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.

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.

GALACTORRHEA

Nonphysiologic galactorrhea is a common problem that has been estimated to occur in approximately one fourth of all previously parous women sometime during their reproductive life. The condition is most common in women between ages 20 and 35 and is less common in nulligravid women.²⁸ The most common pathologic condition resulting in galactorrhea is hyperprolactinemia, which has several possible underlying causes (Tables 17-3 and 17-4).

Table 17-3 Pathologic Etiologies of Hyperprolactinemia

Central nervous system disorders

Pituitary tumors/lesions

Adenomas (most common: prolactinomas, gonadotroph or nonfunctioning adenomas)

Infections (e.g., tuberculosis, schistosomiasis)

Sarcoidosis

Hypothyroidism

Chest wall irritation

Breast surgery or tumors

Thoracic neoplasms

Ectopic prolactin secretion

Bronchogenic carcinoma

Renal adenocarcinoma

Hypernephroma

Gonadoblastoma

Decreased prolactin metabolism

Renal failure

Cirrhosis

Pseudocysesis false pregnancy

Table 17-4 Drug Class Associated with Galactorrhea

The listed drugs are only examples and do not represent a complete list

Hyperprolactinemia

Hyperprolactinemia occurs in less than 1% of the general population. When patients present with secondary amenorrhea, approximately 30% will be found to have hyperprolactinemia. When patients present with both galactorrhea and amenorrhea, 75% will have hyperprolactinemia. Approximately 30% of these patients will be found to have prolactin-secreting tumors.

Clinical Manifestations of Hyperprolactinemia

The most common presenting symptoms of hyperprolactinemia are galactorrhea, infertility, menstrual dysfunction, and headaches. Galactorrhea is seen in more than 80% of hyperprolactinemic patients.

Hyperprolactinemia is known to be causally related to several pathologic conditions (see Table 17-3). As noted, a physiologic response to hyperprolactinemia is anovulation.^29,³⁰ High levels of prolactin inhibit the pulsatile release of GnRH, thereby reducing pituitary release of both luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The LH surge is also inhibited.

There is evidence that high serum prolactin levels also have a direct effect on the ovary.²⁸ Hyperprolactinemia inhibits androgen synthesis, thereby reducing substrate for estrogen formation, and may block aromatase activity. All of these effects lead to hypoestrogenism and explain the disrupted or absent menstrual cycles in women with high prolactin levels. Elevated serum prolactin levels have a luteolytic effect that can disrupt the cycle. Elevated prolactin levels should be considered in the differential diagnosis of luteal phase disorders.

ETIOLOGIES OF HYPERPROLACTINEMIA

Galactorrhea is most commonly a normal response of the breast to a normal or abnormal endocrine signal (i.e., hyperprolactinemia). Once elevated prolactin is detected, the goal of the clinician is to determine the underlying cause. After pregnancy is excluded, the clinician must assess the patient for drug causes, thyroid disease, anatomic breast or chest wall abnormalities, and pituitary disorders (see Table 17-3).

Physiologic Causes

Pregnancy

Whenever investigating hyperprolactinemia, clinicians should exclude an unrecognized early pregnancy. As discussed, the primary physiologic function of prolactin is to induce breast development and lactogenesis during pregnancy. By the end of the first trimester, prolactin levels will be 5 to 10 times the nonpregnant levels.

Activities that Stimulate Prolactin Release

When evaluating a patient’s serum prolactin levels, it is important to be aware of activities that can stimulate a temporary increase in prolactin through normal physiologic mechanisms. These include sleeping, eating, sexual intercourse, breast or chest stimulation, and stress. For this reason, if a borderline elevation of serum prolactin is detected on initial evaluation, it is prudent to avoid these stimulants by repeating the prolactin determination in the morning after fasting remote from any breast stimulation to avoid expensive evaluation of a fallacious prolactin elevation.³¹

Central Nervous System Disorders

Pituitary Adenomas

Pituitary adenomas can result in hyperprolactinemia by two different mechanisms. Prolactinomas, which account for approximately 70% of pituitary adenomas, secrete prolactin and are the most common cause of very high serum prolactin levels (usually >100 μg/L).

Other types of pituitary adenomas result in hyperprolactinemia by a completely different mechanism. Clinically nonfunctioning adenomas usually originate from gonadotroph cells. They represent almost 30% of pituitary adenomas. Less common adenomas are those that originate from the somatotrophs (produce growth hormone), corticotrophs (secrete corticotropin), or thyrotrophs (secrete thyrotropin). The gonadotroph adenomas incommonly secrete FSH or LH. These tumors increase prolactin by compressing the pituitary stalk and interfering with the release of dopamine, the putative PIF. As a result of decreased exposure of the lactotrophs to the inhibitory influence of dopamine, prolactin levels increase, usually to the range of 30 to 100 μg/L. The nonfunctioning tumors usually present with neurologic symptoms rather than symptoms related to the hyperprolactinemia. These include visual impairment (bitemporal hemianopsia) and headache.

Large tumors of the hypothalamus may also cause compression of the portal system that carries the prolactin inhibitors. Structural lesions such as empty sella syndrome or a cyst of Rathke’s pouch can also cause hyperprolactinemia and associated galactorrhea.³² The diagnosis and treatment of pituitary abnormalities are addressed in Chapter 22.

Any disease that causes pituitary inflammation can result in hyperprolactinemia, probably as a result of decreased dopamine effect on lactotrophs. Uncommon causes of hypophysitis include autoimmune disease, infections (e.g., tuberculosis, schistosomiasis), and sarcoidosis.

Hypothyroidism

Hypothyroidism, even if subclinical, may result in elevated prolactin levels. When levels of circulating thyroxine are low, the lack of negative feedback on the hypothalamus results in increased release of thyrotropin-releasing hormone (TRH) into the portal circulation. As thyrotrophs are stimulated to release thyrotropin, lactotrophs are stimulated to release prolactin. This cross-reactivity is thought to be related to the embryologic derivation of both of these cell types from the same precursor cells.³³ Thyroid replacement will uniformly reduce both thyrotropin and prolactin release, and alleviate the associated galactorrhea.³⁴

Chest Wall Lesions

Because chest stimulation can result in elevations of prolactin, it isn’t surprising that trauma or lesions of the chest wall may result in hyperprolactinemia and galactorrhea.³⁵ Tumors, herpes zoster, spinal cord injury, and other lesions have been associated with hyperprolactinemia.³⁶

Ectopic Prolactin Production

Rarely, malignant tumors have been reported to secrete prolactin, resulting in hyperprolactinemia. A list of some reported tumor types is given in Table 17-3.

Decreased Prolactin Metabolism

Because most prolactin is excreted by the kidneys, renal disease is associated with galactorrhea due to high prolactin levels resulting from decreased excretion. This effect disappears once normal renal function is restored via transplant.³⁷ Elevated prolactin has long been associated with cirrhosis of the liver, although the mechanisms for this remain unclear.

Medications

Many psychotropic medications have been shown to cause galactorrhea via elevations of prolactin (see Table 17-4). The mechanism by which dopamine blocking agents (such as phenothiazines) increase prolactin is obvious, because they result in decreased exposure of lactotrophs to dopamine. It is less obvious how other centrally acting drugs increase prolactin levels, but this side effect is common with major neuroleptics such as haloperidol and antidepressants, including the tricyclics and the SSRIs.³⁸^–⁴² The SSRIs are probably the most frequent drug class associated with increased serum prolactin.

Other commonly used drugs associated with hyperprolactinemia include antihypertensive medications such as methyldopa and verapamil.⁴³ Protease inhibitors used for the treatment of human immunodeficiency virus infections have also been associated with hyperprolactinemia.⁴⁴ The list of other medications associated with hyperprolactinemia is extensive. For this reason, the clinician should consult the product information for any medications being taken by women found to have hyperprolactinemia to determine if they could be associated with the galactorrhea.

EVALUATION OF GALACTORRHEA

A general approach to the investigation and management of galactorrhea is outlined in Fig 17-2.

Figure 17-2 Flow diagram for the evaluation of galactorrhea.

History

It is important to determine the time of onset, duration, and frequency of galactorrhea. The amount and quality of the discharge should be defined as well as whether the leakage is spontaneous or needs to be induced. Galactorrhea associated with hyperprolactinemia is usually bilateral and spontaneous.

Gynecologic history should include menstrual and contraception history, with special attention to the possibility of pregnancy. Obstetric history should include number of pregnancies, time since last delivery, menstrual cycle data, and medications.

General symptoms can often give clues to underlying diseases associated with hyperprolactinemia. Symptoms of hypothyroidism include lethargy, weight gain, heat or cold intolerance, and nail and skin changes. Brain tumors are often associated with headaches and visual symptoms. History or symptoms of underlying renal or liver disease should be elicited. Finally, any history of chest lesion or trauma should be noted.

Physical Examination

The physical examination of the breast for the presence of masses and discharge should be performed. An important objective is to differentiate galactorrhea from other pathology. A dark or bloody secretion is clearly not milk, and a local cause should be sought. Palpable masses should be evaluated following normal protocols for this finding.

The clinician should attempt to express the discharge or ask the patient to demonstrate the galactorrhea. The fluid may be milky, tan, green, or clear but should not be bloody. Placing a drop of the fluid under the microscope and visualizing multiple fat droplets can easily verify galactorrhea. The presence of a bloody discharge or fluid is not galactorrhea and should prompt consideration of ductogram or other localized evaluation to rule out malignancy. An examination for galactorrhea should also include assessment for thyroid disorders, including palpation of the thyroid, and neurologic assessment, including visual fields.

Diagnostic Tests

Serum Prolactin Levels

In the nonpregnant woman, the range of normal prolactin levels is from 1 to 20 ng/mL. There is a diurnal variation, such that prolactin levels are higher during sleep. During pregnancy, prolactin levels normally increase to as high as 300 ng/mL.

Prolactin levels can be temporarily increased by breast stimulation related to medical or self-examination or sexual activity. However, in the nonpregnant patient, routine breast examination does not acutely alter serum prolactin levels, and thus measurement.

If prolactin is elevated, the test should be repeated fasting and in the morning, when it would be expected to be lowest. The patient should be instructed to abstain from any breast or nipple stimulation immediately prior to the test.

Other Laboratory Tests

Whenever hyperprolactinemia is suspected, a urine or blood pregnancy test and a serum thyrotropin level should be evaluated simultaneously with a serum prolactin level. In women at risk for kidney disease, a serum creatinine level should also be evaluated.

Imaging Studies

In the presence of reproducible hyperprolactinemia, evaluation of the pituitary and hypothalamus with magnetic resonance imagining is indicated to check for an intracranial lesion. Computed tomography can be used, but has the disadvantage of lower resolution. The most common brain tumor in women with hyperprolactinemia is a benign pituitary adenoma. These are classified as being either a microadenoma (<1 cm) or a macroadenoma (>1 cm). Their treatment and prognosis are discussed in Chapter 22.

Postmenopausal women with no evidence of pituitary or hypothalamic lesions should be further evaluated with a chest radiogram and a mammogram, because hyperprolactinemia has been associated with both breast and lung cancer.

TREATMENT FOR GALACTORRHEA RELATED TO HYPERPROLACTINEMIA

When galactorrhea is found to be a symptom of significant pathology, the treatment of the underlying problem becomes paramount. Many women will have resolution of their galactorrhea with appropriate therapy that normalizes their prolactin levels. When women are found to have a pituitary microadenoma or idiopathic hyperprolactinemia, the treatment decision is usually made based on the symptoms the patient is having. The most common symptoms associated with hyperprolactinemia are excessive galactorrhea, infertility, and hypoestrogenemic amenorrhea.

Indications for Treatment

Excessive Galactorrhea

Galactorrhea itself is not a dangerous condition but can have significant impact on lifestyle if excessive. Whereas most women with minimal galactorrhea rarely request treatment for symptoms alone, women who have enough leakage to keep their clothing moist will often request treatment to avoid social embarrassment and/or the skin disorders associated with chronic dampness, including excoriation and fungal infections.

Infertility

Women unable to achieve pregnancy found to have galactorrhea and hyperprolactinemia are at risk for ovulation dysfunction that can range from subclinical to obvious anovulation and amenorrhea. If a pituitary adenoma is diagnosed, the prognosis of this lesion during pregnancy should be discussed prior to therapy. Treatment with dopamine agonists will often result in pregnancy without further treatment.

Hypoestrogenemic Amenorrhea

Menstrual abnormalities in women with galactorrhea and hyperprolactinemia are often the result of hypoestrogenemia. The most significant long-term medical problem associated with this condition is decreased bone mineral density due to their hypoestrogenic state.⁴⁵ Treatment to lower prolactin and thus increase estrogen will increase bone mass in these women.⁴⁶ However, eumenorrheic women with galactorrhea demonstrate normal bone density and do not require treatment for this indication.⁴⁷

Treatment Options

The treatment of hyperprolactinemia is covered fully in Chapter 22. In brief, elevated prolactin levels related to pituitary causes can usually be decreased to the normal range using a dopamine agonist. In most cases, this will result in resolution of galactorrhea, associated menstrual abnormalities, and infertility.

If infertility persists with normalized prolactin, ovulation induction medications may be used successfully in these patients.⁴⁸ Conversely, if pregnancy is not desired, care must be taken to avoid pregnancy when hyperprolactinemia is corrected because a previously anovulatory patient has an 80% chance of becoming ovulatory after 6 months or less of treatment.⁴⁹

If pregnancy is not desired, oral contraceptives can be used, especially if menstrual abnormalities persist. Oral contraceptives with higher levels of ethinyl estradiol (i.e., ≥50 μg) have been associated with galactorrhea and hyperprolactinemia.⁵⁰ However, modern oral contraceptives (i.e., ≤35 μg) can be used in women with hyperprolactinemia with no measurable risk of enlargement of pituitary lesions.⁵¹

Galactorrhea not associated with elevated prolactin is uncommon. In the absence of other lesions, it is believed that some women have an increased sensitivity to normal levels of prolactin. Other women are thought to have elevated levels of abnormal prolactin that is not measured using normal assays. If these women have indications for treatment, a trial of dopamine agonist therapy is warranted.

PEARLS

• Lactation is a complex multistep process under hormonal control.

• Breast milk is a neonate’s best source of water, organic nutrients, minerals, and bioactive substances.

• Pregnancy and hypothyroidism should be excluded in women with hyperprolactinemia.

• Galactorrhea of endocrine origin is often associated with amenorrhea.

• Galactorrhea associated with a normal menstrual cycle and a normal serum prolactin level is usually not associated with a pituitary tumor.

• Centrally acting drugs associated with galactorrhea include antipsychotics, antidepressants (e.g., imipramines, SSRIs) opiates, histamine (H₂) receptor antagonists (e.g., cimetidine), and calcium channel blockers.

• The highest levels of serum prolactin are usually related to pituitary prolactinomas; lower levels can be seen with any lesion that compresses the pituitary stalk.

• Treating hyperprolactinemia with dopamine agonists will resolve galactorrhea and usually result in normalized menstrual cycles and fertility.

REFERENCES