Hyperprolactinemia

HYPERPROLACTINEMIA

• Prolactin(PRL) is a single-chain peptide hormone secreted from lactotroph cells of the anterior pituitary gland.
• Prolactin exerts its main physiological role by promoting milk secretion of mammary glands during the postpartum period.

PROLACTIN SERUM ISOFORMS

Prolactin exists in three major circulating molecular isoforms.

• Monomeric or little PRL (molecular weight [MW] 23 kDa) - the major circulatory isoform (80–95%) of the total prolactin in healthy subjects and those with prolactinomas.
• Dimeric or big PRL (MW 45–60 kDa)
• Multimeric / big-big PRL or macro prolactin ( MW> 150 kDa)

Dimeric and Multimeric correspond to less than 10% of the total PRL (1).

PROLACTIN SECRETION

• Prolactin secretion is pulsatile and follows a circadian rhythm with the highest plasma concentration reached during sleep, and the lowest observed in the morning about 2–3h after waking up (2).

Fig. 1. Prolactin secretion(3).

NOTE -The predominant regulatory signal is the inhibition of prolactin secretion by the neurotransmitter, dopamine, from neurons in the hypothalamus (2).

HYPERPROLACTINEMIA

• Hyperprolactinemia is defined as the presence of abnormally high levels of prolactin in the blood above normal levels 0f 10–28 mg/L in women and 5–10 mg/L in men. 

PREVALENCE

• The prevalence of hyperprolactinemia ranges from 0.4% in an unselected adult population to as high as 9-17% in women with reproductive diseases.

CLINICAL SIGNS AND SYMPTOMS

• It is present in 10% to 25% of women with secondary amenorrhea or oligomenorrhea, in  30% of women with galactorrhea or infertility, and in 75% of those with both amenorrhea and galactorrhea (4).
• Hyperprolactinemia causes hypogonadotropic hypogonadism (HH) which is due to suppression of pulsatile GnRH thus causing anovulation, hypoestrogenism, and thus osteoporosis in perimenopausal women.
• When hyperprolactinemia is caused by a prolactinoma, additional pressure symptoms may include headaches, visual field defects, and abnormal pituitary function.
• Hyperprolactinemia in men may result in decreased libido, impotence, decreased sperm production, infertility, weight gain, and osteoporosis [4]

ETIOLOGY

Potential causes of hyperprolactinemia are listed in the table 1below .(5)

• The most frequent cause of persistent hyperprolactinemia is the presence of a micro- (<10 mm diameter) or macroprolactinoma(>10 mm). These pituitary tumors either may produce an excessive amount of prolactin or disrupt the normal delivery of dopamine from the hypothalamus to the pituitary. Raised prolactin levels can also be caused by pituitary adenomas consecrating prolactin hormone. (4)

• Idiopathic hyperprolactinemia accounts for 30–40% of cases where there is no obvious cause for the disorder and hypothalamic-pituitary anatomy is normal. (4) 
• Macroprolactinemia–It's a condition where more than 60% of circulating PRL is made up of macroprolactin, which has low biologic activity instead of the normal 5-10%. Hyperprolactinemia related to macroprolactin is due to its lower renal clearance, longer half-life, and its lower capability to activate hypothalamic dopaminergic tone, which negatively regulates the secretion of pituitary prolactin(6). These patients are usually asymptomatic and no medication or further tests are recommended.

DIAGNOSIS

• Exclude physiological and pharmacological causes on history.
• Evaluate signs of hypothyroidism, hypogonadism, renal failure, and visual field defects.
• Measure S. Prolactin. Also measure  TSH, free T4, and creatinine levels  to rule out primary hypothyroidism and renal failure (7)
• PRL levels greater than 500 mg/l are commonly seen in macroprolactinoma. PRL levels> 250mg/l usually indicate the presence of a prolactinoma; however, prolactinoma cannot be excluded in the presence of lower levels, and PRL levels >100mg/l are present in some patients with idiopathic hyperprolactinemia. Several drugs may cause PRL elevations above 200 mg/l (8 ).
• Hyperprolactinemia without an identified cause requires imaging of the hypothalamic-pituitary area. Although Computerized axial tomography  (CAT) scan can be used, a magnetic resonance image (MRI) with gadolinium enhancement provides the best visualization of the sellar area. (8)

Endocrine Society Clinical Practice Guidelines for Diagnosis (9).

• To establish the diagnosis of hyperprolactinemia, a single measurement of fasting serum prolactin is recommended(2-3 hrs after waking up ); a level above the upper limit of normal confirms the diagnosis as long as the serum sample was obtained without excessive venipuncture stress. Dynamic testing of prolactin secretion for the diagnosis of hyperprolactinemia is not recommended (1 )

• In patients with asymptomatic hyperprolactinemia, the screening of macroprolactinomas is recommended by polyethyleneglycol- (PEG-) precipitation method and the confirmative and qualitative examinations include gel chromatography, protein A/G column and 125I-PRL binding studies (6)(2|).

• When there is a discrepancy between a very large pituitary tumor and a mildly elevated prolactin level, do serial dilution of serum samples to eliminate an artifact that can occur with some immune radiometric assays leading to a falsely low prolactin value (“hook effect”) (1| ).

TREATMENT :

Endocrine Society Clinical Practice Guideline for Management of drug-induced hyperprolactinemia (9).

• Exclude medication use, renal failure, hypothyroidism, and para-sellar tumors in patients with symptomatic non-physiological hyperprolactinemia (1| ). 
• In a symptomatic patient with suspected drug-induced hyperprolactinemia,   discontinue the medication for 3 days or substitute an alternative drug, followed by remeasurement of serum prolactin(2|).
• If the drug cannot be discontinued and the onset of the hyperprolactinemia does not coincide with therapy initiation, do a pituitary magnetic resonance image (MRI) to differentiate between medication-induced hyperprolactinemia and symptomatic hyperprolactinemia due to a pituitary or hypothalamic mass (1|).

• Do not treat patients with symptomatic medication-induced hyperprolactinemia(2|).

• Use estrogen or testosterone in patients with long-term hypogonadism (hypogonadal symptoms or low bone mass) related to medication-induced hyperprolactinemia(2|ÅOOO).

TREATMENT OF PROLACTINOMAS – Dopamine agonists are the drug of choice.

Table 2. Comparison between Bromocriptine and Cabergoline in the treatment of hyperprolactinemia (10).

Endocrine Society Clinical Practice Guideline for Management of Prolactinoma (9).

• Use dopamine agonist therapy to lower prolactin levels, decrease tumor size, and restore gonadal function for patients harboring symptomatic prolactin-secreting microadenomas or macroadenomas( 1|).

• Cabergoline is preferred to other dopamine agonists because it has higher efficacy in normalizing prolactin levels, as well as a higher frequency of pituitary tumor shrinkage( 1|).

• Do not treat asymptomatic patients harboring micro prolactinomas with dopamine agonists(2|).
• Treat with dopamine agonist or oral contraceptive in patients with amenorrhea caused by a microadenoma(2|).
• With careful clinical and biochemical follow-up, therapy may be tapered and perhaps discontinued in patients who have been treated with dopamine agonists for at least 2 yr, who no longer have elevated serum prolactin, and who have no visible tumor remnant on MRI(2|).

Endocrine Society Clinical Practice Guideline for ManagementofResistant and malignant prolactinoma (9)

• For symptomatic patients who do not achieve normal prolactin levels or show a significant reduction in tumor size on standard doses of a dopamine agonist,  increase the dose to maximal tolerable doses before referring the patient for surgery ( 1|).
• Patients who are resistant to bromocriptine be switched to cabergoline( 1|).
• Trans-sphenoidal surgical resection of the prolactinoma remains the main option for patients who may refuse or do not respond to long-term pharmacological therapy (2|ÅOOO)
• Radiotherapy and/or estrogens are also reasonable choices if surgery fails. (2|)
• Chemotherapy with temozolomide is limited to resistant and malignant prolactinomas (2|)

Fig. 2 -Management of Hyperprolactinoma (3)
 

MANAGEMENT OF PROLACTINOMAS DURING PREGNANCY

During normal pregnancy, serum prolactin rises progressively to around 200-500 ng/mL.

The Endocrine Society clinical guidelines for the  diagnosis and treatment of hyperprolactinemia during pregnancy (9)

• Women with prolactinomas are instructed to discontinue dopamine agonist therapy as soon as they discover that they are pregnant(1|).
• . In selected patients with macroadenomas who became pregnant on dopaminergic therapy and who have not had prior surgical or radiation therapy, it may be prudent to continue dopaminergic therapy throughout the pregnancy, especially if the tumor is invasive or is abutting the optic chiasm(1|).

• In pregnant patients with prolactinomas, do not perform serum prolactin measurements during pregnancy (1| ).

• Pituitary MRI during pregnancy in patients with microadenomas or intrasellar macroadenomas is not recommended unless there is clinical evidence of tumor growth such as visual field compromise (1|).

• Women with macroprolactinomas who do not experience pituitary tumor shrinkage during dopamine agonist therapy or who cannot tolerate bromocriptine or cabergoline be counseled regarding the potential benefits of surgical resection before attempting pregnancy(1|).

• Visual field assessment followed by MRI without gadolinium in pregnant women with prolactinomas is recommended who experience severe headaches and/or visual field changes(1|).

• Bromocriptine therapy is recommended  in patients who experience symptomatic growth of a prolactinoma during pregnancy s(1|)

CONCLUSIONS

• Hyperprolactinemia is a common pituitary hormone disorder usually found in both sexes with abnormal sexual and/or reproductive function or with galactorrhea. 
• Asymptomatic patients with microprolactinemia do not require any treatment.
• Cabergoline is the drug of choice, however, in pregnancy, Bromocriptine is preferred.
• Persistent Hyperprolactinemia without an identified cause requires imaging of the hypothalamic-pituitary area. 
• Giant or aggressive prolactinomas may require multiple approaches involving surgery, radiotherapy, or both.