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Indication -
Endocrine disorders
Prolactin
Assay formats
Immunoassay
Status history
First added in 2020
Purpose type
Diagnosis, Monitoring
Purpose
To diagnose and monitor hyperprolactinaemia (including prolactinoma)
Specimen types
Serum, Plasma
WHO prequalified or recommended products
N/A
WHO supporting documents
N/A
Codes
ICD11 code:
5B3Z
Summary of evidence evaluation
The main goal of the test for prolactin is to diagnose hyperprolactinaemia (including caused by a prolactinoma) and to follow up patients treated for hyperprolactinaemia (including prolactinoma).
Guidelines suggest that prolactin measurement using immunoassays for detecting hyperprolactinaemia is appropriate. Both guidelines and reviews repeatedly emphasize that prolactin measurement alone is insufficient to further subclassify the etiologic cause of hyperprolactinaemia (e.g. pituitary tumour, drugs, idiopathic). For that, other tests such as anamnesis, biomarker measurement (thyroid-stimulating hormone (TSH), free T4 and creatinine) and MRI scans are needed.
The claims made on the diagnostic accuracy of PRL testing for hyperprolactinaemia are not made in terms of traditional diagnostic test accuracy measures, although they do suggest that it is adequate. The submission only lists one study with diagnostic test accuracy of PRL for etiologic causes of hyperprolactinaemia.
Claims made of impact on health outcomes or costs assume that a root cause of hyperprolactinaemia is identified, and are circumstantial. No evidence-based conclusion can be drawn for the effect of PRL testing on health outcomes or costs.
The full evidence review for this test category is available online at: https://www.who.int/medical_devices/diagnostics/selection_in-vitro/selection_in-vitro-meetings/new-prod-categories_3
Summary of SAGE IVD deliberations
Prolactinoma is a pituitary tumour that responds to medical treatment and, if necessary, to surgical treatment. PRL testing is a simple test that is commonly used in clinical practice to diagnose and follow up on prolactinoma and conditions associated with hyperprolactinaemia, such as infertility and menstrual irregularities. While the EML does not include any medicines for managing hyperprolactinaemia, PRL testing for it is included in the guidelines of many professional societies. There is limited evidence regarding the test’s impact on health outcomes or cost.
SAGE IVD raised concerns about the potential to overuse PRL testing as well as the potential for abnormal results that are not associated with hyperprolactinaemia. Like cortisol testing, PRL testing requires appropriate laboratory infrastructure and quality assurance. And, depending on the type of assay used, PRL testing can also be affected by biotin ingested by the patient.
Importantly, SAGE IVD emphasized the need to interpret PRL results with care, not least because macroprolactin, which is present in 3.7% of the general population, causes high levels of PRL but is inactive. The group noted that laboratory procedures such as precipitation by polyethylene glycol are required to estimate the amount of biological active monomeric PRL.
SAGE IVD recommendation
SAGE IVD recommended including the prolactin test category in the third EDL:
• as a disease-specific IVD for use in clinical laboratories (EDL 3, Section II.b, within a new subsection for endocrine disorders);
• using an immunoassay format;
• to diagnose and monitor hyperprolactinaemia (including prolactinoma).
The group further requested the addition of a note to the test category entry in the EDL stating that it is only recommended for use in specialized health care settings.
Details of submission from 2020
Background
Disease condition and impact on patients
The main function of PRL lies in the development of mammary glands, milk synthesis and maintenance of milk secretion during pregnancy and lactation. Serum prolactin levels rise rapidly during pregnancy with increase in the size and number of lactotrophs. During lactation, suckling induces rapid secretion of PRL via a neuroendocrine reflex pathway. In the absence of pregnancy, hyperprolactinaemia (elevated levels of PRL) may present with symptoms of HH, including menstrual disturbance and infertility or visual symptoms from a pituitary mass effect by a prolactinoma, the most common pituitary tumour.
Prolactinoma is a benign tumour of the pituitary gland. It is divided into microadenoma (< 10 mm) or macroadenoma (> 10 mm). Symptoms include infertility, galactorrhoea (milk leaking from nipples), amenorrhoea or oligomenorrhoea, loss of libido, vaginal dryness, acne, hirsutism as well as visual or neurological symptoms caused by the mass of the tumour itself. Treatment is primarily medical (bromocriptine or cabergoline as first-line agents); but a surgical approach may be needed in large tumours that compress other brain structures and do not respond to the pharmacological approach.
There are many other causes of functional hyperprolactinaemia, including stress, medicines, pregnancy and compression of the pituitary stalk by other tumours. These (usually) mild elevations of PRL may be symptomatic or asymptomatic and do not usually require pharmacological treatment.
Does the test meet a medical need?
Determining serum PRL is the key test for diagnosing hyperprolactinaemia secondary to prolactinoma. When history and PRL levels are suggestive, magnetic resonance imaging (MRI) is needed to define the presence of a lesion compatible with a pituitary tumour (1, 2). A prolactinoma diagnosis cannot be made without measuring PRL levels, which makes the test necessary for specific pharmacological treatment.
Assay-specific normal values are higher in women than men and are generally lower than 25 μg/L. In patients with pituitary adenomas, including prolactinomas, lengthy active disease is associated with a greater risk of comorbidities and lower quality of life. Timely diagnosis and treatment is therefore recommended to prevent or at least limit deleterious effects of hormone excess. Compared with no treatment, appropriate treatment (pharmacological with dopamine agonists or surgical resection of the adenoma) can lead to disease remission, improved quality of life, decreased incidence and severity of comorbidities, and fewer deaths.
Regardless of cause, hyperprolactinaemia is frequently associated with hypogonadism and its consequences. Timely diagnosis and treatment have been shown to reverse these symptoms and others. Normalizing PRL levels restores fertility in more than 80–90% of patients with prolactinomas, at a significantly lower cost compared with fertility induction treatments. Quality of life is impaired in patients with hyperprolactinaemia; indeed, studies have shown that it is inversely associated with PRL levels among these patients, reinforcing the importance of providing adequate disease control.
Treating prolactinomas aims to reverse clinical signs, decrease tumour size, restore gonadal function and other pituitary hormone deficiencies, and prevent tumour recurrence and progression. All these are usually achieved progressively, as the concentrations of serum PRL normalize. Measuring PRL can help during medical treatment adjustment. The Endocrine Society guidelines recommend periodic PRL measurement starting 1 month after therapy, to guide treatment intensification so as to achieve normal PRL levels and reverse hypogonadism.
How the test is used
PRL is measured in the serum in symptomatic patients through a single blood test. Dynamic testing has no demonstrated advantages. The first step in diagnosing and evaluating hyperprolactinaemia is a detailed history of clinical symptoms and possible causes, including medications, comorbidities and lifestyle factors. The physical examination evaluates signs of hypothyroidism, hypogonadism, renal failure and visual field defects. Blood samples should be collected under resting basal conditions without excessive venepuncture stress. A serum PRL result above the upper limit of normal after ruling out macroprolactin or other interferences (medicines, stress) is required to diagnose hyperprolactinaemia. Sometimes a repeat PRL test is needed if the initial prolactin result is borderline high, especially in children, or if the normal reference interval provided by the laboratories is not appropriate.
The use of PRL measurement to diagnose hyperprolactinaemia, however, is not simple (3, 4).
First, elevated PRL levels can be caused by other conditions, which need to be ruled out before a diagnosis of hyperprolactinaemia can be considered. Although PRL levels above 200–250 μg/L suggest prolactinomas, they can also occasionally be found in people with macroprolactinaemia, drug-induced hyperprolactinaemia, chronic renal failure, primary hypothyroidism and pregnancy.
Second, macroprolactinaemia is a common finding that must be identified as it usually requires no treatment. Most macroprolactinaemic patients are asymptomatic, but many can present coincidental galactorrhoea or menstrual disorders, as well as neuroradiological abnormalities, due to the presence of other diseases. Macroprolactinaemia is the third most frequent cause of non-physiological hyperprolactinaemia after drugs and prolactinomas.
Third, the hook effect, which is an assay artifact caused by an extremely high PRL level, can result in falsely low PRL results. The hook effect should be considered in all cases of large (≥ 3 cm) pituitary adenomas associated with normal or mildly elevated PRL levels (≤ 250 μg/L). An overlooked hook effect may lead to incorrect diagnosis and unnecessary surgical intervention in patients with prolactinomas, and may be identified by repeating PRL measurement after a 1 : 100 serum sample dilution.
Fourth, patients with non-functioning pituitary adenomas typically have PRL levels of 100 μg/L, but there are frequent exceptions. Up to 25% of patients harbouring a microprolactinoma or a cystic macroprolactinoma may have PRL levels below 100 μg/L.
Serum PRL levels are key to follow-up in patients under medical treatment. They are used to titrate the dose of the dopamine agonist (1, 2, 5). There are no evidence-based recommendations for how often to measure PRL during treatment, but common practice is initially every 1–3 months, followed by every 3–6 months once PRL levels normalize, and yearly after treatment finishes (sooner if there are symptoms).
Public health relevance
Prevalence and socioeconomic impact
Hyperprolactinaemia is one of the most frequently diagnosed clinical disorders in routine endocrine practice. It is prevalent in around 0.4% of the general adult population, but its prevalence increases substantially among people with reproductive diseases (6). Hyperprolactinaemia is noted in 15–20% of women with secondary amenorrhoea or oligomenorrhoea, in approximately 30% of those with galactorrhoea or infertility, and in 75% of those with both amenorrhoea and galactorrhoea. (7, 8). Its prevalence was reported to be 5% in a family planning clinic and 17% among women with PCOS.
PRL-secreting tumours (prolactinomas) are the most frequently occurring pituitary tumours and account for up to 40% of pituitary adenomas in the clinical setting. They are divided into microadenomas (≤ 10 mm diameter) and macroprolactinomas (≥ 10 mm). They occur with an incidence of 6–10 cases per million population per year, which translates into a prevalence of approximately 60–100 cases per million (1, 8). Recent research indicates, however, that the prevalence of all pituitary tumours, including prolactinomas, may be three to five times higher than once thought. A prevalence of 55 per 71 000 (775 per million) inhabitants was found in Belgium (9), with similar findings in other populations (9–11). The prevalence of pituitary adenomas has been estimated to be higher than 10% in imaging-based screening or autopsy studies, although most of these patients have small tumours and are asymptomatic (12).
In young adults, prolactinomas occur much more frequently in women than in men, with a female-to-male ratio of approximately 10 : 1 between the ages of 20 and 50 years (8). The highest incidence rate is found in women between 25 and 34 years of age: almost 24 per 100 000 person-years (13). It is possible that the diagnosis is more frequent in young adult women because of the sensitivity of menses to disruption by hyperprolactinaemia. The adenomas that occur in men are usually larger, in part due to the lack of symptoms or delay in seeking medical attention for symptoms such as erectile dysfunction; but adenomas in men may also have an inherently greater rate of growth. Over the age of 50 there are no differences across gender. Prolactinomas are rare in children and adolescents, but they still account for approximately half of all pituitary adenomas in that population (8, 13–15).
Pregnancy, breastfeeding, stress, exercise and sleep can also elevate PRL levels in generally healthy people (16, 17). Medication-related hyperprolactinaemia has been reported in up to 25–30% of patients treated with neuroleptics, neuroleptic-like drugs and antidepressants, and in 5% of patients taking H2-receptor antagonists. In such drug-induced cases, PRL elevation is usually mild but can be highly variable. Risperidone and metoclopramide can lead to PRL levels above 200 μg/L (18, 19).
Hyperprolactinaemia inhibits the secretion of hypothalamic GnRH. Consequently, the most common symptoms of hyperprolactinaemia in premenopausal women are amenorrhoea and galactorrhoea, while symptoms in men include impotence and decreased libido. Hyperprolactinaemia is an important cause of infertility among both genders. Bone loss and vertebral fractures are common comorbidities of hyperprolactinaemia-mediated sex steroid attenuation (20). In particular, spinal bone density is decreased, although overt osteoporosis is rare. Metabolic consequences of untreated hyperprolactinaemia can be expected (21).
Even though there are few available data on mortality associated with hyperprolactinaemia, studies have suggested that high serum PRL levels might be associated with an increased risk of death (22). In a recent study, no increased mortality was observed in patients with pituitary microadenomas, but other subgroups – including pituitary macroadenomas, drug-induced and idiopathic hyperprolactinaemia – had an increased risk of death, with adjusted hazard ratios ranging between 2.8 and 3.7 (23).
Quality of life is significantly affected in patients with hyperprolactinaemia. Hyperprolactinaemia causes infertility by interfering with ovulation. Infertility has particularly severe consequences for men and women in LMICs, including stigma, detrimental psychological effects and loss of economic security (24). Patients with hyperprolactinaemia have lower scores in physical functioning, general health, social functioning, emotional aspect and mental health. Treatment of prolactinoma, either with surgery or with bromocriptine and cabergoline, has been linked to a QALYs gain of approximately 20 years (25).
WHO or other clinical guidelines relevant to the test
In all guidelines, PRL levels are considered to be normal if less than 25 μg/L, with an association between tumour size and PRL levels. PRL levels above 250 μg/L usually indicate the presence of a prolactinoma, although some drugs, including risperidone and metoclopramide, may cause PRL elevations above 200 μg/L. If there is hyperprolactinaemia discordant with the clinical picture, macroprolactin measurement is recommended.
The Endocrine Society clinical guidelines (26) recommend dopamine agonist therapy to lower PRL levels, decrease tumour size and restore gonadal function for patients harbouring symptomatic PRL-secreting microadenomas or macroadenomas.
Evidence for diagnostic accuracy
No systematic review of the accuracy of the PRL test in clinical studies could be found.
Saleem et al. (26) look at the issues relating to the laboratory measurement of PRL and find considerable variability in routinely available PRL immunoassays as a result of differing reactivity towards monomeric PRL and macroprolactin and lack of commutability of the WHO third International Standard between routine methods. Macroprolactinaemia is a relatively common cause of interference in the PRL assay that may lead to incorrect diagnosis and unnecessary investigations. Measuring PRL after precipitation by polyethylene glycol when PRL levels are above the reference interval is routinely used to identify macroprolactin, although harmonization of the precipitation process and reporting may improve clinical care.
As the differential diagnosis for hyperprolactinaemia is very broad, other causes must be ruled out before considering a diagnosis of prolactinoma (27). Kawaguchi et al. (28) did a retrospective chart review to differentiate prolactinomas from non-functioning pituitary tumours and found the area under the ROC to be 0.96, with 99% sensitivity and 81% specificity at a cut-off PRL value of 38.6 μg/L. But this PRL level also included 18.9% of patients with non-functioning pituitary adenomas. The study has some limitations, including the fact that the authors did not identify macroprolactin. This showed that PRL alone is not definitive for diagnosing prolactinoma. Neuroimaging may help reduce false-positive diagnoses. Some studies even propose using PRL/adenoma maximum diameter and PRL/adenoma volume to distinguish prolactinoma from other types of pituitary adenomas (29).
Evidence for clinical usefulness and impact
Measurement of serum PRL is required to diagnose and manage hyperprolactinaemia.
In 2012, Wang et al. (30) did a systematic review and meta-analysis of outcomes of hyperprolactinaemic patients, including micro- and macroprolactinomas, to provide evidence-based recommendations for practitioners. The authors aimed to compare efficacy and adverse effects of medications, surgery and radiotherapy in the treatment of hyperprolactinaemia. The review included eight randomized and 178 non-randomized studies (more than 3000 patients). Compared with no treatment, dopamine agonists significantly reduced PRL levels (weighted mean difference: –45; 95% CI: –77 to –11) and the likelihood of persistent hyperprolactinaemia. Cabergoline was more effective than bromocriptine in reducing persistent hyperprolactinaemia, amenorrhoea/oligomenorrhoea and galactorrhoea. A large body of non-comparative literature showed dopamine agonists improved other patient-important outcomes. Low-to-moderate quality evidence was found supporting improved outcomes with surgery and radiotherapy compared with no treatment in patients who were resistant to or intolerant of dopamine agonists. Their results provide evidence to support the use of dopamine agonists in reducing PRL levels and persistent hyperprolactinaemia, with cabergoline proving to be more efficacious than bromocriptine.
Another systematic review and meta-analysis of randomized controlled trials by dos Santos Nunes et al. (31) compared cabergoline with bromocriptine for treating patients with idiopathic hyperprolactinaemia and prolactinomas and found similar results. The meta-analysis of normalization of serum PRL levels and menstruation with return of ovulatory cycle showed a significant difference in favour of cabergoline, with a risk ratio (RR) of 0.67 (95% CI: 0.57–0.80) and 0.74 (95% CI: 0.67–0.83), respectively. The number of adverse effects was significantly higher in the bromocriptine group (RR 1.43 ). This showed new evidence favouring the use of cabergoline compared with bromocriptine for treating prolactinomas and idiopathic hyperprolactinaemia. Further support for the use of cabergoline is provided by a systematic review on the treatment of giant prolactinomas by Huang et al. (32).
As for the impact of treatment on other comorbidities, a recent meta-analysis by D’Sylva et al. (33) showed that fracture prevalence was increased in patients with untreated hyperprolactinaemia compared with those on treatment, independent of gonadal function; this preliminary evidence would support treatment in postmenopausal women with no other symptoms.
There are several studies showing the clinical impact of treating hyperprolactinaemia; 10 have been chosen based on clinical relevance and publication date.
Various studies show that dopamine agonists normalize PRL levels and reduce the size of prolactinomas in a significant proportion of patients. For example, Berinder et al. (34) found that among women with hyperprolactinaemia, treatment with dopamine agonists (including bromocriptine, cabergoline and quinagolide) normalized PRL levels in 71% of patients, with 80% exhibiting total or partial tumour shrinkage. Similarly, Colao et al. (35) did a prospective study of patients with macroprolactinomas and found normal PRL levels were achieved within 6 months in 81% of patients receiving cabergoline, with 92% exhibiting significant tumour shrinkage. This effect has also been shown in patients with idiopathic hyperprolactinaemia: in Verhelst et al.’s (36) retrospective study, cabergoline normalized PRL levels in 92% of patients with idiopathic hyperprolactinaemia or a microprolactinoma and in 77% of patients with macroadenomas. Pinzone et al. (37) found that 80% of men with prolactinomas had normalized PRL after treatment with other dopamine agonists. And Ono et al. (38) showed that individualized high-dose cabergoline treatment can normalize hyperprolactinaemia and hypogonadism, irrespective of tumour size or preceding treatments, even for large tumours previously thought to have poor response (38).
Ezzat et al. (12) found that hyperprolactinaemia treatment induces restoration of menses. Ono et al. (39) also found that high-dose cabergoline in infertile women with prolactinoma showed high rates of pregnancy with uneventful outcomes. And de Rosa et al. (40, 41) did studies in men which showed that treatment with cabergoline restored erectile function and sperm count and motility.
As for other comorbidities related to hyperprolactinaemia, recent studies by Auriemma et al. (42) and Berinder et al. (43) associate the treatment of prolactinoma with reduced prevalence of metabolic syndrome and improved metabolic profile.
Evidence for economic impact and/or cost–effectiveness
It is important to ensure proper use of the PRL test. For instance, health professionals should know that using antipsychotic medications causes hyperprolactinaemia. Inappropriate detection of hyperprolactinaemia in these patients has been associated with substantial health care costs. A retrospective study of 1000 patients receiving antipsychotic medications in the USA found that compared with the hyperprolactinaemia-free cohort, health care costs increased by nearly US$ 6000 in the hyperprolactinaemia group (44). There are no studies on health care costs of this condition in low-resource settings, but these data emphasize the importance of properly educating health care professionals and the risk of overusing this test.
Ethical issues, equity and human rights issues
The availability of the PRL test will enable the diagnosis of hyperprolactinaemia due to prolactinoma and other causes. Pharmacologic treatment of hyperprolactinaemia has proven to be clearly beneficial in terms of several patient outcomes. Their use controls hormonal secretion and tumour growth in approximately 80% of cases and also leads to resolution of symptoms, including infertility, amenorrhoea, sexual dysfunction and galactorrhoea.
1. Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, et al. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(2):273–288. doi:10.1210/jc.2010-1692.
2. Casanueva FF, Molitch ME, Schlechte JA, Abs R, Bonert V, et al. Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas. Clin Endocrinol. 2006;65(2):265–273. doi:10.1111/j.1365-2265.2006.02562.x.
3. Vilar L, Vilar CF, Lyra R, Freitas MDC. Pitfalls in the diagnostic evaluation of hyperprolactinemia. Neuroendocrinology. 2019;109(1):7–19. doi:10.1159/000499694.
4. Vilar L, Fleseriu M, Bronstein MD. Challenges and pitfalls in the diagnosis of hyperprolactinemia. Arq Bras Endocrinol Metabol. 2014;58(1):9–22. doi:10.1590/0004-2730000003002.
5. Snyder PJ. Management of hyperprolactinemia. In: UpToDate . Waltham: UpToDate Inc; 2019 (https://www.uptodate.com/contents/management-of-hyperprolactinemia?topicRef=6638&source=see_link, accessed 30 March 2020).
6. Biller BM, Luciano A, Crosignani PG, Molitch M, Olive D, et al. Guidelines for the diagnosis and treatment of hyperprolactinemia. J Reprod Med. 1999;44(12):1075–1084.
7. Mancini T, Casanueva FF, Giustina A. Hyperprolactinemia and prolactinomas. Endocrinol Metab Clin North Am. 2008;37:67–99. doi:10.1016/j.ecl.2007.10.013.
8. Ciccarelli A, Daly AF, Beckers A. The epidemiology of prolactinomas. Pituitary. 2005;8(1):3–6. doi:10.1007/s11102-005-5079-0.
9. Beckers A, Adam C, Ciccarelli A, Rixhon M, Daly A, et al. Approaching the true prevalence of pituitary tumors. In: ENEA Congress 2004; Abstract O1.1:23 .
10. Fernandez A, Karavitaki N, Wass JA. Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clin Endocrinol. 2010;72(3):377. doi:10.1111/j.1365-2265.2009.03667.x.
11. Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA, et al. High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium. J Clin Endocrinol Metab. 2006;91(12):4769–4775. doi:10.1210/jc.2006-1668.
12. Ezzat S, Asa SL, Couldwell WT, Barr CE, Dodge WE, et al. The prevalence of pituitary adenomas: a systematic review. Cancer. 2004;101(3):613–619. doi:10.1002/cncr.20412.
13. Davis JR, Farrell WE, Clayton RN. Pituitary tumours. Reproduction. 2001;121(3):363–371. doi:10.1530/rep.0.1210363.
14. Mindermann T, Wilson CB. Age-related and gender-related occurrence of pituitary adenomas. Clin Endocrinol. 1994;41(3):359–364. doi:10.1111/j.1365-2265.1994.tb02557.x.
15. Fideleff HL, Boquete HR, Suárez MG, Azaretzky M. Prolactinoma in children and adolescents. Horm Res. 2009;72(4):197–205. doi:10.1159/000236081.
16. Vance ML, Thorner MO. Prolactin: hyperprolactinemic syndromes and management. In: DeGroot LJ, editor. Textbook of Endocrinology, 2nd edition. Philadelphia: WB Saunders Company; 1989:408–418.
17. Arafah BM, Nasrallah MP. Pituitary tumors: pathophysiology, clinical manifestations and management. Endocr Relat Cancer. 2001;8(4):287–305. doi:10.1677/erc.0.0080287.
18. Petit A, Piednoir D, Germain ML, Trenque T. Drug-induced hyperprolactinemia: a case–non-case study from the national pharmacovigilance database. Therapie. 2003;58(2):159–163. doi:10.2515/therapie:2003023.
19. Molitch ME. Drugs and prolactin. Pituitary. 2008;11(2):209–218. doi:10.1007/s11102-008-0106-6.
20. Mazziotti G, Mancini T, Mormando M, De Menis E, Bianchi A, et al. High prevalence of radiological vertebral fractures in women with prolactin-secreting pituitary adenomas. Pituitary. 2011;14(4):299–306. doi:10.1007/s11102-011-0293-4.
21. Bernabeu I, Casanueva FF. Metabolic syndrome associated with hyperprolactinemia: a new indication for dopamine agonist treatment? Endocrine. 2013;44(2):273–274. doi:10.1007/s12020-013-9914-1.
22. Haring R, Friedrich N, Volzke H, Vasan RS, Felix SB, et al. Positive association of serum prolactin concentrations with all-cause and cardiovascular mortality. Eur Heart J. 2014;35(18):1215–1221. doi:10.1093/eurheartj/ehs233.
23. Soto-Pedre E, Newey PJ, Bevan JS, Leese GP. Morbidity and mortality in patients with hyperprolactinemia: the PROLEARS study. Endocr Connect. 2017;6(8):580–588. doi:10.1530/EC-17-0171.
24. Rouchou B. Consequences of infertility in developing countries. Perspect Public Health. 2013;133(3):174–179. doi:10.1177/1757913912472415.
25. Zygourakis CC, Imber BS, Chen R, Han SJ, Blevins L, et al. Cost-effectiveness analysis of surgical versus medical treatment of prolactinomas. J Neurol Surg B Skull Base. 2017;78(2):125–131. doi:10.1055/s-0036-1592193.
26. Saleem M, Martin H, Coates P. Prolactin biology and laboratory measurement: an update on physiology and current analytical issues. Clin Biochem Rev. 2018;39(1):3–16.
27. Vilar L, Freitas MC, Naves LA, Casulari LA, Azevedo M, et al. Diagnosis and management of hyperprolactinemia: results of a Brazilian multicenter study with 1234 patients. J Endocrinol Invest. 2008;31:436–444. doi:10.1007/bf03346388.
28. Kawaguchi T, Ogawa Y, Tominaga T. Diagnostic pitfalls of hyperprolactinemia: the importance of sequential pituitary imaging. BMC Res Notes. 2014;7:555. doi:10.1186/1756-0500-7-555.
29. Huang Y, Ding C, Zhang F, Xiao D, Zhao L, et al. Role of prolactin/adenoma maximum diameter and prolactin/adenoma volume in the differential diagnosis of prolactinomas and other types of pituitary adenomas. Oncol Lett. 2018;15(2):2010–2016. doi:10.3892/ol.2017.7462.
30. Wang AT, Mullan RJ, Lane MA, Hazem A, Prasad C, et al. Treatment of hyperprolactinemia: a systematic review and meta-analysis. Syst Rev. 2012;1:33. doi:10.1186/2046-4053-1-33.
31. dos Santos Nunes V, El Dib R, Boguszewski CL, Nogueira CR. Cabergoline versus bromocriptine in the treatment of hyperprolactinemia: a systematic review of randomized controlled trials and meta-analysis. Pituitary. 2011;14:259–265. doi:10.1007/s11102-010-0290-z.
32. Huang HY, Lin SJ, Zhao WG, Wu ZB. Cabergoline versus bromocriptine for the treatment of giant prolactinomas: a quantitative and systematic review. Metab Brain Dis. 2018;33(3):969–976. doi:10.1007/s11011-018-0217-3.
33. D’Sylva C, Khan T, Van Uum S, Fraser LA. Osteoporotic fractures in patients with untreated hyperprolactinemia vs. those taking dopamine agonists: a systematic review and meta-analysis. Neuro Endocrinol Lett. 2015;36(8):745–749.
34. Berinder K, Stackenäs I, Akre O, Lindén Hirschberg A, Hulting AL. Hyperprolactinaemia in 271 women: up to three decades of clinical follow-up. Clin Endocrinol. 2005;63(4):450–455. doi:10.1111/j.1365-2265.2005.02364.x.
35. Colao A, Di Sarno A, Landi ML, Scavuzzo F, Cappabianca P, et al. Macroprolactinoma shrinkage during cabergoline treatment is greater in naive patients than in patients pretreated with other dopamine agonists: a prospective study in 110 patients. J Clin Endocrinol Metab. 2000;85(6):2247–2252. doi:10.1210/jcem.85.6.6657.
36. Verhelst J, Abs R, Maiter D, van den Bruel A, Vandeweghe M, et al. Cabergoline in the treatment of hyperprolactinemia: a study in 455 patients. J Clin Endocrinol Metab. 1999;84(7):2518–2522. doi:10.1210/jcem.84.7.5810.
37. Pinzone JJ, Katznelson L, Danila DC, Pauler DK, Miller CS, et al. Primary medical therapy of micro- and macroprolactinomas in men. J Clin Endocrinol Metab. 2000;85(9):3053–3057. doi:10.1210/jcem.85.9.6798.
38. Ono M, Miki N, Kawamata T, Makino R, Amano K, et al. Prospective study of high-dose cabergoline treatment of prolactinomas in 150 patients. J Clin Endocrinol Metab. 2008;93(12):4721–4727. doi:10.1210/jc.2007-2758.
39. Ono M, Miki N, Amano K, Kawamata T, Seki T, et al. Individualized high-dose cabergoline therapy for hyperprolactinemic infertility in women with micro- and macroprolactinomas. J Clin Endocrinol Metab. 2010;95(6):2672–2679. doi:10.1210/jc.2009-2605.
40. de Rosa M, Zarrilli S, Vitale G, Di Somma C, Orio F, et al. Six months of treatment with cabergoline restores sexual potency in hyperprolactinemic males: an open longitudinal study monitoring nocturnal penile tumescence. J Clin Endocrinol Metab. 2004;89(2):621–625. doi:10.1210/jc.2003-030852.
41. de Rosa M, Ciccarelli A, Zarrilli S, Guerra E, Gaccione M, et al. The treatment with cabergoline for 24 months normalizes the quality of seminal fluid in hyperprolactinaemic males. Clin Endocrinol. 2006;64(3):307–313. doi:10.1111/j.1365-2265.2006.02461.x.
42. Auriemma RS, Granieri L, Galdiero M, Simeoli C, Perone Y, et al. Effect of cabergoline on metabolism in prolactinomas. Neuroendocrinology. 2013;98(4):299–310. doi:10.1159/000357810.
43. Berinder K, Nyström T, Höybye C, Hall K, Hulting AL. Insulin sensitivity and lipid profile in prolactinoma patients before and after normalization of prolactin by dopamine agonist therapy. Pituitary. 2011;14(3):199–207. doi:10.1007/s11102-010-0277-9.
44. Cloutier M, Greene M, Touya M, Gagnon-Sanschagrin P, Guerin A. A real-world analysis of healthcare costs and relative risk of hyperprolactinemia associated with antipsychotic treatments in the United States. J Med Econ. 2018;21(12):1183–1190. doi:10.1080/13693998.2018.1521415