REVIEW ARTICLES

Received: September 21^st 2015

Accepted: October 13^th 2015

Current diagnosis and treatment of hyperprolactinemia

Virgilio Melgar,^a Etual Espinosa,^b Ernesto Sosa,^b María José Rangel,^a Dalia Cuenca,^a Claudia Ramírez,^b Moisés Mercado^b

^aCentro Neurológico, Centro Médico ABC

^bUnidad de Investigación en Endocrinología Experimental,

Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social

Distrito Federal, México

Communication with: Moisés Mercado

Thelephone: (55) 5281 3085

Correos electrónicos: mmercadoa@yahoo.com; moises.mercado@endocrinologia.org.mx

Hyperprolactinemia is a frequent neuroendocrinological condition that should be approached in an orderly and integral fashion, starting with a complete clinical history. Once physiological causes such as pregnancy, systemic disorders such as primary hypothyroidism and the use of drugs with dopamine antagonistic actions such as metochlopramide have been ruled out, the most common cause of hyperprolactinemia is a PRL-secreting pituitary adenoma or prolactinoma. Prolactinomas are usually classified as microprolactinomas (less than 1 cm) or macroprolactinomas (larger than 1 cm), which can either be confined or invasive. The hormonal consequence of hypeprolactinemia is hypogonadism; in women, this is manifested as amenorrhea/oligomenorreha, anovulation and galactorrhea, whereas in men the main complaints are a diminished libido and erectile dysfunction. Macroprolactinomas can also present with symptoms and signs resulting form mass effect of the tumor, such as headaches and visual field defects. Other structural causes of hyperprolactinemia include non-functioning pituitary adenomas and infiltrative disorders, which can interrupt the inhibitory, descending dopaminergic tone. The primary treatment of prolactinomas is pharmacological with dopamine agonists such as cabergoline.

Keywords: Prolactin; Hyperprolactinemia; Prolactinoma; Dopamine agonists; Ergolines.

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Prolactin (PRL) is a glycoprotein hormone produced by the anterior pituitary lactotroph. While its regulatory functions for breastfeeding are well-established, the biological effects of PRL are not yet fully known and include actions at metabolic and immunological levels. Hyperprolactinemia is one of the most common neuroendocrine disorders, and it may be due to physiological conditions (such as intercourse and nipple stimulation), the effect of dopaminergic tone inhibiting drugs (such as metoclopramide) or the presence of tumors in the lactotroph. In the evaluation of patients with hyperprolactinemia, a detailed medical history can avoid unnecessary laboratory and imaging studies, whose results may confuse rather than help establish an etiological diagnosis.^1-3

Epidemiology

The incidence and prevalence of hyperprolactinemia varies depending on the population studied. The incidence is estimated at 8.7 per 100,000 people per year in women and 1.4 per 100,000 people per year in men.⁴ In the general population, a prevalence of 0.4% and 5% is estimated in women who attend family planning clinics.⁵ Among women with menstrual disorders such as primary amenorrhea, oligomenorrhea, and dysfunctional uterine bleeding, the prevalence of hyperprolactinemia is low; however, in women with secondary amenorrhea the prevalence can be between 5.5 and 13.8% for women between 11 and 20 years and 21 and 30 years, respectively.⁶ In women with galactorrhea, the prevalence is 25; if there are menstrual disorders in addition to galactorrhea, the prevalence rises to 46%.^7,8 The age group most commonly affected by hyperprolactinemia is women between 25 and 34.⁴ Although most publications talk about a prevalence between 30 and 80% among women attending fertility clinics, the frequency of hyperprolactinemia in asymptomatic but infertile women is around 5%.^8,9

Among men with erectile dysfunction, the prevalence of hyperprolactinemia is 13%, although more recent studies do not seem to find a statistically significant difference in the prevalence of hyperprolactinemia between men with and without erectile dysfunction.^2,3

Prolactin regulation

PRL is a hormone of 199 amino acids and molecular weight of 23 kDa, and which has significant homology to growth hormone (GH) and human placental lactogen (HPL). It is synthesized primarily in the lactotroph cells of the anterior pituitary, which are unique among endocrine cells, as they have high basal secretory activity. For the same reason, the regulation of PRL secretion is mainly inhibitory and is mediated by dopamine.¹⁰ Dopaminergic neurons of the arcuate and paraventricular nuclei are directly involved in the regulation of PRL. These neurons release dopamine to the perivascular region of the median eminence, from which the neurotransmitter enters long portal vessels and reaches the anterior pituitary. Dopamine acts on specific G protein-coupled receptors (D2R) located on the lactotroph membrane, which inhibits PRL synthesis and release. Other PRL-inhibiting factors are gamma aminobutyric acid (GABA) and somatostatin. There are also PRL secretion-stimulating factors such as neurotensin, oxytocin, serotonin, and, most importantly, thyrotropin releasing hormone (TRH), although its importance in the physiological regulation of PRL is minimal (Figure 1).^10,11

Prolactin action mechanism

PRL exerts its various effects in target tissues by binding to a specific membrane receptor (PRLR), which belongs to the cytokine receptors type I superfamily, which also includes GH receptor and various interleukins. PRLR consists of an extracellular domain that is responsible for attaching to the ligand, a transmembrane portion, and an intracellular domain that is responsible for signal translation; the signaling of this receptor depends on Janus kinase (JAK2) recruitment, which phosphorylates specific sites of the intracellular portion of PRLR; this results in phosphorylation of STAT 5 (signal transducers and activators of transcription), which ultimately leads to regulation in the expression of various genes (Figure 2).^12-14

Physiological and pathophysiological effects of prolactin in human reproduction

Differentiation and growth of the mammary gland

PRL is necessary for the proliferation of epithelial breast tissue, an action indirectly achieved through induction of expression of the RANK ligand (receptor activator of nuclear factor kappa). RANK induces the proliferation and differentiation of mammary alveolar cells, which are responsible for the secretion of milk. During lactation, prolactin regulates the secretion of milk proteins (including casein, lactoglobulin, lactalbumin) and enzymes (such as lactose synthetase, lipoprotein lipase, and fatty acid synthase).^12-14

Reproductive effects

The reproductive effects of PRL in humans are not fully known, and a syndrome associated with its deficiency has not yet been identified. The best-known hormonal effect of hyperprolactinemia is hypogonadotropic hypogonadism. PRL acts on its receptors in neurons of the hypothalamic arcuate nucleus, which decreases kisspeptin production and results in decreased amplitude of the pulses of gonadotropin releasing hormone (GnRH). There is a consequent reduction in the synthesis and secretion of LH and FSH, and then of estrogen and testosterone.¹⁵ Recent studies indicate that PRL may participate in the regulation of libido, especially in men.^3,15

Clinical manifestations of hyperprolactinemia

The classic symptoms of hyperprolactinemia are galactorrhoea, oligomenorrhea, decreased libido, erectile dysfunction, and infertility. When hyperprolactinemia is caused by a pituitary adenoma, depending on the size and location of it, we may find signs and symptoms resulting from the effect of the mass of the lesion, such as headaches and visual field disorders.^6,9,16

Diagnosis and causes of hyperprolactinemia

The documentation of hyperprolactinemia should be done in a blood sample taken by venipuncture and with the least possible stress, as this can raise PRL figures to more than 30 ng/mL.^17,18

The differential diagnosis of hyperprolactinemia is extensive and sometimes complex; physiological and pathological causes, medications, and analytical problems such as macroprolactinemia should all be considered.^8,18

Physiological causes

The main physiological cause of hyperprolactinemia is pregnancy. During pregnancy there is a hyperplasia of the anterior pituitary gland, especially at the expense of the lactotroph due to persistent estrogenic stimulus. In pregnancy, the anterior pituitary may increase up to two or three times its normal size, and serum PRL may increase more than 10 times.¹⁹ In the postpartum period, breastfeeding produces peaks in PRL secretion through a reflex arc which begins with nipple suction, moves to the spinal cord, and travels to the hypothalamus via the vagus nerve where the dopaminergic neurons are inhibited. In case of lack of maternal lactation, serum PRL concentrations normalize six weeks after childbirth.²⁰

Other physiological conditions that result in PRL elevation are intercourse, stress, pain, and exercise; however, these rarely produce significant increases in serum concentrations of the hormone.¹⁸

Medication-related causes

The list of drugs capable of producing hyperprolactinemia is long; however, the most common are the typical antipsychotics (Table I). Between 38 and 70% of patients treated with these drugs have hyperprolactinemia. Most typical antipsychotics are dopamine antagonists, which is the mechanism that makes them cause hyperprolactinemia. Atypical antipsychotics are less able to produce hyperprolactinemia. Other drugs, such as selective serotonin reuptake inhibitors, can also induce hyperprolactinemia, and benzodiazepines, by potentiating GABAergic stimulation, also have this capability. Another group of drugs known for their ability to induce hyperprolactinemia are antiemetic dopaminergic antagonists, such as metoclopramide and domperidone. The drug-induced PRL serum concentration is usually between 25 and 100 ng/mL; however, risperidone and amisulpiride can raise PRL up to 200 ng/mL. It is important to rule out the use of these drugs considering that some of them are used often and in some cases, patients are unaware of their consumption or give it little importance.^21-25

Macroprolactinemia

The monomeric form of PRL has a molecular weight of 23 kDa and represents 65-85% of circulating PRL. There are other circulating forms, such as the 40-60 kDa big prolactin and the big-big prolactin (macroprolactin) which is more than 150 kDa, which represent less than 20% of circulating PRL. 90% of macroprolactin consists of prolactin bound to IgG.^26,27 In 3.68% of the general population and 10 to 26% of the population with hyperprolactinemia, macroprolactin is the dominant form. This form of PRL has no biological activity, but has a prolonged half-life in circulation because it does not cross the glomerular membrane. The importance of diagnosing macroprolactinemia is that it is a common cause of hyperprolactinemia that does not warrant treatment.²⁸ Macroprolactinemia investigation is simple, but is not available in most regular laboratories. The most widely-used diagnostic method is serum treatment with polyethylene glycol (PEG) to precipitate the PRL bound to immunoglobulins, followed by measurement of PRL in the supernatant serum. If the percentage of PRL recovered in the PEG-treated serum is less than 60% compared to untreated serum, the diagnosis of macroprolactinemia is established. If the measurement of serum PRL in the precipitate is within the laboratory’s range of normal, the patient does not need treatment; however, if the measurement of serum PRL in the precipitate continues to be above the upper limit of normal for the laboratory, the diagnosis of hyperprolactinemia with macroprolactinemia is established, and these patients may be candidates for therapeutic intervention.^26-28

Pathological causes

Infiltrative and granulomatous diseases of the pituitary

These diseases do not usually produce hormonal hypersecretion syndromes; rather, they usually result from hormonal deficiencies. In this context, hyperprolactinemia is due to the interruption of hypothalamic dopaminergic tone due to pituitary stem infiltration.²⁹ Conditions such as lymphocytic hypophysitis, sarcoidosis, granulomatosis with polyangiitis, and Langerhans cell histiocytosis may present with hyperprolactinemia, usually less than 100 ng/mL, in 20 to 50% of cases.^30-32 One even rarer cause of the same mechanism is the hyperprolactinemia sometimes found in the pituitary abscesses and tubercular and fungal infections, as well as in pituitary metastases.^29,33

Systemic diseases

• Chronic renal failure. Hyperprolactinemia occurs between 30 and 65% of cases as a result of decreased renal elimination and perhaps also due to increased pituitary secretion by a stimulus as yet unidentified.^34,35
• Chronic liver failure. While advanced liver failure has traditionally been considered a cause of hyperprolactinemia due to hyperestrogenism, in a study of 178 patients with liver failure, most in Child-Pugh stage B and C, only 18 presented with hyperprolactinemia. Of these 18 patients, only three had no other factor identified to explain the hyperprolactinemia.³⁶
• Primary hypothyroidism. In primary hypothyroidism, there is an elevation of HRT, which acts on the lactotrophs, stimulating PRL synthesis and secretion. The prevalence of hyperprolactinemia in primary hypothyroidism and subclinical hypothyroidism is about 21 and 8%, respectively.³⁷
• Polycystic Ovarian Syndrome. Polycystic ovarian syndrome has traditionally been associated with hyperprolactinemia. The characteristic hyperestrogenic state of polycystic ovarian syndrome has been proposed as a stimulus to the pituitary lactotroph. This proposal has been questioned in recent days. Recent studies have found no link between polycystic ovarian syndrome and hyperprolactinemia, so this is still a matter of controversy.^38,39

Non-prolactinoma pituitary tumors

Perhaps one of the greatest diagnostic challenges in the evaluation of hyperprolactinemia is the differentiation between prolactinoma and other pituitary tumors that present with hyperprolactinemia. Any sellar tumor causing compression of the pituitary stalk can produce hyperprolactinemia by disrupting the inhibitory effect of dopamine on the lactotroph (stem effect). However, when it comes to somatotropic tumors and biochemically silent tumors, this distinction may be more difficult.^40,41 It is known that between 20 and 25% of tumors of the somatotropic co-secrete PRL and may present with hyperprolactinemia in higher numbers than that seen in the stalk effect.⁴²

Clinically nonfunctioning pituitary adenomas can cause hyperprolactinemia by the stem effect, and can present with moderate hyperprolactinemia rarely greater than 200 ng/mL. To differentiate this phenomenon from a prolactinoma, it is essential to note two important concepts: 1) there is often a correlation between the size of a prolactinoma and the amount of PRL that it secretes; 2) in situations of extreme hyperprolactinemia, with PRL above the upper limit of detection of the test used to measure it, the concentration can be erroneously reported as lower than the actual concentration, a phenomenon called the hook effect. Therefore, to differentiate a nonfunctioning pituitary macroadenoma from a prolactinoma with this effect, it is recommended to measure the diluted PRL, especially when there is mild hyperprolactinemia.⁴³

Prolactinoma

This is the most common cause of sustained hyperprolactinemia, after medications and hypothyroidism, and it represents approximately 50% of anterior pituitary adenomas.⁴⁴ Like most anterior pituitary tumors, the tumorigenesis is unclear. Among the oncogenic mechanisms proposed is alterations in gene expression such as PTTG, E2F1, Myc, IGF-1, CEBPD, and signaling via Erb2 receptors.^45,46 Its prevalence is approximately 500 cases per million inhabitants and the incidence is 27 cases per million per year. Prolactinomas are classified according to their size into microprolactinomas if less than 10 mm, macroprolactinomas if greater than 10 mm, and giant if greater than 40 mm. 70% of tumors occur in women and 64% are microprolactinomas (with a female to male ratio of 20 to 1). Macroprolactinomas and giant prolactinomas are more prevalent in men (macro to microprolactinoma ratio 5 to 1).^17,47,48

Hypogonadotropic hypogonadism is manifested as decreased libido, infertility, and decreased bone mass in both sexes. In premenopausal women it is common to find menstrual disorders and in men, erectile dysfunction. In the case of macroprolactinomas, symptoms may also result from the mass, such as visual impairment, headache, and signs of skull hypertension. On rare occasions they can debut in the context of a pituitary apoplexy.^1,49

Hyperprolactinemia due to prolactinoma is generally greater than 250 ng/mL; PRL greater than 500 ng/mL is almost always indicative of the presence of a macroprolactinoma. When we find pituitary macroadenomas and elevated serum prolactin it is important to request the measurement of PRL in serum diluted with a value of 1:100 to rule out the hook effect.^1,50

Evaluation of hyperprolactinemia

In patients with hyperprolactinemia the first step in establishing the diagnosis is to do a thorough medical history by interviewing them directly about the use of drugs (legal or illegal) that cause hyperprolactinemia or about the presence of thoracic injuries and the coexistence other diseases that can produce hyperprolactinemia, such as hypothyroidism. Initial biochemical studies are intended to rule out diseases such as chronic renal failure and cirrhosis of the liver. This initial assessment should also include a thyroid profile, and if the clinical signs suggest it, complementary tests should be done to rule out specific diseases, such as polycystic ovarian syndrome. In the case of a woman with amenorrhea and hyperprolactinemia it is imperative to rule out pregnancy.^1,17

Having ruled out physiological and pathological causes, one should also consider macroprolactinemia when the patient is asymptomatic and has normal gonadotropins and sex steroids. Once the previously mentioned causes have been ruled out, one must proceed with an MRI of the skull for pituitary lesions. It is important to remember that the concentration of serum PRL can also guide diagnosis. In cases of PRL-producing macroadenomas, it is important to measure IGF-1 to rule out the possibility of a GH-co-secretory tumor and to make an assessment of all pituitary axes. To differentiate between the stem effect and the hook effect it is important to make serum dilutions.^17,47,48 When the cause of hyperprolactinemia cannot be identified, this is classified as idiopathic (Figure 3).⁵¹

Treatment

The treatment of hyperprolactinemia secondary to systemic disease involves correcting the underlying cause, such as treating hypothyroidism.¹⁷ Hyperprolactinemia caused by medications should be treated only if symptoms occur. The drug causing this should be discontinued whenever this is feasible, or change it for one that does not cause hyperprolactinemia.¹⁷

Antipsychotic drugs deserve special consideration. The physician treating the psychiatric pathology should always be consulted in-depth for options as to changing the precipitant drug. When it is not possible to suspend or change the drug in question, and hyperprolactinemia causes hypogonadism, this should be treated by estrogen or testosterone hormone replacement. Treatment with dopamine agonists is controversial. 75% of patients present improvement; however, there is a risk of exacerbating the underlying psychiatric pathology. It has currently been found that the use of aripiprazole, an atypical antipsychotic with partial D2 agonist, partial 5-HT1A agonist, and 5-HT2A antagonist effects is effective, together with typical antipsychotics, to treat both the psychiatric disorder and hyperprolactinemia induced by typical antipsychotics.^17,21,23,24

The goal in prolactinoma treatment is to normalize PRL, reduce tumor size, restore eugonadism, restore normal pituitary function, and resolve symptoms resulting from the mass.^1,17 The treatment of choice for prolactinoma is dopaminergic agonists, more specifically cabergoline. This is a selective D2 dopamine receptor agonist whose efficacy and safety have been widely demonstrated. Using doses of 0.25 to 3 mg per week, normoprolactinemia is achieved, as is significant reduction of tumor size in about 91% of patients with microprolactinomas and 77% of those with macroprolactinomas. As for effectiveness, with bromocriptine (another dopamine agonist), normoprolactinemia is achieved in 80% of microprolactinomas and 70% of macroprolactinomas, only with a higher frequency of adverse effects, particularly gastrointestinal. 10 to 15% of patients treated with cabergoline do not achieve normoprolactinemia, and these patients are considered resistant to dopamine agonists.^1,17,47 

Transsphenoidal surgical treatment is reserved for cases of intolerance or resistance to dopamine agonists, when there is a rapidly progressive chiasmal syndrome, when the tumor size decrease with the dopamine agonist is suboptimal, and in some cases of pituitary apoplexy. Another situation that may require surgical treatment is when there is herniation (traction of the optic chiasm) or where there is cerebrospinal fluid fistula. Both are complications that can occur with decreased tumor size with dopamine agonists.^1,17,52 Radiotherapy is a treatment method seldom turned to because prolactinomas are the most radio-resistant pituitary tumors.¹

Discontinuation of treatment

The Endocrine Society guidelines recommend that after at least two years of treatment with dopamine agonist, with normal serum PRL levels and in the absence of residual tumors, the suspension of dopamine agonist treatment can be assessed in patients with prolactinoma.¹⁷ In a meta-analysis of 11 studies and 637 patients with prolactinomas, hyperprolactinemia recurrence was observed after cabergoline discontinuation in 65% of cases; however, two factors seem to be of good prognosis: the maintenance of normoprolactinemia with the lowest dose of cabergoline, and a significant reduction in tumor size. Other factors such as tumor size, treatment time, or the initial concentration of prolactin were not related to the probability of success or failure in the removal of cabergoline.⁵³ Out of 25 patients with non-tumor hyperprolactinemia, after a cabergoline treatment period of 36 months and 18 months after stopping treatment, six (24%) had recurrence of hyperprolactinemia; however, 19 (74%) remained asymptomatic. Two years after the discontinuation of treatment, 100% of the latter maintained normoprolactinemia and were asymptomatic.^54,55

Special considerations

Prolactinoma and pregnancy

The correction of hyperprolactinemia with dopamine agonists restores ovulatory cycles in 90% of women, which is why it is not uncommon for patients with prolactinomas to become pregnant during treatment with dopamine agonists. One of the main concerns is the teratogenic effect of cabergoline or bromocriptine. So far no teratogenic effect has been shown from bromocriptine, and with each day cabergoline shows more evidence of safe use during pregnancy. However, it still considered by WHO to be in class B for use in pregnancy.

A second important issue is tumor growth during pregnancy. It is a fact that the pituitary gland and prolactinomas increase in size during pregnancy; however, only 2.4% of microadenomas will have a clinically significant increase to warrant any intervention during pregnancy; therefore, treatment with dopamine agonists can be discontinued in these cases. These patients require only the routine monitoring of pregnancy. When it comes to macroprolactinoma, 21% will have clinically significant growth, and treatment should be individualized. When the tumor spreads, especially in the infrasellar direction, one may opt to suspend dopamine agonists; however, when the extension is suprasellar, with risk of compression of the optic chiasm, one may continue with the dopamine agonist and in some exceptional cases opt for surgery.^56-58

Prolactinoma and contraception

Prolactinoma is more common in women of childbearing age and treatment with dopamine agonists restores ovulatory cycles in 90% of cases; therefore, these women need contraception in the case that they do not want pregnancy. Evidence on the effect of estrogen as a contraceptive or as hormone replacement in postmenopausal patients with prolactinoma or a prolactinoma history is scarce; however, this evidence indicates that there is no contraindication to its use. Macroprolactinoma should be monitored closely, and in case of signs and symptoms of effect from the tumor mass, imaging studies should be conducted.^59,60

Prognosis and safety considerations

One disadvantage of treatment with dopamine agonists is the prolonged time of use. While some patients manage to discontinue treatment, most of them need it for indefinite periods. One of the situations that often worries the clinician and patient is valve diseases related to the use of dopamine agonists. At this time there is no evidence that the risk of developing heart valve disease increases at the doses commonly used to treat prolactinomas.

Conclusions

Hyperprolactinemia is a frequent cause of consultation and represents a diagnostic challenge in many cases. Systematic evaluation is needed to reach a correct diagnosis. With proper history and physical examination, the etiology of hyperprolactinemia can be arrived at in most cases. As part of the basic and initial biochemical evaluation, one must rule out hypothyroidism, chronic kidney disease, and liver failure. Medications are a common cause of hyperprolactinemia, especially antipsychotics and medications commonly used in gastroenterology. It is important to note the methodological problems of measuring the PRL hook effect and macroprolactinemia. When the diagnosis of hyperprolactinemia due to prolactinoma is established, the treatment of choice is dopamine agonists such as cabergoline, with which adequate control is achieved in most patients.

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