Overview

What is Prolactinoma?

Prolactinoma is a benign tumour originating from the pituitary gland that produces elevated amounts of the prolactin (PRL) hormone known as hyperprolactinemia, It is more common in women and accounts for an average of 40% of the majority of pituitary adenomas. Their classification depends on the tumour size; the tumours less than 10 mm are termed as microprolactinoma, and macroprolactinoma for those more than 10 mm. PRL can be altered by dopamine levels naturally, thus, hyperprolactinaemia can occur due to other pathological or physiological factors such as medications that disrupt dopamine levels.¹

Prolactinoma management

Patients with prolactinoma should be followed and monitored closely and get high medical supervision due to the several health feedbacks and symptoms caused by high levels of prolactin such as menstrual irregularities and infertility. Dopamine is the cornerstone treatment for these cases due to the natural inhibitory mechanism between prolactin and dopamine.²

Etiology

• There are several factors or conditions that induce hyperprolactinaemia, categorised into physiological, pharmacological, hypothalamic pituitary conditions, and other concerns¹
• The physiological factors include exercise, stress, pregnancy, intercourse, lactation, and sleep
• The most prevalent cause of hyperprolactinaemia is pharmacological, a drug that impacts dopamine and/or prolactin levels due to its mechanism of action or side effects. Examples of these drugs are antipsychotic and neuroleptic drugs. In addition to antidepressants, calcium channel blockers, antihypertensives, and antiemetics
• Hypothalamic pituitary conditions can induce prolactinoma through different mechanisms in terms of brainstem compression, dopamine neuron damage, or hormone co-secretion (Gonadotropin and prolactin hormone secretion)
• PRL levels can be elevated due to reduced clearance in patients with liver and kidney failure. 
• Most common endocrine disorders can cause hyperprolactinaemia. One of the most familiar endocrine disorders is primary hypothyroidism, which might be linked to mild hyperprolactinaemia, but this can be reversed through levothyroxine medication, which is the common treatment for hypothyroidism
• Women with polycystic ovary syndrome can show mild elevation in PRL levels

Pathogenesis 

Patients with macroadenomas aged less than 30 who have a family history of pituitary adenomas should be screened for MEN1 germline mutation (weak evidence).³ It is strongly not recommended to have somatic mutation screening on a routine basis (strong evidence). The molecular pathophysiologic mechanism of prolactinoma requires further investigation. Most of the cases are linked to somatic genetic events; 20% of prolactinomas demonstrate SF3B1R625H mutation, which is characterised by higher levels of prolactin and severe type. Germline mutations are uncommon with earlier onset.MEN1 mutations in macroprolactinomas are the most aggressive type and resistant to therapy, unlike macroprolactinomas, which exhibit lower severity. 

Clinical presentation

• Loss of libido and/or infertility
• Erectile dysfunction in men
• Menstrual irregularities in women

This is due to the fact that high levels of prolactin impairs the secretion of gonadotropin-releasing hormone (GnRH), which in turn causes the inhibition of luteinizing hormone (LH) and follicular-stimulating hormone (FSH) sex hormones.^1,3

The presence of a sellar mass (the area of the brain in which the pituitary gland is located) via imaging should be investigated and tested further as it could be prolactinoma.¹

Galactorrhea is a condition characterised by the spontaneous flow of milk due to an uncommon health reason such as medication, pregnancy and lactation. 

Diagnosis

Initial assessment

• Medication review should be done to exclude any drug-induced hyperprolactinemia³
• Renal impairment, primary hypothyroidism, and liver failure should be considered as causes of mild hyperprolactinemia
• Overall, pituitary tumour size and prolactin levels are strongly correlated to hyperprolactinemia and prolactinoma
• Pregnancy is excluded from the causes of hyperprolactinemia
• If the serum levels of prolactin are less than five times the upper limit of normal, the test should be repeated
• A blood sample should be taken through the cannula to measure prolactin levels in case stress is suspected to be a factor which induced hyperlactatemia temporarily

Biochemical evaluation

In patients with insufficient symptoms and fluctuating prolactin serum levels can result in false-negative or false-positive results. The sample of prolactin levels tested should be diluted in border to get a reliable value where the prolactin levels are above the upper detection limit. In macroprolactinaemia, where prolactin binds to protein forming in larger molecules, it can result in misleadingly higher prolactin levels. Thus, patients with moderate levels should be tested again for prolactin. Polyethylene glycol precipitation is used to distinguish prolactinemia from true hyperprolactinemia. Patients who show variable symptoms and prolactin serum levels and have biotin exposure or human anti-animal antibodies should be considered for false positive results. In patients with normal or slightly elevated prolactin levels and similar characteristics of hyperprolactinemia, in addition to the presence of giant adenoma should be retested after 1:100 dilution to exclude the phenomena of high-dose hook effect in which low concentration of hormone is detected falsely due to the full saturation of binding sites on the assay antibodies because of the high levels of hormone. 

Prolactin assay

This is assessed by immunoassays using stimulating and suppressing techniques to detect the function of the pituitary gland via the measurement of prolactin levels response. The reference intervals vary by assay and gender, with normal values being higher in women than men.

Magnetic Resonance Imaging (MRI)

MRI plays an essential role in hyperprolactinemia management through confirming the diagnosis of pituitary adenoma and thus saving time for treatment and follow-ups. It is also a significant diagnostic tool for monitoring the case post-surgery and evaluating the treatment response. Repeated scans depend on prolactin levels and adenoma size. Follow-up imaging should consider clinical symptoms in line prior scan findings, and biochemical markers, particularly in cases with treatment resistance. Gadolinium-based contrast helps with the initial diagnosis but should be conducted with attention in patients suffering from chronic kidney diseases. Moreover, MRI improved to detect the growth of the tumour and check surgical options. 

Treatment

Dopamine agonists

Dopamine agonists are the first line of treatment for prolactinoma. Some examples of these drugs are:

1. Cabergolin e: It is an ergot dopamine agonist with a long half-life, thus, it is administered orally once or twice a week. Cabergolin is highly recommended as first-line treatment due to its potential efficacy
2. Bromocriptine: It is the best dopamine agonist choice in cases of pregnancy and economic reasons. Side effects are nausea, vomiting, headache, and arterial postural hypertension
3. Quinagolide: It is a non-ergot dopamine agonist, used in bromocriptine refractory cases, as 50 % of patients are refractory to bromocriptine

Side effects

Side effects occur initially, which is why it is recommended to start with low doses then increase it gradually. 

• Neurological: Dizziness, confusion, headache
• Gastrointestinal: nausea, vomiting, reflux, constipation
• Cerebrospinal fluid fistula: Large adenomas cause complications as they allow the cerebrospinal fluid to leak out of the spaces surrounding the brain and spinal cord
• Cardiovascular: as postural hypertension
• Other: dry mouth and muscle cramps

Refractory prolactinoma

• Achieving the maximum tolerated dose
• Switching to cabergoline as an alternative to bromocriptine in refractory conditions (when the patient is not responding to bromocriptine anymore)
• Surgery option in patients who failed all the treatment regimens above
• In case surgery fails as well, consider the radiotherapy option

Other alternatives

Women with amenorrhea can be treated with estrogens instead. Prolactin levels should be checked every year. MRI repetition in cases of elevated PRL levels or presence of tumour growth and expansion signs. For women who are not planning for pregnancy, dopamine agonists cannot be considered. 

Surgery

The positive outcomes of surgery range from 75%-90% for microadenomas and 18-80% for macroadenomas. This success rate relies on several factors in terms of surgeon experience and skills, pre-surgery prolactin levels (>200μg/L lowers success rates) and tumour size. The dopamine agonists indicated prior to surgery can reduce the chances of remission. Postsurgical PRL levels, which are less than 20μg/L, suggest remission. Monitoring should be done every three months at the beginning, then annually for five years. 

Radiotherapy

When surgery fails to achieve a positive outcome, radiotherapy is the alternative option in these cases, particularly when the tumour is aggressive. Initial radiotherapy normalises prolactin levels in about 34.1% of patients. However, it puts them at risk for secondary brain tumours, optic nerve damage, and hypopituitarism.

Summary

• Prolactinoma is a benign tumour at the level of the pituitary gland that produces elevated amounts of the prolactin (PRL) hormone. It is more common in females
• There are several factors or conditions that induce hyperprolactinaemia categorised into physiological, pharmacological, hypothalamic pituitary conditions, and other concerns
• The molecular pathophysiologic mechanism of prolactinoma requires further investigation. Most of the cases are linked to somatic genetic events
• Clinical manifestations are Loss of libido and/or infertility, the presence of a sellar mass (the area of the brain in which the pituitary gland is located), and galactorrhea
• Medication review should be done to exclude any drug-induced hyperprolactinaemia. Renal impairment, primary hypothyroidism, and liver failure should be considered as causes of mild hyperprolactinemia. Overall, pituitary tumour size and the levels of prolactin are strongly correlated to hyperprolactinemia and prolactinoma. Pregnancy is excluded from the causes of hyperprolactinemia
• Dopamine agonists are the first line of treatment for prolactinoma. In case the patient is refractory to all dopamine agonists, surgery is considered, and if surgery fails as well, radiotherapy can be an alternative