How to proceed with suspected hyperprolactinaemia

A prolactin assay forms part of the routine analysis of hormone levels in women with menstrual cycle disorders and/or galactorrhoea, and in men presenting with gynaecomastia, erectile dysfunction or decreased libido. Identification of hyperprolactinaemia, once under control, should be followed with a rigorous diagnostic process to begin appropriate treatment.

Hyperprolactinaemia is common and is often discovered by chance. Prolactinomas or pituitary adenomas secreting prolactin are the most common causes of true hyperprolactinaemia, however they are not the starting diagnosis for hyperprolactinaemia discovered in a laboratory.

Physiopathology

Prolactin (PRL) is a 199-aa polypeptide hormone (MM = 23 kDa) with a 3-D structure, coded by a single gene on chromosome 6. Secreted by pituitary lactotrophs, the main regulator for prolactin is dopamine produced by the hypothalamus. Any weakening of this regulator, either medical or pathological, results in hyperprolactinaemia. There are also factors that stimulate its production (TRH, oestradiol). Finally, it also has negative feedback on its own secretion and the secretion (pulsatile) of GnRH by the hypothalamus.

PRL acts directly by binding to its receptor in the target tissues: the breast, the pituitary gland, the liver, the kidneys and the prostate. Physiologically, it is involved in the development of the mammary glands and the preparation for lactation during pregnancy (the serum concentration multiplies by a factor of 5 to 20 by the end of pregnancy, which is why it is recommended to wait 6 to 9 months after stopping breastfeeding before assaying PRL levels).

The three circulating forms of PRL

• The monomeric form is a protein of approximately 23 kDa and is the predominant form (60-90%), which is bioactive.
• The homo-diametric or ‘big prolactin’ form is a complex protein of intermediate size ranging from 45 to 60 kDa: normally makes up 15-30% of total circulating PRL (limited bioactivity).
• The hetero-diametric form, ‘big-big PRL’ or ‘macro-PRL’, is a complex protein with a high molecular weight above 100 kDa, comprising a PRL molecule and an IgG molecule. It normally makes up less than 10% of total PRL and has no effect in vivo.

Indications for a PRL assay

Presenting with symptoms of hyperprolactinaemia

In pre-menopausal women, presenting with hypogonadotropic hypogonadism

• Menstrual cycle disorders (secondary amenorrhoea, oligo-spaniomenorrhoea) as part of an infertility assessment.
• Galactorrhoea (rarely isolated, most commonly associated with menstrual cycle disorders).
• Signs of oestrogen deficiency (decreased libido, dry mucous membranes, osteopaenia).

In post-menopausal women

Few indications, often mild.

In men

• Sexual dysfunction: decreased libido, erectile dysfunction.
• Gynaecomastia, more rarely galactorrhoea.

In boys

• Delayed or arrested puberty.
• Delayed growth, could reveal damage to the pituitary gland.

Presenting with symptoms suggestive of pituitary gland tumour process

• Headaches caused by the pituitary gland: predominantly frontal, not pulsating, the intensity of which is not correlated to the volume of the tumour.
• Visual disorders related to compression of the optic chiasm: bitemporal hemianopsia, late onset.

In a pituitary gland pathology assessment

• Secretion of PRL by the tumour itself (prolactinoma): PRL microadenoma, PRL macroadenomas, mixed-secretion adenoma (most commonly PRL/GH).
• Hyper-PRL, known as disconnection hyperprolactinaemia, by compression of the pituitary stalk (following head trauma).

In an infertility assessment

• PRL assay requested at least in cases of menstrual cycle disorder in a woman or decreased libido in a man.

Diagnostic process for a case of hyperprolactinaemia

1 – Confirm the assay using a second sample

Hyperprolactinaemia can be transitory and not detected in a later test. These physiological fluctuations, of unknown cause, do not require any treatment.

In principle, hyperprolactinaemia should thus be verified using a second sample while avoiding any situation that could cause an increase in prolactin (see below): avoiding taking any medications that increase prolactin in the days prior to taking the sample; avoiding a taking a sample soon after eating, during the middle of the menstrual cycle or when there has been significant stress beforehand.

2 – First investigate a potential physiological cause:

• Pregnancy, breastfeeding
• Significant stress, intense physical activity, seizure
• Nipple stimulation, damage/burns to the chest wall

3 – Always rule out medications as a cause:

• Antiepileptics: phenothiazines, butyrophene, thioxanthenes, benzamides, risperidone, veralipride, and, to a lesser extent, loxapine, olanzapine, pimozide.
• Tricyclic antidepressants, some reported cases of hyperprolactinaemia with fluoxetine, paroxetine and potential effect from citalopram, fluvoxamine, sertraline and venlafaxine.
• Antiemetic (benzamides and phenothiazine derivatives), and H2 antihistamines (cimetidine and ranitidine).
• High blood pressure medication: verapamil, methyldopa, reserpine.
• Other: morphine, methadone, high doses of oestrogen.

4 – Screen for a general pathology (or other) that could cause hyperprolactinaemia

• Severe peripheral hypothyroidism (TSH assay).
• Moderate to severe kidney failure (electrolytes, creatinine).
• Liver failure (liver work-up).
• Polycystic ovary syndrome: this diagnosis should only be investigated after ruling out all other causes, especially if PRL is > 2 times normal levels. An MRI of the pituitary gland should not be delayed because of this possibility.
• Damage to related nerves (chest wall, spinal cord).

5 – Screen for macroprolactinaemia 

This situation is an artefact in which there is a predominance of heavy forms of PRL circulating that are not biologically active. Screening for macroprolactinaemia should be carried in cases of:

• Hyperprolactinaemia with persistence of ovulatory cycles.
• Hyperprolactinaemia and galactorrhoea only.
• Persistence of hyperprolactinaemia while receiving treatment.

As a first line, screening is carried out via polyethylene glycol (PEG) precipitation of molecules with a high molecular weight (including “big big” prolactin) and then calculating a ratio between the prolactin values assayed using an RIA assay method, before and after PEG precipitation.

When this ratio is < 0.65, gel-filtration chromatography is indicated, to determine the precise percentage of each form of prolactin and identify whether there is a predominance of the “big big” form.

If, on the contrary, the ratio is greater than 0.65:  the presence of abnormally high levels of “big big” prolactin is ruled out and investigations should proceed with an MRI of the hypothalamus-pituitary gland to identify any potential adenoma or damage to the pituitary stalk.

6 – In a case with symptoms of hyperprolactinaemia: screening for a hypothalamus-pituitary tumour via an MRI of the pituitary gland 

• PRL microadenoma (diameter < 10 mm, PRL < 100 ng/ml).
• PRL macroadenoma (diameter ≥ 10 mm, PRL > 200 ng/ml).
• Mixed-secretion adenoma (most commonly PRL/GH).
• Disconnection hyperprolactinaemia, by compression of the pituitary stalk.
• Non-lactotrophic or non-functioning macroadenoma (gonadotroph).
• Brain tumour (meningioma, craniopharyngioma).
• Sarcoidosis/histiocytosis (infiltration of the pituitary stalk).
• Hypothalamus-pituitary stalk section (head trauma, surgery, radiotherapy).

Laboratory diagnosis of hyperprolactinaemia

Pre-analysis conditions and physiological variations

There is no need to fast before the sample is taken and there is no significant impact from the time of day or day of the menstrual cycle. It is preferable that the individual is at rest, however there is no need to insert a catheter or take multiple samples.

Oestrogen stimulates the production and secretion of PRL, which explains the slightly higher concentrations observed in pre-menopausal women. PRL rises physiologically throughout pregnancy, rising to values of 200 to 400 mg/L at the end of the third trimester.

Treating Hyperprolactinaemia

Treating prolactinomas

The first-line treatment is via medication, with a dopamine agonist: bromocriptine (Parlodel®), quinalogide (Noprolac®), cabergoline (Dostinex®). Typically, PRL normalises in a few weeks to a number of months.

Surgical treatment is indicated as a second-line treatment, in case of intolerance or resistance to treatment using medication, or if there is mixed PRL-GH secretion.

Medication-induced hyperprolactinaemia

Dopamine agonists must not be used as they are often ineffective or even dangerous. If possible, it is recommended to stop administration of the medication inducing the hyperprolactinaemia and replace it with one that does not induce hyperprolactinaemia. Otherwise, the symptomatic treatment using oestrogen or oral contraceptives (as a substitute/contraceptive) can be proposed to correct the hypoestrogenism.

Macroprolactinaemia

No treatment.

Conclusion

Hyperprolactinaemia is a common situation, and so should be confirmed in a second assay, if possible by a different laboratory. As a first step, the possibility of pregnancy or it being medically induced should be investigated, being aware of the symptoms and circumstances that motivated the assay, and knowing to investigate the possibility of macroprolactinaemia. Discussions between clinicians and clinical biologists is essential for a critical comparison of assays with clinical data and imaging.