Hyperprolactinemia

Etiology

Physiological, pathological, or pharmacological conditions can cause hyperprolactinemia.[2][3] Any condition that affects secretion and clearance of prolactin will cause hyperprolactinemia. Physiological hyperprolactinemia is transient and adaptive; whereas, pathological and pharmacological hyperprolactinemia are symptomatic with unwanted long-term consequences.

Physiological Causes

• Pregnancy
• Nipple stimulation and lactation
• Exercise
• Stress (hypoglycemia, myocardial infarction, surgery)
• Seizures
• Sleep
• Neonatal period
• Sexual intercourse

During pregnancy, the pituitary gland increases in size, also increasing the size of lactotrophs. The gland may double in size during pregnancy.[4] Serum prolactin increases throughout the pregnancy and reaches a peak at delivery.[5] It is probably because of increased serum estradiol concentration. After delivery, estradiol secretion decreases and the serum prolactin becomes normal with breastfeeding. In pregnancy, serum prolactin usually becomes 10 times normal with a range of 35 to 600 ng/ml at term[5]; prolactin in amniotic fluid is 100 times more compared to levels in maternal and fetal blood.[5]

Nipple stimulation increases prolactin secretion which is mediated by neural pathways during breastfeeding. Prolactin secretion increases transiently with suckling reaching up to 300 ng/ml above baseline. The levels increase to 10 ng/ml above baseline in the first week and continue to rise for several months after delivery.[5]

Pathological Causes 

Pituitary Disease

• Prolactinoma 
• Acromegaly
• Cushing disease
• Macroadenoma (compressive)
• Plurihormonal adenoma
• Lymphocytic hypophysitis
• Parasellar mass
• Macroprolactinemia 

Prolactinoma is a benign tumor of lactotrophs. It accounts for up to 40% of all pituitary adenomas. It can present with any level of prolactin elevation from mild elevation to 50,000 ng/ml. In contrast, prolactin elevation from other causes rarely exceeds 200 ng/ml.[6] 

Hypothalamic Disease - Stalk Damage

• Tumors like craniopharyngioma, suprasellar pituitary mass extension, meningioma, dysgerminoma, hypothalamic metastases
• Granulomas (sarcoidosis, tuberculosis)
• Infiltrative disease (histiocytosis disease)
• Rathke's cyst
• Pituitary stalk transection (Sellar surgery, head trauma)
• Cranial Irradiation

Pharmacological Causes

• Estrogen therapy
• Thyrotropin-releasing hormone
• Antipsychotic/dopamine receptor blocking agents:  risperidone, haloperidol, fluphenazine, among others
• Antiemetic/dopamine receptor blocking agents: metoclopramide, domperidone, prochlorperazine
• Tricyclic antidepressant, selective serotonin receptor inhibitor: amitriptyline, clomipramine, fluoxetine
• Anticonvulsant: Phenytoin
• Antihypertensive: Verapamil, methyldopa, labetalol
• H2 Antihistamines: Cimetidine, ranitidine
• Opioid analgesics: Methadone, morphine, apomorphine, heroin
• Cholinergic agent: Physostigmine

Systemic Disorder

• Chronic renal failure
• Polycystic ovarian disease
• Liver cirrhosis
• Pseudocyesis
• Reflex causes: Chest wall trauma, surgery, herpes zoster
• Primary hypothyroidism

Genetic

Inactivating prolactin receptor mutation[7]

Ectopic Production

Bronchogenic carcinoma and hypernephromas[8]

Idiopathic

Epidemiology

Hyperprolactinemia occurs in less than 1% of the general population and 5% to 14% of patients presenting with secondary amenorrhea.[9] The most common type is a prolactin-secreting tumor (prolactinoma), accounting for up to 40% of all clinically recognized pituitary adenomas.[10] The mean prevalence of prolactinoma is estimated to be around 30 per 100,000 in women and 10 per 100,000 in men; with peak prevalence in women aged 25 to 34 years.[10] Clinical manifestations in women are more obvious and present earlier than in men.

Pathophysiology

Prolactin is responsible for milk production during pregnancy and lactation. Along with estrogen, progesterone, possibly insulin-like growth factor-1 (IGF-1), and placental hormones, prolactin stimulates breast alveolar element proliferation in pregnancy.[11] Lactation is suppressed during pregnancy due to the high level of estrogen. Active lactation occurs because of decreased estrogen and progesterone levels and an increase in prolactin levels after delivery. During pregnancy, estrogen has a stimulatory effect on the proliferation of lactotrophs, thereby secreting prolactin. Lactation results in amenorrhea and secondary infertility because of prolactin-mediated suppression of gonadotropins.

The hypothalamic control of prolactin secretion is mostly inhibitory by prolactin inhibiting factor and dopamine is the main inhibitor that acts via type 2 dopamine (D2) receptor[12] located on lactotrophs. Thyrotropin-releasing hormone (TRH) is a potent prolactin-releasing factor. There is an elevated response to both thyroid-stimulating hormone (TSH) and prolactin in primary hypothyroidism. Other prolactin-releasing factors are a vasoactive intestinal peptide (VIP), endothelial growth factor, and dopamine antagonists.

Drugs like neuroleptics elevate prolactin because of their dopamine receptor antagonist property, and atypical antipsychotics act by antagonizing both secretions of serotonin and dopamine.

Pituitary or sellar tumors inhibit dopamine-induced hyperprolactinemia because of pressure on the pituitary stalk or interruption of the vascular connections between the pituitary and hypothalamus.

Prolactin causes inhibition of gonadotropin-releasing hormone (GnRH) leading to inhibition of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion.[13] Symptoms of hypogonadism depend upon the magnitude of prolactin elevation. Serum prolactin greater than 100 ng/dl will have overt hypogonadism with the presentation of amenorrhea, hot flashes, and vaginal dryness. Serum prolactin between 50 to 100 ng/dl may cause amenorrhea or oligomenorrhea and serum prolactin 20 to 50 ng/dl may only shorten the luteal phase because of insufficient progesterone secretion.[14][15]

History and Physical

The symptoms of hyperprolactinemia can be due to a direct effect of excess prolactin or the compressive effect of the structural lesion. Hyperprolactinemia causes typical symptoms in premenopausal women and men but not in postmenopausal women.  Reproductive dysfunction and galactorrhea are the hallmarks of hyperprolactinemia. Children and adolescent may have growth arrest, pubertal delay, and primary amenorrhea.

Sign and Symptoms Caused by High Prolactin

Women

• Menstrual disturbance: Oligomenorrhea, amenorrhea, menorrhagia or infertility 
• Galactorrhea: Most women who have hyperprolactinemia may not have galactorrhea
• Low bone mass

Men

• Hypogonadotropic hypogonadism: Decreased libido, impotence, infertility, oligospermia or gynecomastia [16]
• Erectile dysfunction
• Galactorrhea: Rare
• Low bone mass

Sign and Symptoms Caused by Mass Effect 

• Headache
• Visual field defect
• External ophthalmoplegic

Evaluation

The clinician starts the evaluation of suspected hyperprolactinemia with serum prolactin level, ideally with a fasting mid-morning sample. An increase in prolactin secretion is associated with sleep. However, it is not part of the circadian rhythm. The peak level of prolactin is usually between 4 AM and 7 AM. The ideal time to measure prolactin is during the midmorning hours and in the fasting state. Food has a minimal effect on the serum concentration of prolactin. So, fasting is not always an essential condition to measure serum prolactin levels except when there is a mild elevation on the initial value.

If serum prolactin is elevated, the next step is to determine the cause in the following order:

1. Exclusion of physiological causes
2. Exclusion of pharmacological causes
3. Neuroradiological imaging of the hypothalamic-pituitary region.

An extensive history and physical examination are important to exclude causes of hyperprolactinemia and inquire about signs and symptoms of hyperprolactinemia.

Laboratory Tests

Following tests are generally needed depending upon gender, age, and clinical presentation:

• Serum prolactin
• Thyroid function test
• Renal function test
• Insulin-like growth factor-1 (IGF-1)
• Adrenocorticotrophic hormone (ACTH)
• Luteinizing hormone (LH)
• Follicle-stimulating hormone (FSH)
• Testosterone/estradiol
• Pregnancy test

Imaging Test

Magnetic resonance imaging (MRI) of the pituitary with contrast is the preferred imaging study.

Visual field testing should be done in case of macroadenoma and tumor that is adjacent to/or compressing to optic chiasma.

Pitfalls in Diagnosis

Hook Effect: It is because of an artifact in the immunoradiometric assay giving a falsely low concentration of prolactin. Hook effect should be kept in mind with large pituitary adenoma with mild or moderate elevation in prolactin. When there is very high serum prolactin concentration, both the capture and tracer antibodies used in immunoradiometric assays become saturated, preventing the binding of the two, to create a sandwich. Then the test result will read low. This effect can be overcome by repeating the test using a 1:100 dilution of serum. This artifact is uncommon.

Macroprolactin represents large circulating aggregates of prolactin and antibodies of size about 150 kD; whereas, native prolactin in serum is 23 kD.[17] These complexes are detectable in test assay but are biologically inactive. They can be misdiagnosed as prolactin hypersecretion. [18]. Clinicians can avoid this misdiagnosis by precipitating macroprolactin by pretreating with polyethylene glycol before measuring prolactin.

Treatment / Management

Treatment of hyperprolactinemia depends upon the cause. Once the physiological cause of hyperprolactinemia is excluded, we should look for other possible systemic causes and address them for the symptomatic patient. Here, we are discussing treatment options based on etiology.

Etiology Type

Hypothyroidism

The patient should be treated with thyroid replacement therapy and confirm the normalization of prolactin level after treatment.

Drug-Induced Hyperprolactinemia

Treatment is only necessary if patients develop hypogonadism, osteoporosis, or troublesome galactorrhea.[19] If hyperprolactinemia is suspected because of drugs, it should be discontinued temporarily, if possible, to see if prolactin level normalizes. If medication cannot be discontinued, especially antipsychotics, it should be changed to a different antipsychotics that do not increase prolactin, e.g., quetiapine. If that is not possible, the addition of dopamine agonists should be considered. These changes should be made in consultation with a psychiatrist. The addition of estradiol in women and testosterone in men can be considered for hypogonadism and low bone mass. If prolactin level does not normalize after stopping meds or if discontinuation of meds is not possible, pituitary MRI should be done. 

Hypothalamic Disease: Stalk Damage

Removal of the cause should be the first choice; if not, hyperprolactinemia should be treated with the dopamine agonist.

Idiopathic Hyperprolactinemia

Idiopathic hyperprolactinemia is treated with the dopamine agonist. However, these patients are relatively resistant to dopamine agonists. Dosage can be adjusted to keep the lowest possible dose with the normal level of prolactin. If the patient attains normal prolactin on the lowest dose of a dopamine agonist for 2 years, the drug can be discontinued as a trial.

Macroprolactinemia

It does not require treatment.

Prolactinoma

It has medical, surgical, and radiation treatment.

Medical Treatment

Endocrine society guideline recommends against treatment with a dopamine agonist for asymptomatic microadenoma but recommends dopamine agonist therapy to decrease prolactin levels, tumor size, and normalize gonadal function for symptomatic patients with microadenomas or macroadenomas. Cabergoline is preferred to other dopamine agonists due to higher efficacy in normalizing prolactin levels and tumor shrinkage

Cabergoline and bromocriptine are commonly used dopamine agonists. Quinagolide is not available in the United States but used in some other countries. Pergolide had been withdrawn from the United States because of concern of valvular heart disease. Cabergoline is the first choice because of its efficacy and fewer side effects.[20] Bromocriptine is preferred during pregnancy because of more favorable data than cabergoline.[10] Cabergoline has a long duration of action than bromocriptine and is administered once or twice a week. Bromocriptine is administered once daily. Common side effects are nausea, vomiting, nasal stiffness, digital vasospasm, depression, and postural hypotension. High doses of dopamine agonists are associated with a risk of heart valve regurgitation.[21](A1)

Dopamine agonist therapy can be tapered and discontinued after 2 years of continuous therapy if serum prolactin level is normal and no adenoma is visible in magnetic resonance imaging (MRI).

Surgery/Radiation Treatment

Most of the prolactinomas are treated with medical therapy only. Surgery and radiotherapy are reserved for those who are resistant to medical therapy with the dopamine agonists. Endoscopic endonasal transsphenoidal surgery is the preferred surgical method. Prophylactic surgery is considered in women with large prolactinoma which potentially threatens vision during pregnancy.[22] Adjuvant radiation therapy should be considered for residual tumor. Gamma knife stereotactic radiosurgery is often effective in treating prolactinomas resistant to or intolerant of dopamine agonists.[23]

Differential Diagnosis

Possible causes of hyperprolactinemia have been mentioned in the etiology section. In clinical practice, it is important to exclude two important causes of hyperprolactinemia. They are hypothyroidism and the use of drugs that inhibit dopamine.

• Cirrhosis
• Dopamine antagonist medications
• Hypothalamic disease
• Idiopathic hyperprolactinemia
• Pituitary tumors
• Pregnancy
• Primary hypothyroidism
• Prolactinoma
• Renal failure

Prognosis

Most patients with micro prolactinomas have good prognosis and normalize prolactin levels with treatment. These patients can be managed with medical therapy for a prolonged period. The success of the pituitary surgery also depends upon the size of the tumor, the serum prolactin level, and the experience of the neurosurgeon. The success rate of pituitary surgery is related inversely to tumor size and prolactin levels.[24] Although micro prolactinoma surgery has a high success rate, the recurrence of hyperprolactinemia is relatively high[25] which is about 17% in patients initially considered cured. In the case of macroprolactinoma, around 50% of the patients are in remission after the surgery. In the case of invasive tumors, complete resection may not be possible, and prolactin normalizes in only 32% of patients with a recurrence rate of about 19%.

Complications

• Mass effect leading to visual deficits, cranial nerve palsies and pituitary apoplexy
• Infertility
• Osteoporosis
• Blindness
• Complications related to cerebrospinal fluid (CSF) leak and hypopituitarism
• Hypogonadism