Prolactinoma, the most common functional pituitary tumor, accounts for 25%–40% of all pituitary adenomas and is typically benign. Clinically, 30%–75% of women with amenorrhea and galactorrhea have prolactinomas, while approximately 8% of men with erectile dysfunction and 5% of men with infertility exhibit hyperprolactinemia. The annual incidence of prolactinoma is estimated to be 3–7 per 100,000 people, with women being significantly more affected than men. Among women, microadenomas constitute 2/3 of cases, while macroadenomas account for 1/3; postmenopausal women are more likely to develop macroadenomas, and nearly all cases in men involve macroadenomas.
Etiology and Pathogenesis
Prolactinomas can be divided into familial and sporadic cases, with sporadic cases being more common. The development of sporadic prolactinomas may be related to dysregulation of prolactin-releasing factors (PRF) and prolactin-inhibiting factors (PIF). Dysregulated prolactin cell function may also play a role in the pathogenesis of prolactinomas. In addition, estrogen promotes the proliferation of prolactin-secreting cells as well as the synthesis and secretion of prolactin. Pregnancy can enlarge existing prolactinomas and contribute to their development. Familial prolactinomas are associated with gene mutations, such as those of MEN1 (multiple endocrine neoplasia type 1), PRKAR1A (Carney complex), CDKN1B (multiple endocrine neoplasia type 4), and AIP (familial isolated pituitary adenoma).
Clinical Manifestations
The clinical manifestations of prolactinomas mainly include symptoms associated with hyperprolactinemia and tumor mass effects.
In female patients, common symptoms include amenorrhea and galactorrhea. Amenorrhea occurs due to excessive prolactin’s suppression of gonadotropin-releasing hormone (GnRH) from the hypothalamus and subsequent inhibition of gonadotropic hormones from the pituitary. Galactorrhea results from prolactin's direct action on the mammary glands. Some patients present with oligomenorrhea. In patients who still menstruate, luteal phase abnormalities may cause infertility. Postmenopausal reductions in estrogen can decrease bone density, thereby increasing the risk of fractures.
In male patients, the onset is often insidious, characterized by decreased libido, erectile dysfunction, reduced sperm production, infertility, gynecomastia, and reduced secondary sexual characteristics. Galactorrhea occurs in rare cases. Male patients are often diagnosed late, commonly with macroadenomas accompanied by compression symptoms, such as headache and visual field loss. Severe cases may feature signs of increased intracranial pressure, headache, and vomiting. Compression of normal pituitary tissue may lead to hypofunction of the thyroid gland, adrenal glands, and gonads. In rare cases, prolactinomas occur in children, manifesting as tumor mass effects or delayed puberty.
Diagnosis
Amenorrhea and galactorrhea are typical clinical features in female patients with prolactinomas, although some patients may remain asymptomatic. Diagnosis of prolactinoma involves both qualitative and localization assessments.
Qualitative Diagnosis
This step aims to confirm the presence of hyperprolactinemia. Normal baseline serum prolactin (PRL) concentrations are generally less than 20 μg/L. When PRL levels are between 20 and 200 μg/L, a prolactinoma should be suspected; levels above 200 μg/L strongly suggest prolactinoma. It is essential to account for other factors, such as physiological conditions or medications, which may also elevate PRL levels. Differential diagnoses should be carefully performed to rule out these causes.
False-positive and false-negative results may occur when measuring baseline PRL concentrations in blood samples. In patients with significantly elevated PRL levels (e.g., >1,000 μg/L) but no clinical symptoms, macroprolactinemia must be excluded. Macroprolactinemia results from aggregation of PRL into dimers or multimers, or complexes formed through binding with antibodies. Although biologically less active, these complexes can interfere with immunoassays. In such cases, polyethylene glycol (PEG) precipitation can be used to treat samples, followed by retesting for PRL concentrations.
Additionally, in cases of pituitary macroadenomas that secrete very high PRL levels, the hook effect may lead to falsely low PRL measurements. The hook effect occurs when excessive concentrations of free PRL saturate capture and detection antibodies in immunoassays, thereby preventing the formation of the antibody-antigen-antibody sandwich complex, which results in underestimated PRL levels. Dilution of serum samples (e.g., 1:100) prior to testing can mitigate this effect.
Localization Diagnosis
This step seeks to determine the cause of elevated PRL levels. MRI scans of the hypothalamic-pituitary region facilitate localization diagnosis and allow evaluation of tumor compression effects on surrounding tissues. If no apparent cause is identified, a diagnosis of idiopathic hyperprolactinemia may be made, necessitating regular follow-ups with repeated PRL testing and sellar MRI scans.
Differential Diagnosis
Physiological Causes
The synthesis and secretion of prolactin (PRL) under physiological conditions are primarily regulated by hypothalamic dopamine inhibition and are stimulated by thyrotropin-releasing hormone (TRH) and estrogen. Physiologically, PRL plays a positive role in promoting mammary gland development during pregnancy and lactation post-delivery. Factors such as eating, exercise, and sleep may increase serum PRL levels. Conditions like pregnancy, lactation, and stress can also lead to elevated PRL levels, though physiological PRL elevation generally does not exceed 100 μg/L.
Pathological Causes
Pathological factors causing elevated PRL levels include hypothalamic-pituitary stalk damage (e.g., craniopharyngiomas, meningiomas, granulomatous infiltrative diseases, Rathke’s cleft cysts, or other space-occupying lesions), trauma, or radiation injury. Pituitary disorders (e.g., compression from a macroadenoma, lymphocytic hypophysitis, or acromegaly) and systemic diseases (e.g., chronic kidney failure, primary hypothyroidism, or liver cirrhosis) can also contribute to elevated PRL levels.
Drug-Induced Causes
Medications that can cause elevated PRL levels include neuropeptides, drugs targeting dopamine pathways (e.g., chlorpromazine, metoclopramide, perphenazine, methyl-dopa), antihypertensive drugs (e.g., labetalol, reserpine, verapamil), H2 receptor blockers (e.g., cimetidine, ranitidine), oral contraceptives, antipsychotic drugs (e.g., chlorpromazine, risperidone, promethazine, perphenazine), opioids, opioid receptor agonists (e.g., heroin, methadone, morphine), and antidepressants (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors). Identifying drug-induced hyperprolactinemia may involve temporarily discontinuing or replacing the suspected drug and rechecking serum PRL levels several days later.
Treatment
Microadenomas without clinical symptoms do not require treatment, but regular follow-up should monitor clinical manifestations, PRL levels, and tumor size. Treatment indications include macroadenomas, progressively enlarging microadenomas, infertility, galactorrhea, gynecomastia, testosterone insufficiency, oligomenorrhea or amenorrhea, as well as significant clinical symptoms like acne or hirsutism. Treatment primarily involves medication and surgery, while radiotherapy is rarely used as a third-line choice.
Pharmacological Therapy
Dopamine receptor agonists (bromocriptine and cabergoline) are the first-line treatment options for most prolactinomas. These medications effectively reduce PRL secretion from the tumor and decrease tumor size. Bromocriptine is initiated at a low dose, typically 1.25 mg at bedtime, and can be gradually increased to a therapeutic dose over approximately one week if tolerated. Dosage adjustments are guided by serum PRL levels, aiming for the lowest effective dose to achieve optimal results, with a daily maximum not exceeding 20 mg.
Cabergoline is also an effective initial treatment option with higher tolerability and fewer side effects compared to bromocriptine. The starting dose of cabergoline is 0.25 mg twice per week or 0.5 mg once per week, administered during dinner or before bedtime to minimize side effects such as nausea or drowsiness.
Dopamine receptor agonists achieve favorable outcomes for 70%–90% of patients, with some even achieving complete remission. Patients who maintain normal PRL levels on low-dose therapy and show a near-complete tumor resolution on MRI may consider discontinuing the medication after two years of treatment. If PRL levels rise upon drug withdrawal, long-term medication may be necessary. For patients with macroadenomas, even when PRL levels normalize with medication, surgical intervention may be evaluated if significant tumor shrinkage does not occur.
Surgical Treatment
Surgical indications include patients with refractory disease or suboptimal outcomes from pharmacological treatment, those unable to tolerate side effects, patients who refuse medication, those with giant pituitary adenomas causing significant visual impairment or visual field defects, invasive tumors accompanied by cerebrospinal fluid (CSF) leaks, and recurrent patients seeking surgery. Postoperative follow-up should include regular reassessment of pituitary hormone levels and imaging to evaluate tumor resection effectiveness. Follow-up intervals of six months to one year are recommended. For patients with residual tumors after surgery, additional pharmacological or radiotherapy options may be required.
Management During Pregnancy
Dopamine receptor agonists are considered relatively safe for fetal development. The incidence of complications such as spontaneous abortion, intrauterine fetal demise, and fetal malformation in patients treated with these agents is comparable to that of the general pregnant population. If pregnancy occurs during treatment, the medication is typically discontinued. In specific cases, patients requiring luteal function support may continue the medication until the 12th week of pregnancy. For patients with macroadenomas, conception is more advisable after tumor size has been reduced with dopamine receptor agonist therapy. During pregnancy, continuous medication and close monitoring may be necessary, and pregnancy termination could be considered if needed. Normal pregnant individuals typically exhibit rising PRL levels, but these rarely exceed 300–400 μg/L.