Prolactin

Prolactin is a hormone produced in the pituitary gland, named because of its role in lactation. Prolactin is a hormone named originally after its function to promote milk production (lactation) in mammals in response to the suckling of young after birth.

Synthesis

PRL consists of 198 amino acids and has a molecular mass of 21,500 kDa; it is weakly homologous to GH and human placental lactogen (hPL), reflecting the duplication and divergence of a common GH-PRL-hPL precursor gene on chromosome 6. PRL is synthesized in lactotropes, which constitute about 20% of anterior pituitary cells. Lactotropes and somatotropes are derived from a common precursor cell that may give rise to a tumor secreting both PRL and GH. Marked lactotrope cell hyperplasia develops during the last two trimesters of pregnancy and the first few months of lactation. These transient functional changes in the lactotrope population are induced by estrogen.

Secretion

Normal adult serum PRL levels are about 10–25 µg/L in women and 10–20 µg/L in men. PRL secretion is pulsatile, with the highest secretory peaks occurring during rapid eye movement sleep. Peak serum PRL levels (up to 30 µg/L) occur between 4:00 and 6:00 A.M. The circulating half-life of PRL is about 50 min.

PRL is unique among the pituitary hormones in that the predominant central control mechanism is inhibitory, reflecting dopamine-mediated suppression of PRL release. This regulatory pathway accounts for the spontaneous PRL hypersecretion that occurs after pituitary stalk section, often a consequence of compressive mass lesions at the skull base. Pituitary, dopamine type 2 (D2) receptors mediate PRL inhibition. Targeted disruption (gene knockout) of the murine D2 receptor in mice results in hyperprolactinemia and lactotrope proliferation. As discussed below, dopamine agonists play a central role in the management of hyperprolactinemic disorders

Thyrotropin-releasing hormone (TRH) (pyro GluHis-Pro-NH2) is a hypothalamic tripeptide that releases CHAPTER 2 Disorders of the Anterior Pituitary and Hypothalamus and the maximum dose is

Serum PRL levels rise transiently after exercise, meals, sexual intercourse, minor surgical procedures, general anesthesia, acute myocardial infarction, and other forms of acute stress. PRL levels increase significantly (about tenfold) during pregnancy and decline rapidly within 2 weeks of parturition. If breastfeeding is initiated, basal PRL levels remain elevated; suckling stimulates reflex increases in PRL levels that last for about 30–45 min. Breast suckling activates neural afferent pathways in the hypothalamus that induce PRL release. With time, the suckling-induced responses diminish and inter-feeding PRL levels return to normal.

Action

The PRL receptor is a member of the type I cytokine receptor family that also includes GH and interleukin (IL) 6 receptors. Ligand binding induces receptor dimerization and intracellular signaling by Janus kinase ( JAK), which stimulates translocation of the signal transduction and activators of transcription (STAT) family to activate target genes. In the breast, the lobuloalveolar epithelium proliferates in response to PRL, placental lactogens, estrogen, progesterone, and local paracrine growth factors, including IGF-I.

PRL acts to induce and maintain lactation, decrease reproductive function, and suppress sexual drive. These functions are geared toward ensuring that maternal lactation is sustained and not interrupted by pregnancy. PRL inhibits reproductive function by suppressing hypothalamic GnRH and pituitary gonadotropin secretion and by impairing gonadal steroidogenesis in both women and men. In the ovary, PRL blocks folliculogenesis and inhibits granulosa cell aromatase activity, leading to hypoestrogenism and anovulation. PRL also has a luteolytic effect, generating a shortened, or inadequate, luteal phase of the menstrual cycle. In men, attenuated LH secretion leads to low testosterone levels and decreased spermatogenesis. These hormonal changes decrease libido and reduce fertility in patients with hyperprolactinemia.

Hyperolactinemia

Hyperprolactinemia is the most common pituitary hormone hypersecretion syndrome in both men and women. PRL-secreting pituitary adenomas (prolactinomas) are the most common cause of PRL levels >100 µg/L. Less pronounced PRL elevation can also be seen with microprolactinomas but is more commonly caused by drugs, pituitary stalk compression, hypothyroidism, or renal failure

Table

Etiology of Hyperprolactinemia

Physiologic hypersecretion

Pregnancy

Lactation

Chest wall stimulation

Sleep

Stress

Hypothalamic-pituitary stalk damage

Tumors

        Craniopharyngioma

        Suprasellar pituitary mass extension

        Meningioma

        Dysgerminoma

        Metastases

Empty sella

Lymphocytic hypophysitis

Adenoma with stalk compression

Granulomas

Rathke’s cyst

Irradiation

Trauma

        Pituitary stalk section

        Suprasellar surgery

Pituitary hypersecretion

Prolactinoma

Acromegaly

Systemic disorders

Chronic renal failure

Hypothyroidism

Cirrhosis

Pseudocyesis

Epileptic seizures

Drug-induced hypersecretion

Dopamine receptor blockers

Phenothiazines: chlorpromazine, perphenazine

Butyrophenones: haloperidol

Thioxanthenes

Metoclopramide

Dopamine synthesis inhibitors

        α—Methyldopa

Catecholamine depletors

        Reserpine

Opiates

H2 antagonists

Cimetidine, ranitidine

Imipramines

        Amitriptyline, amoxapine

Serotonin reuptake inhibitors

        Fluoxetine

Calcium channel blockers

        Verapamil

Hormones

        Estrogens

        Antiandrogens

        TRH

Pregnancy and lactation are the important physiologic causes of hyperprolactinemia. Sleep-associated hyperprolactinemia reverts to normal within an hour of awakening. Nipple stimulation and sexual orgasm may also increase PRL. Chest wall stimulation or trauma (including chest surgery and herpes zoster) invoke the reflex suckling arc with resultant hyperprolactinemia. Chronic renal failure elevates PRL by decreasing peripheral clearance. Primary hypothyroidism is associated with mild hyperprolactinemia, probably because of compensatory TRH secretion.

Lesions of the hypothalamic-pituitary region that disrupt hypothalamic dopamine synthesis, portal vessel delivery, or lactotrope responses are associated with hyperprolactinemia. Thus, hypothalamic tumors, cysts, infiltrative disorders, and radiation-induced damage cause elevated PRL levels, usually in the range of 30–100 µg/L. Plurihormonal adenomas (including GH and ACTH tumors) may directly hypersecrete PRL. Pituitary masses, including clinically nonfunctioning pituitary tumors, may compress the pituitary stalk to cause hyperprolactinemia.

Drug-induced inhibition or disruption of dopaminergic receptor function is a common cause of hyperprolactinemia (Table 2-8). Thus, antipsychotics and antidepressants are a relatively common cause of mild hyperprolactinemia. Methyldopa inhibits dopamine synthesis and verapamil blocks dopamine release, also leading to hyperprolactinemia. Hormonal agents that induce PRL include estrogens, antiandrogens, and TRH.

Presentation and Diagnosis

Amenorrhea, galactorrhea, and infertility are the hallmarks of hyperprolactinemia in women. If hyperprolactinemia develops prior to menarche, primary amenorrhea results. More commonly, hyperprolactinemia develops later in life and leads to oligomenorrhea and, ultimately, to amenorrhea. If hyperprolactinemia is sustained, vertebral bone mineral density can be reduced compared with age-matched controls, particularly when associated with pronounced hypoestrogenemia. Galactorrhea is present in up to 80% of hyperprolactinemic women. Although usually bilateral and spontaneous, it may be unilateral or only expressed manually. Patients may also complain of decreased libido, weight gain, and mild Hirsutism

In men with hyperprolactinemia, diminished libido, infertility, and visual loss (from optic nerve compression) are the usual presenting symptoms. Gonadotropin suppression leads to reduced testosterone, impotence, and oligospermia. True galactorrhea is uncommon in men with hyperprolactinemia. If the disorder is longstanding, secondary effects of hypogonadism are evident, including osteopenia, reduced muscle mass,and decreased beard growth.

The diagnosis of idiopathic hyperprolactinemia is made by exclusion of known causes of hyperprolactinemia in the setting of a normal pituitary MRI. Some of these patients may harbor small microadenomas below MRI sensitivity (~2 mm).

Galactorrhea

Galactorrhea, the inappropriate discharge of milkcontaining fluid from the breast, is considered abnormal if it persists for longer than 6 months after childbirth or discontinuation of breast-feeding. Postpartum galactorrhea associated with amenorrhea is a self-limiting disorder usually associated with moderately elevated PRL levels. Galactorrhea may occur spontaneously, or it may be elicited by nipple pressure. In both men and women, galactorrhea may vary in color and consistency (transparent, milky, or bloody) and arise either unilaterally or bilaterally. Mammography or ultrasound is indicated for bloody discharges (particularly from a single duct), which may be caused by breast cancer. Galactorrhea is commonly associated with hyperprolactinemia caused by any of the conditions listed in Table 2-8. Acromegaly is associated with galactorrhea in about one-third of patients.Treatment of galactorrhea usually involves managing the underlying disorder [e.g., replacing L-thyroxine (T4) for hypothyroidism; discontinuing a medication; treating prolactinoma].

Laboratory Investigation

Basal, fasting morning PRL levels (normally <20 µg/L) should be measured to assess hypersecretion. Because hormone secretion is pulsatile and levels vary widely in some individuals with hyperprolactinemia, it may be necessary to measure levels on several different occasions when clinical suspicion is high. Both false-positive and false-negative results may be encountered. In patients with markedly elevated PRL levels (>1000 µg/L), results may be falsely lowered because of assay artifacts; sample dilution is required to measure these high values accurately. Falsely elevated values may be caused by aggregated forms of circulating PRL, which are biologically inactive (macroprolactinemia). Hypothyroidism should be excluded by measuring TSH and T4 levels.

Treatment: Hyperprolactinemia Treatment of hyperprolactinemia depends on the cause of elevated PRL levels. Regardless of the etiology, however, treatment should be aimed at normalizing PRL levels to alleviate suppressive effects on gonadal function, halt galactorrhea,and preserve bone mineral density. Dopamine agonists are effective for many different causes of hyperprolactinemia. If the patient is taking a medication known to cause hyperprolactinemia, the drug should be withdrawn, if possible. For psychiatric patients who require neuroleptic agents, dose titration or the addition of a dopamine agonist can help restore normoprolactinemia and alleviate reproductive symptoms. However, dopamine agonists sometimes worsen the underlying psychiatric condition, especially at high doses. Hyperprolactinemia usually resolves after adequate thyroid hormone replacement in hypothyroid patients or after renal transplantation in patients undergoing dialysis. Resection of hypothalamic or sellar mass lesions can reverse hyperprolactinemia caused by reduced dopamine tone. Granulomatous infiltrates occasionally respond to glucocorticoid administration. In patients with irreversible hypothalamic damage, no treatment may be warranted. In up to 30% of patients with hyperprolactinemia—with or without a visible pituitary microadenoma—the condition resolves spontaneously

Prolactinoma

Etiology and Prevalence

Tumors arising from lactotrope cells account for about half of all functioning pituitary tumors, with an annual incidence of ~3/100,000 population. Mixed tumors secreting combinations of GH and PRL,ACTH and PRL, and, rarely, TSH and PRL are also seen. These plurihormonal tumors are usually recognized by immunohistochemistry, often without apparent clinical manifestations from the production of additional hormones. Microadenomas are classified as <1 cm in diameter and do not usually invade the parasellar region. Macroadenomas are >1 cm in diameter and may be locally invasive and impinge on adjacent structures.The female/male ratio for microprolactinomas is 20:1, whereas the gender ratio is near 1:1 for macroadenomas.Tumor size generally correlates directly with PRL concentrations; values >100 µg/L are usually associated with macroadenomas. Men tend to present with larger tumors than women, possibly because the features of hypogonadism are less readily evident. PRL levels remain stable in most patients, reflecting the slow growth of these tumors.About 5% of microadenomas progress in the long term to macroadenomas. Hyperprolactinemia resolves spontaneously in about 30% of microadenomas.

Presentation and Diagnosis

Women usually present with amenorrhea, infertility, and galactorrhea. If the tumor extends outside of the sella, visual field defects or other mass effects may be seen. Men often present with impotence, loss of libido, infertility, or signs of central CNS compression including headaches and visual defects. Assuming that physiologic and medication-induced causes of hyperprolactinemia are excluded. The diagnosis of prolactinoma is likely with a PRL level >100 µg/L. PRL levels <100 µg/L may be caused by microadenomas, other sellar lesions that decrease dopamine inhibition, or nonneoplastic causes of hyperprolactinemia. For this reason, an MRI should be performed in all patients with hyperprolactinemia. It is important to remember that hyperprolactinemia caused secondarily by the mass effects of nonlactotrope lesions is also corrected by treatment with dopamine agonists, despite failure to shrink the underlying mass. Consequently, PRL suppression by dopamine agonists does not necessarily indicate that the lesion is a prolactinoma.

Treatment:

Polactinoma

As microadenomas rarely progress to become macroadenomas, no treatment may be needed if fertility is not desired. Estrogen replacement is indicated to prevent bone loss and other consequences of hypoestrogenemia and does not appear to increase the risk of tumor enlargement. These patients should be monitored by regular serial PRL and MRI measurements.

For symptomatic microadenomas, therapeutic goals include control of hyperprolactinemia, reduction of tumor size, restoration of menses and fertility, and resolution of galactorrhea. Dopamine agonist doses should be titrated to achieve maximal PRL suppression and restoration of reproductive function. A normalized PRL level does not ensure reduced tumor size. However, tumor shrinkage is not usually seen in those who do not respond with lowered PRL levels. For macroadenomas, formal visual field testing should be performed before initiating dopamine agonists. MRI and visual fields should be assessed at 6- to 12-month intervals until the mass shrinks and annually thereafter until maximum size reduction has occurred.

Medical Oral dopamine agonists (cabergoline or bromocriptine) are the mainstay of therapy for patients with micro- or macroprolactinomas. Dopamine agonists suppress PRL secretion and synthesis as well as lactotrope cell proliferation. About 20% of patients are resistant to dopaminergic treatment; these adenomas may exhibit decreased D2 dopamine receptor numbers or a postreceptor defect. D2 receptor gene mutations in the pituitary have not been reported.

Cabergoline An ergoline derivative, cabergoline is a long-acting dopamine agonist with high D2 receptor affinity. The drug effectively suppresses PRL for >14 days after a single oral dose and induces prolactinoma shrinkage in most patients. Cabergoline (0.5 to 1.0 mg twice weekly) achieves normoprolactinemia and resumption of normal gonadal function in ~80% of patients with microadenomas; galactorrhea improves or resolves in 90% of patients. Cabergoline normalizes

PRL and shrinks ~70% of macroprolactinomas. Mass effect symptoms, including headaches and visual disorders, usually improve dramatically within days after cabergoline initiation; improvement of sexual function requires several weeks of treatment but may occur before complete normalization of prolactin levels. After initial control of PRL levels has been achieved, cabergoline should be reduced to the lowest effective maintenance dose. In ~5% of treated patients, hyperprolactinemia may resolve and not recur when dopamine agonists are discontinued after long-term treatment. Cabergoline may also be effective in patients resistant to bromocriptine. Adverse effects and drug intolerance are encountered less commonly than with bromocriptine.

Bromocriptine The ergot alkaloid bromocriptine mesylate is a dopamine receptor agonist that suppresses prolactin secretion. Because it is short-acting, the drug is preferred when pregnancy is desired. In patients with microadenomas, bromocriptine rapidly lowers serum prolactin levels to normal in up to 70% of patients, decreases tumor size, and restores gonadal function. In patients with macroadenomas, prolactin levels are also normalized in 70% of patients and tumor mass shrinkage (≥50%) is achieved in up to 40% of patients.

Therapy is initiated by administering a low bromocriptine dose (0.625–1.25 mg) at bedtime with a snack, followed by gradually increasing the dose. Most patients are successfully controlled with a daily dose of <7.5 mg (2.5 mg tid).

Other Dopamine Agonists:  These include pergolide mesylate, an ergot derivative with dopaminergic properties; lisuride, an ergot derivative; and quinagolide (CV 205-502, Norprolac), a nonergot oral dopamine agonist with specific D2 receptor activity.

Side Effects   Side effects of dopamine agonists include constipation, nasal stuffiness, dry mouth, nightmares, insomnia, and vertigo; decreasing the dose usually alleviates these problems. Nausea, vomiting, and postural hypotension with faintness may occur in ~25% of patients after the initial dose. These symptoms may persist in some patients. In general, fewer side effects are reported with cabergoline. For the approximately 15% of patients who are intolerant of oral bromocriptine, cabergoline may be better tolerated. Intravaginal administration of bromocriptine is often efficacious in patients with intractable gastrointestinal side effects. Auditory hallucinations, delusions, and mood swings have been reported in up to 5% of patients and may be due to the dopamine agonist properties or to the lysergic acid derivative of the compounds. Rare reports of leukopenia, thrombocytopenia, pleural fibrosis, cardiac arrhythmias,and hepatitis have been described.

Surgery   Indications for surgical adenoma debulking include dopamine resistance or intolerance, or the presence of an invasive macroadenoma with compromised vision that fails to improve after drug treatment. Initial PRL normalization is achieved in about 70% of microprolactinomas after surgical resection, but only 30% of macroadenomas can be successfully resected. Follow-up studies have shown that hyperprolactinemia recurs in up to 20% of patients within the first year after surgery; long-term recurrence rates exceed 50% for macroadenomas. Radiotherapy for prolactinomas is reserved for patients with aggressive tumors that do not respond to maximally tolerated dopamine agonists and/or surgery.

Pregnancy: The pituitary increases in size during pregnancy, reflecting the stimulatory effects of estrogen and perhaps other growth factors. About 5% of microadenomas significantly increase in size, but 15–30% of macroadenomas grow during pregnancy. Bromocriptine has been used for more than 30 years to restore fertility in women with hyperprolactinemia, without evidence of teratogenic effects. Nonetheless, most authorities recommend strategies to minimize fetal exposure to the drug. For women taking bromocriptine who desire pregnancy, mechanical contraception should be used through three regular menstrual cycles to allow for conception timing. When pregnancy is confirmed, bromocriptine should be discontinued and PRL levels followed serially, especially if headaches or visual symptoms occur. For women harboring macroadenomas, regular visual field testing is recommended, and the drug should be reinstituted if tumor growth is apparent. Although pituitary MRI may be safe during pregnancy, this procedure should be reserved for symptomatic patients with severe headache and/or visual field defects. Surgical decompression may be indicated if vision is threatened. Although comprehensive data support the efficacy and relative safety of bromocriptine-facilitated fertility, patients should be advised of potential unknown deleterious effects and the risk of tumor growth during pregnancy. As cabergoline is long-acting with a high D2- receptor affinity, it is not approved for use in women when fertility is desired.