| Key points |
• In patients with elevated serum prolactin who do not have the typical features of hyperprolactinemia, macroprolactinemia should be suspected. • After confirming the increase in serum prolactin and ruling out physiological or iatrogenic causes, an MRI should be performed to look for a pituitary tumor (prolactinoma or non-prolactinoma). • Bromocriptine and cabergoline are the two dopamine agonists most commonly used to normalize serum prolactin concentrations and induce tumor shrinkage in prolactinomas . Cabergoline is more effective and better tolerated than bromocriptine. • Although there is more safety data for bromocriptine than for cabergoline, both are considered safe during pregnancy. • Current evidence does not demonstrate an association between dopamine agonists - at the doses used to treat hyperprolactinemia - and clinically significant valvular heart disease. |
Prolactin, released by the lactotroph cells of the anterior pituitary, stimulates lactation. Dopamine is transported through pituitary portal vessels from the hypothalamus to the anterior pituitary, where it inhibits prolactin secretion through D2 receptors expressed by lactotroph cells.
Disruption of dopamine secretion or transport to the portal vessels can lead to hyperprolactinemia.
Prolactin hypersecretion causes secondary hypogonadism through inhibitory effects on GnRH and pituitary gonadotropins.
| Etiology and differential diagnosis |
Normal serum prolactin concentrations are <625 mU/liter in women and <375 mU/liter in men. During pregnancy , prolactin progressively increases due to estrogen-induced lactotrophic hyperplasia. The causes of hyperprolactinemia are described in Table 1.
Prolactinomas represent approximately 40% of all pituitary adenomas and show a female preponderance . They are classified according to their size:
- Microadenomas, <1 cm in diameter.
- Macroadenomas ≥1 cm in diameter.
More than 90% of prolactinomas are microprolactinomas.
Generally, prolactin concentrations in patients with prolactinomas are proportional to the size of the tumor, whereas, in disconnection hyperprolactinemia , where prolactin increases as a result of compression of the pituitary stalk by, for example, a non-functioning pituitary adenoma (NFAH). ), serum prolactin is usually <2000 mU/liter.
| Table 1. Causes of hyperprolactinemia | |
| Physiological | |
> Pregnancy and lactation > Nipple stimulation, including chest wall injury (e.g., shingles) > Stress • Venipuncture | |
| Pathological | |
> Hypothalamic-pituitary disease • Secretion by tumor (eg, prolactinoma), sometimes with other pituitary hormones (eg, growth hormone) . > Polycystic ovary syndrome > Primary hypothyroidism > Chronic kidney failure > Cirrhosis | |
| Iatrogenic | |
> Antipsychotics • Typical (e.g., phenothiazines) > Antidepressants • Tricyclics > Opioids > Antiemetics • Metoclopramide > High doses of estrogen > Others • Verapamil |
| Clinical features |
In premenopausal women , hyperprolactinemia usually presents with galactorrhea, menstrual irregularity, and infertility . Galactorrhea is less common in postmenopausal women , in whom there is a reduction in breast glandular tissue caused by a lack of estrogen.
Men may present with symptoms of secondary hypogonadism, such as reduced libido, impotence, and infertility. However, men and postmenopausal women often present signs of tumor compression, such as headache or visual impairment. Chronic hyperprolactinemia with secondary hypogonadism can lead to reduced bone mineral density.
| Investigations |
A single prolactin measurement is usually sufficient to diagnose hyperprolactinemia.
In cases of mild hyperprolactinemia, it may be worth obtaining several measurements separated by at least 20 minutes, using an indwelling cannula to minimize the stress of venipuncture. Secondary causes should be excluded by careful history taking, pregnancy test, and renal and thyroid function tests.
Once pathological hyperprolactinemia is confirmed, pituitary magnetic resonance imaging (MRI) with gadolinium should be performed. Patients with macroprolactinomas or AHNF, particularly with suprasellar extension, should undergo a visual field examination and evaluation of the rest of their pituitary function.
In patients with prolactinoma who are young (<30 years) or have a family history of pituitary adenoma, a diagnosis of familial pituitary adenoma should be considered. This may occur in the context of a genetic predisposition, for example, multiple endocrine neoplasia type 1, or limited to the development of pituitary tumors only. These individuals should be offered genetic screening.
| Diagnostic difficulties |
> Macroprolactin
The majority of circulating prolactin (80-90%) is monomeric and biologically active. Macroprolactin consists of an antigen-antibody complex of monomeric prolactin + immunoglobulin G. This usually represents <5 % of circulating prolactin. Macroprolactin has limited bioavailability and bioactivity.
Macroprolactinemia should be suspected when a patient has an elevated prolactin concentration without the typical manifestations of hyperprolactinemia.
> Hook effect
Very high concentrations of prolactin, for example, in giant prolactinomas, can saturate the antibodies used in immunoradiometric assays to measure prolactin, preventing the formation of the anti-prolactin antibody "sandwich." The resulting loss of labeled antibodies leads to falsely low prolactin values and is called the "hook effect" . The effect can be avoided by performing serial dilutions of serum/plasma before testing for prolactin.
> Management
The goal of treatment in prolactinomas is to normalize serum prolactin concentrations, thereby restoring gonadal function and fertility. In macroprolactinomas, the additional goal is tumor shrinkage.
Pharmacological options : treatment with dopamine agonists . Bromocriptine and cabergoline are the two most commonly used dopamine agonists for the treatment of hyperprolactinemia and prolactinomas. In disconnection hyperprolactinemia, only small doses are required to achieve normal serum prolactin concentrations, whereas, in prolactinomas, gradual dose titration based on sequential prolactin measurements is usually required.
• Bromocriptine. Its relatively short half-life requires dosing 2 to 3 times daily, and adverse effects include nausea and postural hypotension.
• Cabergoline is superior to bromocriptine in controlling hyperprolactinemia and restoring gonadal function, and is better tolerated. Its longer half-life allows for a more convenient dosing schedule and patients generally require 2 mg or less per week. The typical starting dose of cabergoline is 250 to 500 micrograms per week, which is gradually increased based on serum prolactin concentration and tumor size.
• Quinagolide : dopamine agonist not derived from ergot. Data on its effectiveness vs cabergoline are limited.
Currently, the Endocrine Society recommends considering a trial of dopamine agonist withdrawal in patients with a stable normal prolactin level and no visible tumor on pituitary MRI who have received therapy for at least 2 years.
> Safety of treatment with dopamine agonists
About a decade ago, studies demonstrating an association between the use of dopamine agonist therapy in patients with Parkinson ’s disease and the development of valvular heart disease raised concerns about the safety of cabergoline and bromocriptine in the treatment of Parkinson’s disease. hyperprolactinemia. However, most hyperprolactinemic patients are exposed to much lower doses. Current evidence does not support a clinically significant association between treatment for hyperprolactinemia and valvular heart disease.
Dopamine agonist treatment for hyperprolactinemia has also been associated with the development of impulse control disorders, where male sex may be an independent risk factor. It is essential that physicians discuss this potential adverse effect before starting dopamine agonist treatment for hyperprolactinemia and monitor it at subsequent visits.
> Dopamine agonists and pregnancy
There is a minimal risk of microprolactinoma enlargement in pregnancy, and dopamine agonists may be discontinued once pregnancy has been confirmed. The risk of enlargement of macroprolactinomas in pregnancy is higher (20-30%). Both bromocriptine and cabergoline have been shown to be safe during pregnancy , with no adverse fetal outcomes.
> Transsphenoidal surgery and radiotherapy
Cabergoline and bromocriptine are the first-line treatment for prolactinomas. Surgery or radiotherapy is rarely required, usually in patients with malignant prolactinomas, or with intolerance or resistance to dopamine agonists. The alkylating agent temozolamide has been used in the treatment of aggressive prolactinomas resistant to treatment with dopamine agonists.
