Prolactin is an important protein hormone that is in charge of milk production, and also contributes to breast development. Chemically, prolactin is similar to a growth hormone composing of 199 amino acids, and is formed after a 28-amino acid signal peptide is proteolytically cleaved from the prolactin prohormone (pre-prolactin). During pregnancy and lactation, prolactin levels are physiologically elevated consistent with the hormone function to grow breast tissues and to produce milk. The secretion of prolactin by the anterior pituitary is tonically inhibited by dopamine produced by the hypothalamus to maintain a basal level of prolactin. Other factors that stimulate prolactin production include thyrotropin-releasing hormone (TRH), estrogen (pregnancy), suckling, dopamine antagonists (antipsychotics), stress, and sleep. The level of prolactin is low in males and non-lactating non-pregnant females.
Prolactin has a major role in the physiology of the breast, especially in females. Both a lack of prolactin secretion and excessive prolactin secretion result in clinical presentations. The level of prolactin hormone is detrimental to the female’s ability to lactate. Thus, imbalances in the prolactin level can compromise this ability. 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). The physiological reason for this is related to the prolactin role in the hypothalamus-pituitary reproductive axis which will be discussed in detail later. In males, however, prolactin level imbalances have different clinical manifestations. Too much prolactin in males results in headaches and decreased libido. The decreased libido in males is associated with decreased spermatogenesis as a result of elevated prolactin affecting hypothalamus pituitary reproductive axis.
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. Prolactin production is regulated at the gene transcription level. Factors that stimulate prolactin secretion to upregulate prolactin gene transcription while factors that inhibit prolactin secretion downregulate prolactin gene transcription. The 2 most important factors that regulate prolactin secretion are: thyrotropin-releasing hormone (TRH) and dopamine both secreted by the hypothalamus. TRH has a stimulatory effect on thyroid-stimulating hormone (TSH) as well as prolactin; whereas, dopamine has an inhibitory effect on prolactin. In the absence of pregnancy (i.e., high estrogen) or lactation, prolactin is tonically inhibited by dopamine and the effect of dopamine trumpets the effect of TRH. Prolactin has a negative feedback on its own production by stimulating the release of dopamine in the hypothalamus. Medications that antagonize dopamine production, for example, an antipsychotic block, the tonic inhibition of dopamine result in symptoms of excessive prolactin. Conversely, medications that are dopamine agonists such as bromocriptine or cabergoline inhibit prolactin secretion. Thus, these medications are used in the treatment of prolactinoma. Estrogen in high levels, as the case with pregnancy, stimulate prolactin release directly from the anterior pituitary. Interestingly, suckling stimulates sensory nerves in the nipple that carries the signal via the spinal cord to arcuate nucleus which inhibits dopamine release by 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 ejection. Prolactin also has an inhibitory effect on the release of gonadotropin-releasing hormone (GnRH) produced by the hypothalamus-inhibiting FSH and LH release from the anterior pituitary. This leads to inhibition of the ovulatory cycle in females which explains the lactational amenorrhea. This mechanism serves as a natural contraceptive and may play a role in spacing out pregnancies. Similarly, prolactin in males inhibits GnRH release resulting in decreased spermatogenesis and infertility.
The main 2 functions of prolactin are to stimulate milk production and to develop breast tissues. Prolactin plays a role in breast development with estrogen and progesterone by stimulating further breast growth and enlargement of the alveoli in preparation for lactation. In addition to breast tissues development, prolactin is an essential player in milk production. Prolactin stimulates milk production by inducing the enzyme that synthesizes the constituents of milk, such as lactose (the carbohydrate of milk), casein (the protein of milk), and lipids. Prolactin is involved in the biosynthesis of milk constituents by binding to the cell membrane and inducing the transcription cascade to make the necessary enzymes for milk production. Lactogenesis does not occur, however; until after parturition because high estrogen and progesterone during pregnancy down regulate prolactin receptors in the breasts. After parturition, the estrogen and progesterone levels fall precipitously. Thus, the inhibitory effects on the breast are removed. As long as suckling is maintained, prolactin level stays elevated after the pregnancy with each episode of feeding producing peak prolactin levels. If the mother does not nurse her baby, prolactin levels fall to non-pregnant levels after 1 to 2 weeks.
If either prolactin excess or deficiency is suspected, measuring the serum prolactin level is appropriate. Measuring TSH and reviewing medications are indicated in the workup of prolactin issues to rule out hypothyroidism or medication side effect 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 10 to 210 ng/ml. In prolactinoma, the serum prolactin level is typically greater than 200 mg/mL. MRI is the imaging modality of choice in the workup of prolactinemia to visualize the prolactin-secreting tumor or prolactinoma.
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 or hypothalamo-hypophyseal tract. Prolactin-secreting tumor can also cause prolactin excess as 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.
As stated before, prolactin-related pathologies are either associated with prolactin deficiency or prolactin excess.
Prolactinoma is the most common secreting pituitary adenoma. It is characterized by proliferation of pituitary lactotrophs in the anterior pituitary. 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 result of hypogonadism caused by reduced secretion of LH and FSH. If the prolactinoma is large (i.e., macroadenoma greater than 1 cm) patient might present with compressive symptoms; such as bitemporal hemianopsia as the tumors compresses the optic chiasma. As stated before, dopamine agonist such as bromocriptine or cabergoline is the first line treatment in a prolactinoma. Cabergoline is preferred over bromocriptine due to its fewer side effects and 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.
Antipsychotic especially the first generation such as Haloperidol and Fluphenazine can cause symptoms of prolactin excess such as galactorrhea and gynecomastia. The mechanism of antipsychotic in which prolactinemia is produced involves non-selectively blocking D2 dopamine receptors in multiple dopaminergic pathways including the tuberoinfundibular tract where dopamine tonically inhibits prolactin resulting in disinhibition of prolactin release.
Sheehan syndrome is characterized by infarction of the anterior pituitary following postpartum. The pathophysiology of Sheehan syndrome involves a significant blood loss during childbirth which compromises the blood supply to the enlarged anterior pituitary causing it to undergo ischemic necrosis. This results in failure to produce the hormones made by the anterior pituitary such as prolactin. The signs and symptoms might not occur until months after the blood loss. 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 and decreased sex drive. Sheehan syndrome represents one of the pathology scenarios where prolactin deficiency is apparent.
Prolactin deficiency can be secondary to other etiologies that primarily affect the anterior pituitary. Anterior pituitary function to produce hormone such as prolactin can be impaired due to mass effect (tumor) or infections such as tuberculosis and histoplasmosis, or infiltrative process such as; sarcoidosis and hemochromatosis. Lastly, Hyperprolactinemia has been reported in several autoimmune conditions such as SLE, antiphospholipid syndrome, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, autoimmune thyroid disease, and celiac disease.
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