DISORDERS OF BREAST DEVELOPMENT

Mammary Hypoplasia

There are two categories of breast hypoplasia or hypomastia. The first involves congenital abnormalities, which are rare. As noted previously, Blomstrands chondrodysplasia, which is caused by inactivating mutations in the PTH1R, is associated with complete amastia and athelia (lack of nipples) 12. Another congenital syndrome associated with variable failure of breast development is ectodermal dyplasia. This is actually a collection of disorders defined by defects in the formation of ectodermal appendages such as teeth, hair follicles, sweat glands and breasts 73-77. X-linked anhidrotic ectodermal dysplasia has recently been shown to be caused by mutations in ectodysplasin or EDAR, members of the tumor necrosis family of ligands and receptors, respectively 73, 77. However, thus far, neither of these molecules has been directly implicated in the regulation of embryonic mammary development. Breast hypoplasia can be asymmetrical and has also been associated with mitral valve prolapse in some patients 78.

The second type of hypomastia is the result of a lack, or delay, of hormonal stimulation of breast development. Thus, any disorder that results in an impairment of sexual maturation may cause breast hypoplasia. Conditions such as gonadal dysgenesis, Turners syndrome or anorexia nervosa fall into this category 79. Unlike the first category, breast growth in these patients is often amenable to treatment with estrogens. There are also some patients who present with minimal breast development in the absence of either a clear congenital defect or a defined defect in sexual maturation. These women can often successfully lactate, so it may be that this represents a problem in the stromal rather than the epithelial compartment of the breast. It has been suggested that these patients may suffer from an insensitivity of the breast tissue to normal levels of circulating hormones 79. Women with underdeveloped breasts and normal ovarian function should not be treated with estrogens in order to attempt to stimulate breast growth. If treatment is desired, mammoplasty is the appropriate choice for these women as well as those with clear congenital defects such as ectodermal dysplasia 75, 80.

Polythelia/Polymastia

Unlike the failure of breast development, the formation of extra nipples, with or without associated breast tissue, is fairly common. Historically, polythelia was though to indicate increased fertility 81. Interestingly, extra nipples and mammary tissue almost always form along the embryonic milk or nipple lines and thus are located along a curved line extending from the axilla to the inguinal ligaments bilaterally 82. Extra nipples can be associated with variable amounts of mammary ductal tissue, which can undergo functional differentiation and produce milk. There have been reports of familial polythelia and, in some families, the presence of extra nipples has been associated with renal anomalies 83-85. This suggests that the determination of mammary gland number and location is under the control of specific developmental regulatory genes. However, to date, the identity of these genes remains obscure. In the vast majority of cases, supernumerary nipples are a benign curiosity. However, various breast pathologies, including breast cancer have been reported to occur within ectopic breast tissue 85. Therefore, their presence should be noted and, if present, extra nipples should be periodically examined for mass lesions.

Macromastia

Macromastia refers to excessive or massive breast enlargement. For the purposes of diagnosis this has been defined as a degree of breast enlargement that leads to a sense of discomfort due to the weight of the breast tissue or to stretching of the skin so that ulceration occurs 86. The breast enlargement may be asymmetrical. This disorder has been described in three settings, during puberty, during pregnancy and in association with penicillamine therapy. Pubertal macromastia has been described as occurring before or after the onset of menstrual cycling 81, 87. Breast enlargement in pregnancy-associated macromastia usually begins in the first or second trimester. It has been noted in first pregnancies but also after previous uneventful pregnancies. Breast enlargement can resolve or persist after delivery, and in some patients further enlargement has been described with subsequent pregnancies 88-90. Interestingly, pregnancy-associated macromastia has been reported to cause hypercalcemia due to the production of PTHrP by breast tissue 91. Finally, macomastia has been reported in women taking penicillamine and, as with the pregnancy-associated cases, it may not resolve after discontinuation of the drug 92, 93. In all these categories, histology of the breast tissue has been reported to be normal, as have circulating levels of sex steroids, prolactin and placental lactogen 81, 86-93. It has been suggested that these patients are overly sensitive to the actions of hormones at the level of the breast 86. It is not clear why penicillamine use is associated with this syndrome. Reduction mammoplasty is the therapy of choice 94, 95. Some cases recur and total mastectomy may be required in this circumstance 96.

DISORDERS OF BREAST FUNCTION

Agalactia

Physiologic failure of lactation is uncommon. Sheehan's syndrome presents with a failure to lactate and a failure to resume normal menses postpartum 97, 98. This initial presentation is accompanied, or followed, by various other symptoms of panhypopituitarism. Classically, this disorder follows significant peripartum hemorrhage and is due to pituitary necrosis. Prolactin deficiency of any cause would be expected to present with an inability to nurse. At least one case of isolated prolactin deficiency has presented in this manner 99. An inability to nurse has also been reported in patients with mutations in the Pit-1 gene, which controls the development of pituitary cells that secrete prolactin, growth hormone and TSH 100, 101. Deletion of the oxytocin gene has been reported to cause lactation failure in mice, but to date, no such cases in humans have been reported 102.

Galactorrhea

Galactorrhea refers to the inappropriate secretion of milk from the breast. By definition, it occurs in the absence of parturition or greater than 6 months postpartum in a non-lactating woman 86. Galactorrhea is most common in women but also occurs in men and, rarely, in children of either sex. Milk secretion may be spontaneous and copious, or it may be minimal and require expression from the breast to be detected. Galactorrhea is a reflection of an underlying endocrine disorder and is not associated with breast cancer or other mass lesions. However, other types of non-milky, serous or sanguineous discharges are often associated with fibrocystic disease, intraductal papillomas and breast cancer 103. The possibility of cancer is especially worrisome if the secretion is bloody. Although the presence of milk secretion as opposed to other types of breast discharge is usually obvious, the type of fluid can be verified by microscopic examination. The presence of fat droplets within the discharge is characteristic of galactorrhea, which requires no further work up for breast cancer. However, other types of discharge should trigger a careful evaluation to rule out cancer. If there is still confusion after simple microscopic examination of the fluid, it can also be analyzed for milk proteins such as casein and a-lactalbumin, or for lactose 86.

Differential Diagnosis

Galactorrhea has been recognized as an entity for thousands of years, but the first "modern" recognition of the common co-occurrence of galactorrhea and amenorrhea was reported by Chiari in 1855 and Frommel in 1882 103. In the mid-20th century it was suggested that galactorrhea was caused by pituitary tumors that secreted prolactin, and in the 1970's when immunoassays for prolactin were developed, the connection between hyperprolactinemia and galactorrhea was confirmed 86. Today, the differential diagnosis of galactorrhea is essentially that of hyperprolactinemia. However, there are some women that present with galactorrhea who do not manifest elevated prolactin levels. The spectrum of disorders causing galactorrhea was established in several series reported in the late 1970's 104-107. The largest of these, by Kleinberg et al., examined 235 patients presenting with galactorrhea 107. This study, as well as the other smaller studies, was performed before the era of high resolution imaging of the pituitary by CT scanning or MRI. Therefore, many patients classified as having idiopathic hyperprolactinemia most likely suffered from pituitary microadenomas secreting prolactin. Because there have not been similar large scale studies that have used sensitive radiologic techniques, the relative frequencies of the disorders as reported in these studies and in subsequent reviews are likely to be inaccurate. Nonetheless, the basic diagnostic categories remain as valid today as they were when originally reported. In Table 1, we present a comprehensive differential diagnosis of galactorrhea. Below, we will discuss the major categories. The reader is referred to Chapter 6 of Neuroendocrinology for a more in depth discussion of the diagnosis and management of hyperprolactinemia.

Pituitary Tumors

Both macroprolactinomas and microprolactinomas can present with galactorrhea 104-107. Prolactinomas are the most common type of pituitary adenoma and have been estimated to be present in as many as 10 - 15% of the population in autopsy studies 108. It is not known how many of these subjects actually manifested hyperprolactinemia or symptoms, but elevations in serum prolactin are found in 10 - 20% of women presenting for work-up of infertility or menstrual irregularities 109. The most common presentation of prolactinomas in women is the combination of galactorrhea and ammenorrhea. The majority of patients presenting in this fashion most likely have microprolactinomas, although in the original series of Kleinberg and colleagues, up to one-third of women presenting with galactorrhea and amenorrhea had a macroadenoma of some kind 107. Most likely due to their preexisting ductal development and prior exposure to higher levels of estrogen, 80% of women with prolactinomas develop galactorrhea while only 20% of men with prolactinomas present in this fashion 110. Therefore, in men, the most common presentation is that of a pituitary mass lesion, and the majority of men with clinically-apparent prolactinomas have macroadenomas. Macroprolactinomas should be suspected in all men presenting with galactorrhea.
The second most common type of pituitary tumors associated with galactorrhea are growth hormone-secreting adenomas 103. Some patients with acromegaly have tumors that co-secrete prolactin and growth hormone, while many others have macroadenomas that cause stalk compression and mild hyperprolactinemia 111. In addition, growth hormone has direct effects on ductal development and has intrinsic lactogenic properties. Therefore, there exists a subset of patients with acromegaly and normal prolactin levels who develop galactorrhea 107.

Finally, a variety of other non prolactin-secreting pituitary tumors have been associated with galactorrhea 107. These tumors are macroadenomas that cause mild to moderate elevations in serum prolactin due to stalk compression and interference with the delivery of dopamine to the anterior pituitary which normally acts to inhibit basal prolactin secretion.

All patients with galactorrhea should have serum prolactin levels measured. It has been suggested that elevations in prolactin of greater than 100 - 200 ng/ml are suggestive of a prolactinoma 104, 107. However, as noted above, mild hyperprolactinemia may be seen with a variety of pituitary macroadenomas. Therefore, every patient with galactorrhea and hyperprolactinemia should have a MRI scan with contrast performed in order to detect or exclude the presence of a pituitary tumor.

Other Disorders of the Pituitary or Hypothalamus

In addition to pituitary adenomas, any lesion of the pituitary or hypothalamus that disrupts the secretion of dopamine from the hypothalamus to the anterior pituitary can cause hyperprolactinemia and galactorrhea. Therefore, other tumors such as meningiomas, craniopharyngiomas, gliomas and metastatic carcinomas have been reported to cause galactorrhea. In addition, infiltrative diseases of the hypothalamus such as eosiniphilic granulama and sarcoidosis can present with glactorrhea 86, 104-106, 111.

Idiopathic Hyperprolactinemia

A subset of women with galactorrhea and abnormal menses presents with mild elevations in serum prolactin levels and no demonstrable adenoma on pituitary MRI scanning. If these women do not have other medical conditions or do not take medications that are known to elevate prolactin levels (see below), then they are labeled as having idiopathic hyperproactinemia 86, 107, 109. Although some of these patients may have microadenomas smaller than the current detection limit of MRI scanning, follow-up studies of these women do not suggest that the hyperprolactinemia becomes more severe, or that detectable adenomas develop over time 109, 112. In fact, in many women, this appears to be a self-limited condition and the prolactin levels return to normal, menses resume and fertility returns. It has been suggested that abnormalities in the hyothalamic regulation of prolactin secretion may exist in some women with this disorder 113. Although controversial, some studies suggest that as many as 20% of women with the polycystic ovarian syndrome (PCO) suffer from idiopathic hyperprolactinemia on this basis 114-116. Finally a form of idiopathic hyperprolactinemia may occur post-partum. Historically, prolonged postpartum galactorrhea and amenorrhea has been termed the Chiari-Frommel Syndrome 103. Some of the patients traditionally assigned to this category most likely harbored pituitary tumors. However, there do appear to be some patients with prolonged galactorrhea (more than 6 mos after the cessation of nursing) and mild hyperprolactinemia that is usually self-limited 107.

Ectopic Production of Prolactin

A variety of tumors, including small cell lung cancer, undifferentiated bronchogenic carcinoma, renal cell carcinoma, gonadolblastoma, trophoblastic tumors and hematologic malignancies have been reported to produce prolactin 117-122. Some of these tumors, especially the hematologic malignancies, have presented with galactorrhea 121, 122. Successful treatment of the underlying tumor has generally resulted in resolution of galactorrhea and hyperprolactinemia, confirming that the malignant cells were indeed the source of the prolactin 121, 122. The case of hematologic malignancy is particularly interesting in that prolactin is naturally produced by some lymphocytes and may have immunomodulatory properties 123. Therefore, in these instances the production of prolactin may be viewed as eutopic rather than truly ectopic. Although rare, the possibility of an underlying malignancy should be kept in mind in the evaluation of patients presenting with galactorrhea, elevated prolactin levels and a negative pituitary MRI.

Reactive Hyperprolactinemia

Prolactin is a "stress" hormone and hyperprolactinemia resulting in galactorrhea has been reported after major surgery 107, 124. In the case of oopherectomy an additional factor may be the withdrawal of estrogen in the setting of hyperprolactinemia. As discussed earlier, suckling normally stimulates prolactin release via stimulation of sensory afferent nerve fibers that traverse the spinal cord to the hypothalamus. The series reported by Boyd and Kleinberg each reported women that had galactorrhea and hyperprolactinemia on the basis of manual stimulation of the nipples 104, 107. The galactorrhea in these patients presumably was secondary to the activation of this neurological reflex and it subsided after this behavior was discontinued. In a similar fashion, irritating lesions of the chest wall such as herpes zoster and/or chest trauma have been reported to cause galactorrhea 125, 126. Finally, spinal cord trauma has been reported as a cause of galactorrhea on this basis 125, 126.

Thyroid Disorders

Although galactorrhea is an uncommon complication of hypothyroidism, series of patients with galactorrhea consistently contain several patients with hypothyroidism 104-107. In children, galactorrhea has been reported as part of a constellation including precocious puberty and hypothyroidism 127. The mechanisms by which hypothyroidism induces galactorrhea are not completely understood. TRH stimulates prolactin secretion and some patients may have changes in the hypothalamic control of prolactin secretion 86. However, only 50% of hypothryoid patients with galactorrhea had elevated prolactin levels in the series reported by Kleinberg et al. 107. Treatment of the hypothyroidism did lead to a reduction in the prolactin levels in this group. Galactorrhea has also been reported to occur in hyperthyroid patients128.

Medications

Medications are a common cause of galactorrhea. Table 2 provides a comprehensive list of those medications known to cause galactorrhea. The most common offenders fall into one of two mechanistic categories; drugs that alter levels of circulating estrogens and those that alter dopaminergic regulation of prolactin secretion causing hyperprolactinemia. In the first category, galactorrhea has been reported to occur with either the institution or withdrawal of oral estrogen-containing contraceptives and with the use of depo-medroxyprogesterone 86, 107, 129. In this setting the galactorrhea is most likely triggered by transient stimulation of mammary epithelial proliferation/differentiation by estrogen and/or progesterone followed by withdrawal of the hormonal stimulation, mirroring the natural pattern at the time of parturition. In addition, estrogen is know to stimulate proliferation of lactotrophs, and prolactin secretion from the pituitary. It should be kept in mind that estrogen treatment has also led to the presentation of galactorrhea in patients with previously silent pituitary tumors 86, 107.

The second major group of agents causing galactorrhea is those with dopamine antagonist activity leading to hyperprolactinemia. The most common in this group are antipsichotic drugs of the phenothiazone and butyrophenone classes 86, 107. It has been reported that up to 15% of women develop galactorrhea after starting an antipsychotic medication 130. These agents antagonize the effects of dopamine on the lactotrophs and lead to mild to moderate levels of hyperprolactinemia. Prolactin levels are usually in the range of 20 - 100 ng/ml and higher levels should raise the possibility of a pituitary tumor 107. Other medications with demonstrated dopamine antagonist activity are metoclorpramide and methyldopa 86.

Many other drugs have been associated with galactorrhea due to unclear mechanisms. In addition to those in use in medical practice, drugs of abuse such as cocaine, opiates amphetamines, benzodiazepines and cannabis, as well as several medicinal herbs have been reported to cause galactorrhea. Fenugreek seed is sometimes used to attempt nonpuerperal lactation in mothers wishing to nurse adopted babies 131. Other regimens used for this purpose include estrogen and progesterone followed by metoclopramide or domperidone 86.

Idiopathic Galactorrhea with Regular Menses

In the series reported by Kleinberg and colleagues, the largest single group of women presenting with galactorrhea fell into this category 107. Menstrual disturbances are a sensitive indicator of hyperprolactinemia and therefore, not surprisingly, the majority of women in this category had normal prolactin levels. Most of these women presented with persistent galactorrhea following the birth of a child. Therefore, they may represent a subgroup in which the breasts did not fully involute. It has also been suggested that women in this group may have breast tissue that is hypersensitive to normal levels of circulating hormones 86. Generally, these patients tend to have minor degrees of milk secretion and retain normal fertility. Although prolactin levels are normal, milk production can be stopped with prolactin-lowering dopamine agonists (see below).

Evaluation of the Patient with Galactorrhea

All patients complaining of galactorrhea require a thorough evaluation to exclude pituitary tumors, hyperprolactinemia, hypothyroidism and the side effects of medication or illicit drug use. A careful history should inquire about the onset, degree and nature of galactorrhea. Perhaps the most important aspect of the evaluation involves a careful reproductive history focusing on the onset of symptoms relative to past pregnancy, and the current pattern of menses. One should inquire about symptoms suggestive of pituitary mass effect. A careful medication history including the use of contraceptives and illicit drugs or medicinal supplements and herbs should be obtained. Finally, one should ask about chest wall or nipple manipulation and/ or irritation. A complete physical exam should be performed, including a careful breast exam to rule out mass lesions and to document the type of breast secretion. If there is any doubt about the nature of the secretion a drop should be examined under the microscope for the presence of fat droplets to confirm it to be milk. The single most useful laboratory test is a serum prolactin level, which should be measured in all patients with galactorrhea. Other important laboratories include a pregnancy test and thyroid function tests and a TSH level. Additional laboratory evaluation should be dictated by the history and physical exam. The majority of patients with galactorrhea will likely have elevations in serum prolactin and all of these patients should have pituitary MRI's with contrast performed to search for a pituitary or hypothalamic mass lesion. Other imaging studies should be dictated by findings on history and physical exam.

Treatment of Galactorrhea

Galactorrhea in and of itself does not require treatment and therefore therapy decisions must be guided by the underlying diagnosis. However, if the degree of milk secretion is bothersome, then intervention may be desired. The majority of patients will also have hyperprolactinemia and the decision-making process is essentially the same for that disorder. For a complete discussion of the therapy for hyperprolactinemia, the reader is referred to Chapter 6 of Neuroendocrinology. Pituitary tumors other than prolactinomas are usually treated with neurosurgical resection of the tumor with or without pituitary irradiation. However, prolactinomas, even macroprolactinomas, are generally very sensitive to dopamine agonists and respond to medical therapy with both a reduction in prolactin levels as well as with a significant reduction in tumor size 132. Therefore, in the vast majority of patients with prolactinomas, the first approach is with either bromocriptine or cabergoline. It is not clear if patients with microprolactinomas require therapy. If fertility is not an issue, then the major concern is the long-term risk of osteoporosis 109. This risk is probably related to the degree of disruption of menses. Patients with amenorrhea are most likely at highest risk and may warrant treatment for the prevention of bone loss. However, if menses are intact, simple follow up of bone density may be enough. Perhaps the most difficult category of patients is those on antipsychotic medications. Discontinuation of the offending medication will result in the cessation of galactorrhea and the resumption of menses, but this may be impossible given the underlying psychiatric disease. These patients also should not be treated with dopamine agonists, as this can destabilize their psychiatric condition. Careful follow up of bone mass should be undertaken in these patients, and the possibility of a pituitary tumor should be kept in mind. If the prolactin level is over 150 - 200 ng/ml or if there are symptoms suggestive of pituitary mass lesions or concurrent abnormalities in other pituitary hormones, then a MRI should be performed. Finally, patients with galactorrhea, normal prolactin levels and normal menses require no therapy. If galactorrhea persists, prolactin levels should be repeated periodically to ensure that they are not increasing into the abnormal range. However, if desired, milk secretion can be stopped with dopamine agonist therapy.