fat content, but also contains antibodies and other bioactive factors.

When human milk is unavailable, modern infant formulas are acceptable but incomplete substitutes. Most commonly made from cow’s milk or soybeans, formulas are similar to human milk in terms of water, fat, carbohydrates, and calories, but are devoid of antibodies and other bioactive factors. The exceptional benefits of human breast milk compared to formulas are so numerous that the American Academy of Pediatrics policy statement is that “pediatricians and other health care professionals should recommend human milk for all infants in whom breastfeeding is not specifically contraindicated.”26

Breastfeeding and Anovulation

Breastfeeding is associated with decreased ovarian function for a variable period of time. This is clinically manifested as anovluation, amenorrhea, hypoestrogenemia, and some degree of vaginal atrophy.

The underlying mechanism of breastfeeding-related anovulation is related to the ability of suckling and prolactin release to inhibit gonadotropin-releasing hormone (GnRH) release. The amount of GnRH suppression varies with the amount and frequency of breastfeeding, use of infant supplements, and the weight and nutritional health of the mother.

As a result of these variables, the length of time a breastfeeding woman will have amenorrhea is highly variable, and women should not rely on lactation to prevent pregnancy. As many as 10% of breastfeeding women will ovulate within 10 weeks of giving birth.27 Two thirds of women who breastfeed for more than 9 months will resume ovulation and menstruation during that time. A small fraction of breastfeeding women will remain anovulatory and amenorrheic for more than 1 year.

Involution

After cessation of breastfeeding (or after delivery in women not breastfeeding), postlactation changes result in involution of ducts and alveoli by apoptosis. Involution

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