Introduction

Prolactin is a polypeptide hormone responsible for lactation, breast development, and hundreds of other actions needed to maintain homeostasis. The chemical structure of prolactin is similar to the structure of growth and placental lactogen hormones. Together, they form the "prolactin/growth hormone/placental lactogen" family, which is characterized by a conserved helix bundle protein composition. All hormones in this family derive from a common ancestral gene.

Prolactin is composed of 199 amino acids after the proteolytic cleavage of the signal peptide from the prolactin prohormone (pre-prolactin) and posttranslationally modified. It is common knowledge that the anterior pituitary synthesizes and secretes prolactin and dopamine-mediated hypothalamic regulation; however, the central nervous system, the immune system, the uterus, and the mammary glands are all capable of producing prolactin. Nipple stimulation, light, olfaction, and stress can all contribute to the initiation of prolactin synthesis in these tissues. Other factors that stimulate prolactin production include thyrotropin-releasing hormone (TRH), estrogen (pregnancy), and dopamine antagonists (antipsychotics). Males have characteristically low levels of prolactin. Abnormal elevation in males is suggestive of a potential underlying pathological process like a pituitary adenoma or a medication adverse effect, which warrants further evaluation. Prolactin is low in males and non-lactating non-pregnant females.[1][2][3][4][5]

Issues of Concern

Prolactin has a significant role in the physiology of the breast, especially in females. A lack of prolactin secretion or excessive prolactin secretion results in clinically significant pathologic processes. The level of prolactin hormone is imperative for normal lactational capabilities. Imbalances in prolactin levels can compromise this ability. If the levels are too low, a mother will not be able to produce milk, and if the levels are inappropriately elevated, this can lead to galactorrhea in non-breastfeeding females or males. Furthermore, disruption in the prolactin balance can have significant effects on the menstrual cycle. In females, too much prolactin leads to amenorrhea (absence of menstruation), which results from the prolactin inhibition of GnRH release. In males, however, prolactin level imbalances have different clinical implications. Too much prolactin in males results in headaches and decreased libido. The decreased libido is associated with decreased spermatogenesis as a result of elevated prolactin affecting the hypothalamus-pituitary reproductive axis.[6][7]

Cellular Level

The pituitary gland sits directly behind the nasal bridge in a protective bony structure called the sella turcica. It is connected to the hypothalamus by the infundibular stalk. The hypothalamus is largely responsible for regulating the synthesis and secretion of various hormones within the pituitary gland, including prolactin. The pituitary gland is structurally divided into anterior and posterior regions. The anterior pituitary is capable of producing and secreting its hormones, compared to the posterior pituitary gland, which acts more as a conduit for presynthesized hormones by the hypothalamus. Prolactin is synthesized by lactotrophs in the anterior pituitary gland. The number of lactotrophs will increase during pregnancy in response to the physiological need to develop breast tissues and to prepare for milk production.

The increase in lactotroph cells is not accompanied by an increase in angiogenesis. This fact is important to understand the pathophysiology behind pituitary infarction and ischemia presented later. Prolactin production is regulated at the gene transcription level. Factors that stimulate production upregulate prolactin gene transcription, while factors that inhibit secretion downregulate prolactin gene transcription.

Thyrotropin-releasing hormone (TRH) and dopamine are both released by the hypothalamus and have activity in modulating lactotophic activity. Dopamine is tonically (ie, continuous) secreted by dopaminergic neurons that project from the arcuate nucleus of the hypothalamus into the anterior pituitary gland via the infundibulum. This pathway is called the tuberoinfundibular pathway. The dopamine released at the terminal buttons of the nerves acts on lactotrophic cells through D2 receptors, modulating intracellular signaling and inhibiting prolactin synthesis. In the absence of pregnancy (ie, high estrogen) or lactation in sexually mature females, prolactin is constitutively inhibited by dopamine, and the effect of dopamine trumps the effect of minimal stimulatory effects of TRH. Additionally, prolactin has negative feedback on its own production by stimulating the release of dopamine in the hypothalamus. Medications that antagonize dopamine production (ie, antipsychotics) or masses that compress the infundibulum disrupt the basal inhibition of prolactin synthesis, resulting in hyperprolactinemia. Conversely, medications that are dopamine agonists, such as bromocriptine or cabergoline, will inhibit prolactin secretion and can be used to treat pathologies associated with hyperprolactinemia. Lastly, the decidua layer of the placenta has also been found to synthesize prolactin. This process is independent of dopamine regulation.[8][9]

During pregnancy, estrogen and progesterone are found at elevated levels, and they function to promote the growth of mammary tissue. The most potent stimulator for prolactin synthesis is suckling or nipple stimulation. This mechanical process stimulates sensory nerves in the nipple that carry the signal via the spinal cord to the arcuate nucleus, which inhibits dopamine release, thus removing the inhibitory action of dopamine on prolactin. At the same time, the afferent signal from the nipple activates supraoptic and paraventricular nuclei to increase the production of oxytocin, which allows for milk "let-down." Oxytocin and vasoactive intestinal peptide (VIP) both promote the inhibition of dopamine, allowing the synthesis of prolactin. During periods of stress, the secretion of prolactin contributes to the modulation of adrenal ACTH sensitivity and hypertrophy of the gland.

Prolactin release has an inhibitory effect on the release of gonadotropin-releasing hormone (GnRH)  from the hypothalamus. The loss of GnRH results in a lack of pulsatile stimulation of gonadotrophic cells, resulting in the loss of FSH and LH release from the anterior pituitary. FSH and LH are the primary hormones needed to regulate menstruation; thus, females who are lactating will experience a period of transient amenorrhea until the cessation of breastfeeding. This mechanism serves as a natural contraceptive and may play a role in pregnancy spacing. Similarly, prolactin in males inhibits GnRH release, resulting in decreased spermatogenesis and infertility, but this is considered pathologic.[10][11][12][13]

Function

Prolactin contributes to hundreds of physiologic functions, but the two primary responsibilities are milk production and the development of mammary glands within breast tissues. Prolactin promotes the growth of mammary alveoli, which are the components of the mammary gland, where the actual production of milk occurs. Prolactin stimulates the breast alveolar epithelial cells to synthesize milk components, including lactose (i.e., the carbohydrate of milk), casein (ie, the protein of milk), and lipids. The prolactin receptors are down-regulated on mammary glandular tissue during periods of elevated progesterone levels (ie, during pregnancy).

After delivery, the serum progesterone level drops, allowing for the up-regulation of prolactin receptors on the mammary alveolar cells, enabling lactogenesis. Even after delivery, prolactin levels will not continuously remain at elevated levels. Prolactin levels will only spike during periods of nipple stimulation, allowing for control over milk production. As long as suckling is maintained, prolactin levels stay elevated. During periods when the mother is not breastfeeding, the prolactin levels decline to a basal level, and mammary gland milk production reduces. If the mother does not nurse her baby, prolactin levels fall to non-pregnant levels after 1 to 2 weeks.[5]

Related Testing

Measuring the serum prolactin level is appropriate in either prolactin excess or deficiency. Measuring TSH and reviewing medication lists are also suggested as part of the workup. These two steps are crucial to rule out hypothyroidism or medication adverse effects as an underlying cause of prolactin excess symptoms.

In males, serum prolactin levels range from 2 to 18 ng/ml; in females, 2 to 30 ng/ml; and during the third trimester of pregnancy, 10 to 210 ng/ml. In cases of prolactinomas, the serum prolactin level is typically greater than 200 ng/mL. MRI is the imaging modality for identifying the presence or absence of a prolactin-secreting tumor called a pituitary adenoma. 

Pathophysiology

The pathophysiology of prolactin can include either lack of prolactin production or excessive prolactin production. Prolactin deficiency results in failure to lactate, while excessive prolactin results in galactorrhea and infertility. Destruction of the anterior pituitary can cause prolactin deficiency. On the other hand, prolactin excess causes include loss of dopamine inhibition under the influence of antipsychotic drugs or destruction of the hypothalamus/hypothalami-hypophyseal tract. Prolactin-secreting tumors can also cause prolactin excess, as is the case with prolactinoma.

Regardless of the etiology of excess prolactin, infertility ensues in both sexes due to GnRH inhibition by prolactin, as well as galactorrhea or the inappropriate flow of breast milk in men and women. Dopamine agonist medications such as bromocriptine and cabergoline are treatment options for prolactin excess regardless of its etiology. It is important to know that hypothyroidism can present with galactorrhea. As mentioned before, TRH has a stimulatory effect on prolactin; thus, with low thyroid hormone in hypothyroidism, the negative feedback on TRH is removed, allowing for excessive prolactin release and galactorrhea.

Clinical Significance

As stated previously, prolactin-related pathologies are associated with prolactin deficiency or excess.

Prolactinoma

Prolactinoma is the most common secreting pituitary adenoma. It is characterized by the proliferation of pituitary lactotrophic cells in the anterior pituitary gland. Most prolactinomas (90%) are microadenomas (less than 1 cm in diameter) and are asymptomatic. The classic presentation of prolactinoma is a young female with menstrual irregularities, galactorrhea, and infertility. Men may report a decrease in libido and erectile dysfunction as a result of hypogonadism caused by reduced secretion of LH and FSH. If the prolactinoma is large (i.e., macroadenoma greater than 1 cm), the patient may present with compressive symptoms, such as bitemporal hemianopsia, as the tumor compresses the optic chiasma. Dopamine agonists such as bromocriptine and cabergoline are both considered a first-line treatment option in prolactinoma cases. Cabergoline is preferable to bromocriptine due to fewer side effects and a longer half-life. Furthermore, cabergoline normalizes prolactin in up to 95% of patients, reduces tumor size by about 90%, and controls symptoms in most patients.    

Medication-induced Prolactinemia

First-generation antipsychotics such as haloperidol and fluphenazine can cause symptoms of prolactin excess, such as galactorrhea and gynecomastia, through their dopamine blockade. The specific mechanism involves non-selective D2 dopamine-receptor inhibiting in multiple dopaminergic pathways, including the tuberoinfundibular tract, where dopamine tonically inhibits prolactin, resulting in disinhibition of prolactin release. The loss of dopamine-mediated disinhibition allows for constitutively active lactotrophic cells. 

Sheehan Syndrome

Sheehan syndrome is characterized by infarction of the anterior pituitary, which often occurs during delivery but does not manifest until the post-partum period with various endocrinopathies. The pathophysiology of Sheehan syndrome involves significant blood loss during childbirth, which compromises the blood supply to the enlarged anterior pituitary gland. Prolonged ischemia progresses to ischemic necrosis of the pituitary gland. This damage results in failure to produce the hormones made by the cells within the anterior pituitary gland, such as prolactin-secreting lactotrophs. Symptoms may not manifest until months after the infarction event; thus, a sense of heightened clinical suspicion is necessary when evaluating post-partum mothers with new-onset endocrinopathies or an inability to lactate. The most common presenting symptom of Sheehan syndrome is the failure to lactate (agalactorrhea). Other symptoms are related to the functions of the hormones made by the anterior pituitary, such as amenorrhea, decreased sex drive, or symptoms of thyroid insufficiency. Sheehan syndrome represents one of the pathology scenarios where prolactin deficiency is apparent.  

Other Conditions

Prolactin deficiency can be secondary to other etiologies that primarily affect the anterior pituitary. The anterior pituitary function to produce hormones can become impaired due to mass effect (ie, craniopharyngiomas) or infections such as tuberculosis and histoplasmosis. Infiltrative disease processes like sarcoidosis and hemochromatosis are also hypoprolactinemic etiologies. Lastly, autoimmune conditions like SLE, antiphospholipid syndrome, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, autoimmune thyroid disease, and celiac disease can also impact prolactin production.