Journal ofClinical MedicineReviewHyperprolactinaemiaIrene Samperi 1,2,3, Kirstie Lithgow 1,2,3 and Niki Karavitaki 1,2,3,*1 Institute of Metabolism and Systems Research, College of Medical and Dental Sciences,University of Birmingham, Birmingham B15 2TT, UK; Irene.samperi89@gmail.com (I.S.);Kirstie.Lithgow@albertahealthservices.ca (K.L.)2 Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners,Birmingham B15 2TH, UK3 Department of Endocrinology, Queen Elizabeth Hospital, University Hospitals Birmingham NHSFoundation Trust, Birmingham B15 2TH, UK* Correspondence: n.karavitaki@bham.ac.uk; Tel.: +44-0121-414-3826Received: 20 November 2019; Accepted: 2 December 2019; Published: 13 December 2019 Abstract: Hyperprolactinaemia is one of the most common problems in clinical endocrinology.It relates with various aetiologies (physiological, pharmacological, pathological), the clarificationof which requires careful history taking and clinical assessment. Analytical issues (presence ofmacroprolactin or of the hook effect) need to be taken into account when interpreting the prolactinvalues. Medications and sellar/parasellar masses (prolactin secreting or acting through “stalk effect”)are the most common causes of pathological hyperprolactinaemia. Hypogonadism and galactorrhoeaare well-recognized manifestations of prolactin excess, although its implications on bone health,metabolism and immune system are also expanding. Treatment mainly aims at restoration andmaintenance of normal gonadal function/fertility, and prevention of osteoporosis; further specificmanagement strategies depend on the underlying cause. In this review, we provide an update on thediagnostic and management approaches for the patient with hyperprolactinaemia and on the currentdata looking at the impact of high prolactin on metabolism, cardiovascular and immune systems.Keywords: prolactin; hyperprolactinaemia; prolactinoma; antipsychotics; hypogonadism; dopamineagonists1. IntroductionProlactin (PRL) was first discovered between the late 1920s and early 1930s after different authorsindependently demonstrated lobular-alveolar development and lactation in rabbits after injection ofan anterior pituitary extracts [1,2]. In 1933, the “pro-lactin” hormone was purified from animals andwas given its name by Riddle et al. [3]. It was first separated from growth hormone (GH) in humanpituitary glands by Friesen et al. in 1970 [4], as prior to this, radioimmunoassay differentiating PRLfrom GH was not available [1,2,5–7]. Though initially recognized for its lactogenic action, PRL is nowunderstood to act at many different tissues producing a diverse range of biological functions [8]. PRLbelongs to the PRL/GH/placental lactogen family, the members of which share common structural,functional, and binding properties, and arise from a common ancestral gene [2,8].Secretion of PRL by the pituitary gland has a circadian rhythm with higher levels during sleep andlower during wakefulness [6]. Increased concentrations are also seen during ovulation [9]. Synthesisand secretion of PRL is regulated through both inhibiting and releasing factors [8]. PRL inhibitingfactors include dopamine, gamma-aminobutyric acid (GABA), and somatostatin [8]. Dopamine is themain inhibitory factor involved in PRL regulation and acts through binding to D2 and D4 receptors inthe pituitary lactotrophs. This results in down-regulation of PRL gene expression, reduced secretionof PRL, and decreased lactotroph proliferation [10]. Several hormones and neuropeptides have beenJ. Clin. Med. 2019, 8, 2203; doi:10.3390/jcm8122203 www.mdpi.com/journal/jcmJ. Clin. Med. 2019, 8, 2203 2 of 24suggested to promote PRL release including thyrotropin-releasing hormone (TRH), endogenousopioids, oxytocin, serotonin, vasopressin, vasoactive intestinal polypeptide (VIP), neurotensin, galanin,and salsolinol [8,11]. Nonetheless, PRL is unique from other pituitary hormones in that a physiological“PRL-releasing factor” has not been as yet identified [11]. PRL is also produced in extra-pituitary sitesincluding the ovaries, mammary glands and endometrium, prostate, lymphocytes and hematopoieticcells, skin, adipose tissue, thymus and lymphatic system, endothelium, and the brain [12,13]. It isstructurally identical to pituitary PRL and binds to the same receptor [13]. Its regulation is site specificand differs from that of pituitary PRL [13].The PRL receptor (PRL-R) is a single membrane-bound protein of the cytokine receptor superfamilyand is structurally and functionally similar to the GH receptor [8]. It is expressed in the pituitary and inmany other tissues including the mammary gland, endometrium, ovaries, heart, lung, thymus, spleen,liver, pancreas, kidney, adrenal gland, skeletal muscle, brain, skin and osteoblasts [8,13].The lactotrophic and reproductive actions of PRL are well established, and in recent years,there has been enhanced understanding of the many other biological effects of extra pituitary PRL inhumans [9,13]. In women, it is involved in follicular development and maintenance of the corpus luteum,and also acts on the mammary gland to induce and maintain lactation [14]. In the adrenals, it stimulatesthe secretion of androgens [including dehydroepiandrosterone (DHEA)], cortisol, and aldosterone [9].PRL has been implicated in the stress-induced activation of the hypothalamic-pituitary-adrenal (HPA)axis [9,13,15]. It increases secretion of ACTH, induces adrenal hypertrophy and storage of cholesterolesters, and stimulates cortisol production [9,15]. PRL produced from lymphocytes and hematopoieticcells has been postulated to be involved in the immune response to stress [8,9,13,15]; its action appearsto be dose-related, with immune stimulation at modest and inhibition at high levels [9]. It has varyingeffects on bone during development and reproduction; in the foetus, it promotes bone growth andmineralization, whereas during pregnancy, it contributes to the accelerated bone resorption providingmicronutrients to the foetus [16]. It has vasoconstrictive action and a role in hypertension andpre-eclampsia has been postulated [14]. Finally, it is thought to be involved in osmoregulation byincreasing water and salt absorption in the bowel and reducing renal Na+ and K+ excretion [9].Further possible actions of extra-pituitary PRL have been explored in animal studies. Knock-outPRL-R male mice have infertility proposing a role of PRL in spermatogenesis [10]. Animal modelshave also suggested metabolic actions including stimulating insulin release, beta-cell proliferation,and adipogenesis [10], whereas in the central nervous system, PRL promotes remyelination [9,17].2. Causes and Mechanisms of HyperprolactinaemiaThe aetiology of hyperprolactinaemia is broad and can be divided into physiological, pathological,and pharmacological causes (Table 1) acting though a number of different mechanisms [6].Table 1. Main Causes of Hyperprolactinaemia.Physiological Pathological Pharmacological• Ovulation• Pregnancy• Breastfeeding• Stress• Exercise• Nipple stimulation orchest wall injury• Prolactin-secreting pituitary adenoma• “Stalk-effect” from sellar/parasellar lesions• Renal Failure• Liver Cirrhosis• Primary hypothyroidism• Polycystic Ovarian Syndrome (PCOS)• Seizures• Antipsychotics/neuroleptics• Antidepressants• Antiemetics• Opioids• Antihypertensives2.1. Physiological Causes2.1.1. Endogenous OestrogensOestrogens enhance PRL secretion via different proposed mechanisms including regulationof PRL gene expression, downregulation of dopamine receptor expression, and stimulation ofJ. Clin. Med. 2019, 8, 2203 3 of 24lactotroph cell hyperplasia [8,11]. Accordingly, PRL levels are influenced by the menstrual cycle,menopause, and pregnancy, and any high oestrogen state (e.g., pregnancy) is a potential causehyperprolactinaemia [18,19]. Tanner et al. assessed PRL concentrations in 6540 subjects including men,non-pregnant women at different phases of the menstrual cycle, and post-menopausal women [18].Pre-menopausal women had significantly higher values compared with post-menopausal ones andmen [18]. Furthermore, PRL was significantly higher during ovulation, leading the authors to advocatefor the use of specific reference intervals according to the phase of menstrual cycle, or measurement ofPRL in the early follicular phase [18].Hyperprolactinaemia is a well-established finding during normal pregnancy [19]. In a study of994 women, non-pregnant, pregnant, or post-partum, Hu et al. [19] found PRL levels progressivelyincreasing across the three trimesters of pregnancy; 29.19 to 168.44 µg/L for the first trimester, 67.3 to251.43 µg/L for the second, and 192.1 to 457.48 µg/L for the third one.Increases in PRL can occur with use of oral contraceptives containing high doses of oestrogen(35 mcg) [20] but this has not been shown with modern contraceptives with lower amounts ofoestrogen [19,21].2.1.2. BreastfeedingSuckling during nursing is a strong physiologic stimulus for PRL secretion [8] possibly by releasingthe lactotrophs from the tonic inhibition of dopamine [8,22]. TRH, vasopressin, oxytocin, and salsolinolhave also been proposed as factors involved in the suckling-induced PRL release [8,22].2.1.3. StressHyperprolactinaemia with values usually up to 100 µg/L may be observed as a response tostress [6,15,23] but the responsible mechanism has not been fully elucidated. It has been postulatedthat stress-induced changes in dopamine and serotonin may affect PRL release contributing tohyperprolactinaemia in this setting [15].2.1.4. ExerciseExercise increases PRL in a magnitude proportional to the intensity and duration of the activity [24,25].Elevation in PRL has been observed following both aerobic and anaerobic exercise but it is greatestin high-intensity anaerobic exercise such as interval training [24]. The peak PRL is thought to occurfollowing exercise [24], and, therefore, it is suggested to avoid vigorous exercise for at least 30 min beforeblood sampling for PRL measurement [26]. The mechanism of exercise induced-hyperprolactinaemiahas not been not fully elucidated.2.1.5. Chest Wall InjuryDifferent processes causing chest wall irritation such as burns, herpes zoster, or injury havebeen associated with hyperprolactinaemia [25]. This is thought to take place via a neural mechanisminterfering with dopamine transmission, as that occurs with suckling [8,22]. Despite the findingthat lactation and nipple stimulation can increase PRL [8], breast examination, breast ultrasound,or mammography do not appear to cause hyperprolactinaemia [27–29].2.2. Pathological Causes2.2.1. Prolactin-Secreting Pituitary TumoursThe most common pituitary cause of hyperprolactinaemia is the presence of prolactinoma. Thisis the most frequent subtype of pituitary adenoma (accounting for 57% of all pituitary adenomas),and presents more commonly in females with a peak prevalence in women aged 16 to 48 years [30].Prolactinomas are classified by their size, with microprolactinomas measuring <1 cm andmacroprolactinomas ≥1 cm (giant ones measure >4 cm) [25,31]. In general, the degree ofJ. Clin. Med. 2019, 8, 2203 4 of 24hyperprolactinaemia correlates with prolactinoma size, however, there are some important caveats tothis which will be addressed in the Diagnosis section below. For microprolactinomas, PRL is usually100 to 200 µg/L, however, outliers exist; in the Brazilian Multicenter Study on Hyperprolactinaemiawhich included 444 patients with microprolactinoma, mean PRL was 165 µg/L but ranged from 32 to525 µg/L [32]. Hyperprolactinaemia is also seen in adenomas co-secreting GH and PRL [33,34].Based on the 2017 WHO classification of pituitary adenomas, morphological variants of thelactotroph adenomas are the sparsely granulated, the densely granulated, and the acidophil stem celladenoma which also expresses GH [35]. PRL expression is also seen by immunohistochemistry inpluri-hormonal Pit-1 adenomas, mammosomatotroph adenomas, and mixed somatotroph-lactotrophadenomas [35].Prolactin secreting adenomas can be part of genetic syndromes, such as multiple endocrineneoplasia type 1 (MEN1) or type 4 (MEN4), familial isolated pituitary adenoma (FIPA) or Carneycomplex [36]. MEN1 is an autosomal dominant condition usually due to loss of heterozygosity ofthe MEN1 gene which encodes the menin protein [36]. Clinical features of MEN1 include primaryhyperparathyroidism, pituitary adenomas, and pancreatic neuroendocrine tumours [36,37]. Althoughless than 3% of pituitary adenomas are associated with MEN1, they are present in 30–40% patientswith this syndrome [36,37] with prolactinoma being the most common subtype [36–38]. Inactivatinggermline mutations of the aryl hydrocarbon receptor interacting protein (AIP) gene are found in 20% offamilies with FIPA [39]. Although AIP mutations are usually associated with GH-secreting adenomas,they can also be detected in patients with prolactinoma [39]. Carney complex is an autosomal dominantcondition characterized by spotty skin pigmentation, myxomas, and multiple endocrine hyperfunction;it is most commonly caused by an inactivating germline mutation in the PRKAR1A gene and theprotein it encodes is a type 1A regulatory subunit of protein kinase A [36]. Pituitary adenomas occur in10 to 20% of patients with Carney complex, most are GH secreting tumours but some of them co-secreteGH and PRL [36,40].2.2.2. “Stalk-Effect”Any lesion leading to interruption of the dopaminergic pathways due to compression of thepituitary stalk and portal vessels can lead to hyperprolactinaemia through the “stalk effect” [includingpituitary adenomas with the most common cause in this setting being the non-functioning pituitaryadenomas (NFA); parasellar tumours (such as Rathke’s cleft cyst, craniopharyngioma, meningiomaor germinoma); metastatic pituitary disease, infiltrative/inflammatory diseases (such as lymphocytichypophysitis, Langerhans cell histiocytosis, and sarcoidosis)] [6,25,41]. Stalk compression from NFA orother parasellar tumours is typically associated with PRL levels <100µg/L [42,43]. Hyperprolactinaemiahas also been reported in 7 to 10% of patients with primary empty sella syndrome attributed tocompression of the pituitary gland against the sellar walls causing stretching of the pituitary stalk [44].2.2.3. Renal FailureHyperprolactinaemia is common in patients with renal disease and is recognized as a causeof hypogonadism and sexual dysfunction in these patients [25,45]. PRL usually ranges between 30and 108 µg/L, although rarely, much higher concentrations exceeding 600 µg/L may be observed [45].Increased PRL secretion and decreased PRL clearance are both thought to contribute [25,45].Hyperprolactinaemia resolves following successful renal transplantation [25].2.2.4. Liver CirrhosisHyperprolactinaemia is common amongst patients with cirrhosis with levels less than 100 µg/L.Its degree correlates with the severity of liver disease [46]. The mechanism is thought to be secondaryto decreased dopamine-mediated PRL inhibition, as well as increased circulating oestrogen levels [46].J. Clin. Med. 2019, 8, 2203 5 of 242.2.5. Primary HypothyroidismIt has been suggested that approximately 40% of cases of primary hypothyroidism are associatedwith hyperprolactinaemia [47,48] caused by stimulation of lactotroph cells from the increased TRHlevels [9]. Its magnitude correlates with the degree of TSH elevation [47]. Hyperprolactinaemia istypically mild with values <100 µg/L [47,48]. A further mechanism of hyperprolactinaemia secondaryto untreated primary hypothyroidism is thyrotroph hyperplasia, which can mimic a pituitary adenomaand induce hyperprolactinaemia via the “stalk effect” [25,49].2.2.6. Polycystic Ovarian SyndromeHyperprolactinaemia has been reported in 7 to 52% of women with polycystic ovarian syndrome(PCOS) [50,51]. Its pathogenesis has not been elucidated; oestrogen-mediated stimulation of lactotrophsand relative dopamine deficiency have been proposed [50,51]. Given the presence of PRL receptors inthe adrenal gland [8], it has also been postulated that hyperprolactinaemia stimulates adrenal androgenproduction contributing to the hyperandrogenism of PCOS [51]. It should be noted that whetherhyperprolactinaemia is truly a clinical feature of PCOS remains controversial. A case-control study of82 women with PCOS showed no difference in the prevalence of hyperprolactinaemia compared towomen with insulin resistance, and notably, all cases of hyperprolactinaemia in the women with PCOSwere finally attributed to a prolactinoma or medication use [52].2.2.7. SeizuresHyperprolactinaemia following seizures is transient with peak levels 10 to 20 min post-seizureand resolution within 2 to 6 h [53]. It has been proposed that this occurs due to propagation of epilepticactivity from the temporal lobe to the hypothalamo-pituitary axis [54]. It is most common followinggeneralized tonic-clonic seizures and can also be seen after alcohol withdrawal seizures or complexpartial seizures; it is rare following simple partial or psychogenic non-epileptic seizures [53]. PRL is,therefore, a potentially useful biomarker in differentiating epileptic seizures from non-epileptic onesbut the sensitivity and specificity of this are highly variable across different series [53].2.3. PharmacologicalA number of drugs can alter PRL homeostasis leading to hyperprolactinaemia via different mechanisms.The most common culprit medications are antipsychotics/neuroleptics and antidepressants [6,55] and themain mechanisms involve reduction in dopamine transmission and increase in serotonin transmission(with the latter leading to augmentation of PRL releasing factors, like oxytocin and VIP) [55,56].The prevalence of hyperprolactinaemia amongst different classes of medications is shown in Table 2.Table 2. Prevalence of hyperprolactinaemia (HPRL) amongst different medications [57,58].DrugClassNo SignificantHPRLHPRL in<25% of PatientsHPRL in25–50% of PatientsHPRL in>50% of PatientsTypicalantipsychotics• Loxapine• Pimozide• Butyrophenone• Phenothiazines• ThioxanthenesAtypicalantipsychotics• Aripiprazole• Clozapine• Ziprasidone• Olanzapine• Quetiapine• Amisulpride• Risperidone• Sultopride• Sulpiride• TiaprideJ. Clin. Med. 2019, 8, 2203 6 of 24Table 2. Cont.DrugClassNo SignificantHPRLHPRL in<25% of PatientsHPRL in25–50% of PatientsHPRL in>50% of PatientsTricyclicantidepressants • Nortriptyline• Amitriptyline• Amoxapine• Clomipramine• Desipramine• Doxepin• Imipramine• Maprotiline• Trimipramine• ClomipramineMonoamine oxidaseinhibitors• Clorgiline• PargylineAntiemetics• Alizapride• Domperidone• Metoclopramide• MetopimazineAntihypertensives • Methyldopa• Reserpine • Verapamil2.3.1. AntipsychoticsAntipsychotics are typically divided into those with PRL-rising and PRL-sparing potential [56].Possible explanations for these differences include variations in the speed of dissociation fromthe D2R, ability to cross the blood-brain barrier, presence of D2R polymorphisms, and degree ofserotonergic inhibition [55,56,59]. First generation antipsychotics are typically associated with moresevere hyperprolactinaemia (two to three times the upper limit of normal) [55]. Second generationantipsychotics have lower D2R affinity and stronger 5HT2A receptor blockage leading to milder PRLelevations [55]. Exceptions to this are risperidone, paliperidone and amisulpride, all second-generationantipsychotics that can cause significant hyperprolactinaemia [55,56]. Both oral and depot formulationsof risperidone and paliperidone increase PRL in a dose dependent manner. Amisulpride is thought tohave the greatest potential for hyperprolactinaemia of all antipsychotics; these effects occur independentof dose and can resolve rapidly after discontinuation of the drug [55]. Aripiprazole and quetiapineshow the lowest possibility for hyperprolactinaemia [55,56].The PRL raising potential of commonly used first and second-generation antipsychotics is shownin Table 3.Table 3. Hyperprolactinaemia (HPRL) amongst different antipsychotics.Drug Mild HPRL (<50 µg/L)(% of Patients)Moderate HPRL (50–100 µg/L)(% of Patients)Severe HPRL (>100 µg/L)(% of Patients)Aripiprazole * √ (0.36) √ (2.55)Olanzapine * √ (26.66) √ (11) √ (2)Quetiapine * √ (9.09) √ (9) √ (5)Depot Risperidone * √ (30.76) √ (23.07) √ (30.79)Oral Risperidone * √ (14.58) √ (43.75) √ (22.91)Oral Paliperidone * √ (18.18) √ (45.45) √ (18.18)Depot Paliperidone * √ (13.33) √ (40) √ (40)Phenothiazines ** √Amisulpride *** √ (45%)Sulpiride ∞ √Haloperidol † √ √* [56], ** [60], *** [61], ∞ [62], † [63].J. Clin. Med. 2019, 8, 2203 7 of 242.3.2. AntidepressantsDifferent classes of antidepressants, including monoamine oxidase inhibitors, tricyclic antidepressants,and selective serotonin reuptake inhibitors (SSRIs) induce hyperprolactinaemia mainly via serotonergicpathways [55,59]. This is typically mild and it is rarely symptomatic [59].2.3.3. AntiemeticsThe antiemetics domperidone and metoclopramide antagonize D2R and can acutely inducehyperprolactinaemia [55,59]. These effects can be harnessed for increasing breast milk production forbreastfeeding [64].2.3.4. OpioidsOpioids can cause hyperprolactinaemia mediated by µ-, κ- and δ-opioid receptors in thehypothalamus [65]. Acute oral or iv opioid administration can induce hyperprolactinaemia inmen and post-menopausal women, while the findings after chronic opioid use have been mixed [65].High PRL has been found in individuals with opioid addiction, with opium smoking and on oralopioids for chronic pain, but not with intrathecal morphine or opioid maintenance therapy withbuprenorphine or methadone [65].2.3.5. AntihypertensivesVerapamil is a non-dihydropyridine calcium channel blocker of the phenylalkylamine class [66].This specific class of calcium channels blocker causes hyperprolactinaemia due to suppression oftuberoinfundibular dopamine; this is not seen with the other commonly used non-dihydropyridineagents diltiazem and nifedipine [67]. Methyldopa is a competitive inhibitor of the enzyme DOPAdecarboxylase and causes hyperprolactinaemia through inhibition of dopamine synthesis [58].Reserpine is an alkaloid used for treatment of hypertension and psychosis; it reduces dopaminetransmission by blockade of vesicular monoamine transporter type 2 in monoamine neurons [68].3. Clinical ManifestationsThe clinical manifestations of hyperprolactinaemia mainly relate with the reproductivesystem [25,43]. The patients may also have other signs and symptoms depending on the aetiologyof the PRL excess (e.g., mass effects, in case of a pituitary tumour (headaches, visual disturbances,hypopituitarism)).3.1. Reproductive Manifestations3.1.1. WomenHyperprolactinaemia suppresses GnRH (via reduction of kisspeptin in the hypothalamic arcuateand periventricular neurons) leading to a decrease in LH pulse amplitude and frequency [43]. It alsodecreases ovarian oestrogen and progesterone production [43]. These result in menstrual irregularities(amenorrhoea or oligomenorrhoea), infertility, decreased libido and galactorrhoea [25]. Galactorrhoea(spontaneous or provoked) is a common manifestation in pre-menopausal females (up to 90%), butoccurs less often in post-menopausal ones as the mammary glands are not primed with oestrogen andprogesterone [69].Hyperandrogenism may be also a manifestation of hyperprolactinaemia due to stimulation of adrenalandrogen production [51,70–72]. In a prospective study including 101 medically and 22 surgically treatedpatients with prolactinoma and normal cortisol reserve, decreases in the adrenal steroid DHEA-Sparalleled PRL reduction after treatment with dopamine agonist or surgery [72]. However, this studydid not report on clinical symptoms of hyperandrogenism [72]. It is also unclear whether there is a linkbetween hyperprolactinaemia and female pattern hair loss [73]. It is possible that PRL exacerbatesJ. Clin. Med. 2019, 8, 2203 8 of 24hyperandrogenism in clinically predisposed women, such as those with PCOS [51] but further studiesare needed on this topic.3.1.2. MenIn males, hyperprolactinaemia causes hypogonadotropic hypogonadism [74] manifesting withreduced libido, erectile dysfunction, and impaired spermatogenesis [75]. Gynaecomastia (secondary tohypogonadism) and galactorrhoea occur rarely [75]. Anaemia, decreased energy and muscle massmay be also present as secondary manifestations of hypogonadism [71,76].3.2. Bone ManifestationsIt is well established that hypogonadotropic hypogonadism has negative impacts on bonehealth [77]. Furthermore, in vitro studies have demonstrated that PRL has variable effects on bonemetabolism, depending on its levels. PRL within the physiological range stimulates bone formation,mild hyperprolactinaemia increases bone resorption, and marked hyperprolactinaemia further increasesbone resorption and inhibits bone formation [77]. This is supported by findings that patients withprolactinoma have suppressed osteocalcin, high NTX (collagen type I crosslinked N-telopeptide),and increased RANKL (receptor activator of nuclear factor-kB ligand)/OPG (osteoprotegerin) ratio,suggesting increased bone resorption and decreased bone formation [77,78]. The relative contribution ofhypogonadotropic hypogonadism and hyperprolactinemia is controversial and it has been hypothesizedthat these mechanisms have synergistic effects on bone loss [77]. In vitro and animal studieshave suggested that hyperprolactinaemia directly stimulates bone resorption independently ofhypogonadism [77] but further research on this topic is needed.Bone loss affects both men and women with prolactinoma, and reduced bone mineral density ismore common in the lumbar spine than in the hip, suggesting that trabecular bone may be damagedearlier than cortical bone [77,79]. In a case control study, higher rates of vertebral fractures were foundin women with prolactinoma compared with controls [80]. A systematic review and meta-analysisdemonstrated that rates of vertebral fractures were significantly lower in treated vs. untreated menand women with prolactinoma, independent of gonadal function [81].4. Diagnostic Approach4.1. Blood Sampling for PRLCurrent guidelines state that serum PRL can be drawn at any time of day [25]. Exercise and nipplestimulation should be avoided for at least 30 min prior to testing [26].Typically, normal PRL levels are <20 µg/L in men and <25 µg/L in women [82], however, itis important to interpret the results according to the assay specific reference ranges [83], and alsoconsidering pre/post-menopausal status. [18,19]. A single PRL value above the upper limit of normalcan be sufficient for confirmation of hyperprolactinaemia, provided blood sampling took place withoutexcessive venepuncture stress [25]. However, if there is doubt, particularly in cases of mildly elevatedPRL, sampling could be repeated at 15 to 20 min intervals to account for pulsatility [9,25]. Dynamictests are not currently used for establishing the diagnosis of hyperprolactinaemia [25].4.2. Biochemical Interpretation4.2.1. MacroprolactinMost circulating PRL (23 kDa) is monomeric, however, serum also contains larger isoforms includingdimeric PRL or big PRL (45 to 60 kDa) and polymeric or big-big PRL (150 to 170 kDa) [25,26]. Big-bigPRL, termed macroprolactin, is mostly complexes of prolactin-IgG, prolactin-IgA, or polymericaggregates of highly glycosylated PRL monomers [84]. In most individuals, the majority ofserum PRL (~85%) is monomeric but in others there is preponderance of macroprolactin, referredJ. Clin. Med. 2019, 8, 2203 9 of 24to as macroprolactinaemia [25,26]. The prevalence of macroprolactinaemia amongst cases withhyperprolactinaemia is reported between 4% and 40% [25,26,85]. Although macroprolactin is notconsidered to have significant biological activity, it retains partial or total immunoreactivity withanti-PRL antibodies used in commercial immunoassays [83–85]. Detection of macroprolactin isclinically important to avoid incorrect diagnosis and unnecessary investigations [83]. Gel filtrationchromatography is regarded as the “gold standard” technique, however, it is labour-intensive andexpensive [83,84,86]. Polyethylene glycol (PEG) precipitation is the most widely used method, as it issimple, fast, and cost effective [25,83,84,86]. It involves mixing and incubating the serum with 25% PEGwhich is then centrifuged and the precipitating PRL complexes are subsequently quantified [83,84,86].Recovery of free PRL > 60% of the total is suggestive of monomeric hyperprolactinaemia, whereasrecovery <40% is consistent with macroprolactinaemia [33,86].Despite the general view that macroprolactin does not have significant biological activity, in recentyears, this has been a matter of debate [83,85]. Thus, it has been proposed that macroprolactin candissociate into biologically active monomeric isoforms; nonetheless, studies assessing the biologicalactivity of macroprolactin in vitro have yielded conflicting results [83,85,86]. Kalsi et al. [87] in a studyof 102 hyperprolactinaemic individuals, found that 68.8% of those with macroprolactinaemia hadreproductive manifestations that could not be otherwise explained. This led the authors to proposethat macroprolactin may have some degree of biological activity [87] but these findings require furthervalidation. In daily practice, if macroprolactin is not assessed in local hospital laboratories, this can beevaluated in most reference laboratories upon request.4.2.2. Hook EffectHook effect is another analytical issue important in clinical practice [25,26]. It is encounteredin the presence of excessively high PRL levels (as seen with macro- or giant prolactinomas) whichsaturate the antibodies used in the two-site immunoradiometric assay leading to artificially low PRLvalues [25,26]. Failure to recognize this effect may result in missing the diagnosis of a prolactinomaand to incorrect therapeutic decisions [88]. Large pituitary macroadenomas (>3 cm with expected PRLlevel >10,000 µg/L) with only mild hyperprolactinaemia should raise suspicion for the hook effect,and close interaction between clinicians and biochemists is required in this scenario [25,26]. It can beovercome by repeating the assay on 1:100 serum sample dilutions, or by performing a washout justafter the binding of PRL to the first antibody aiming to eliminate the excessive unbound PRL [25,26].As many newer PRL assays are no longer susceptible to the hook effect, clinicians should consult withtheir local laboratories when querying this issue [25].4.3. ImagingThe diagnostic work-up of hyperprolactinaemia includes imaging of the sellar area, which isperformed after excluding other common causes of high prolactin (physiological, primary hypothyroidism,drug-induced). Pituitary MRI (magnetic resonance imaging) enhanced with gadolinium is the goldstandard approach [82].4.4. Diagnostic AlgorithmIn patients on PRL-elevating drugs, PRL should be repeated after withdrawal of medicationsfor 72 h, if possible [25,56]. However, this approach may not be safe if this treatment is offered forpsychiatric indications [89]. If stopping the drug is not feasible, pituitary MRI is advised to rule out asellar/parasellar tumour [25,56]. Due to the challenges in investigating hyperprolactinaemia in suchscenarios, checking baseline PRL levels prior to initiation of antipsychotic medication is recommendedaiming to avoid future unnecessary imaging [56].The differentiation between a PRL-secreting tumour and a NFA or other sellar/parasellar masscausing hyperprolactinaemia through “stalk effect” is very important, as these conditions are manageddifferently [42]. In prolactinomas, apart from the cystic ones [43], adenoma size generally correspondsJ. Clin. Med. 2019, 8, 2203 10 of 24with PRL levels. Nonetheless, there is no PRL cut-off with perfect diagnostic value differentiatingprolactinoma from other tumours [42]. Karavitaki et al. [42] in a series of 226 histologically provenNFAs showed that 99% of them had serum PRL of <2000 mU/L (~100 µg/L) suggesting that PRLabove this limit is most likely consistent with a prolactinoma. Rarely, long-standing untreatedprimary hypothyroidism can cause significant lactotroph hyperplasia which may mimic a pituitaryadenoma [49]. A proposed diagnostic algorithm for hyperprolactinaemia is shown in Figure 1.Figure 1. Proposed algorithm for investigating hyperprolactinaemia.5. ManagementThe main goals of therapy for hyperprolactinaemia are restoration and maintenance of normalgonadal function/fertility, and prevention of osteoporosis [74]. Specific management strategies dependon the underlying aetiology [25,43].5.1. ProlactinomasThe therapeutic targets in prolactinomas are to normalize PRL, reduce tumour size, resolveclinical manifestations of hyperprolactinaemia and of mass effects (particularly visual disturbances)and prevent progression or recurrence of the tumour [25,74].5.1.1. Conservative ManagementBased on current guidelines, patients with microprolactinoma who are asymptomatic orpost-menopausal do not require treatment [25,82,90]. However, some authors advocate treatment inpost-menopausal women due to the postulated negative effects of hyperprolactinaemia on bone health,weight gain, and insulin resistance [77,91]. Post-menopausal women managed with a conservativestrategy require ongoing surveillance for tumour progression [25,82,90].5.1.2. Dopamine AgonistsDopamine agonists (DA) are first line treatment for patients with prolactinoma [25,43,82]. Theyinduce apoptosis, autophagic cell death and paraptosis of lactotrophs through different molecularpathways mediated by D2R, leading to reduced prolactin secretion and tumour shrinkage [92].Available DAs include bromocriptine, cabergoline, and quinagolide [25,43,82]. Bromocriptine is asemisynthetic ergot derivative with D2R agonist activity and D1R antagonist activity requiring dailyadministration due to its short half-life; starting doses are 0.625 to 1.25 mg/day and can be titratedJ. Clin. Med. 2019, 8, 2203 11 of 24to 2.5 to 15 mg/day [25,82,93]. Cabergoline is a D2R selective agonist with longer half-life allowing asingle to twice weekly administration; typical starting doses are 0.25 to 0.5 mg once or twice weeklywith titration to usual doses of 0.5 to 3 mg weekly. [25,82,93]. Quinagolide is a non-ergot derived D2Ragonist with a 22-hour half-life which allows for daily dosing; typical starting doses are 25 mcg dailyusually titrated to 75-150 mcg daily [93]. Current guidelines recommend cabergoline to be used as firstline over bromocriptine due to its superior efficacy (attributed to greater affinity and selectivity forD2R) and more optimal side effect profile [25,43,82,92]. Improved adherence due to fewer side effectsand more convenient dosing schedule are also further advantages [25,92]. Results from cumulativestudies have demonstrated that DAs result in reduction in tumour size in 20 to 100% (median 62%),resolution of visual field defects in 33 to 100% (median 67%), resolution of amenorrhea in 40 to 100%(median 78%), resolution of infertility in 10 to 100% (median 53%), improvement of sexual function in6 to 100% (median 57%), resolution of galactorrhoea in 33 to 100% (median 86%), and normalization ofPRL in 40 to 100% (median 68%) of the patients [25].Common side effects of DAs include nausea and/or vomiting and postural hypotension whichcan lead to dizziness and syncope, a digital Raynaud-type syndrome, and, more rarely, leg cramps,flushing, and nasal congestion [94]. High dose DA (as offered in Parkinson’s syndrome) increases therisk of cardiac valvulopathy [95] but the risk of clinically significant valvulopathy in patients withprolactinoma is still not clearly established [96]. Most studies on prolactinoma patients do not show anelevated risk [97–99] but, given the uncertainty around the risk of valvulopathy in this setting, currentguidelines recommend screening echocardiography prior to initiating DA, and thereafter every fiveyears for patients taking cabergoline less than 2 mg per week or annually for those on more than 2 mgper week [100].Rarely, DAs can induce mood changes and psychosis in susceptible patients [101]. More subtlepsychiatric symptoms manifesting as impulse control disorders are also increasingly being recognized [102].Pituitary apoplexy has been reported during use of DA in a small number of cases [103] and usuallythis occurs in patients with macroprolactinoma during the first 1.5 years of treatment [103–105].Guidelines suggest that withdrawal of DA may be attempted after at least two years of therapyif PRL has normalized and there is no visible tumour on MRI; remission rates of 26 to 69% havebeen observed following discontinuation [25,82]. Withdrawal of DA carries risk of tumour recurrenceor regrowth, particularly in the first year, and ongoing regular surveillance is required [25,82]. DAwithdrawal may also be considered in women once they become post-menopausal [25], however,prolactinoma regrowth has been observed in this setting, and continued surveillance is required [90].In case of pregnancy, DA should be discontinued, except in selected patients with macroadenomaat risk of visual deterioration [25]. Although there is longer experience with use of bromocriptinethan with cabergoline during pregnancy, both have demonstrated safety in this setting [106]. The riskof prolactinoma growth during pregnancy is <2% for microprolactinomas and around 18% formacroprolactinomas [25,43,82,106]. If visual deterioration occurs, management options includereinstitution of DA or surgical debulking [25]. If surgery is to be undertaken, the preferred timing isduring the second trimester [43]. If the pregnancy is at or near term, induction of delivery may alsobe considered [25,43]. Remission rates following pregnancy of 10 to 60% (median 27%) have beenreported, and breastfeeding does not appear to increase the risk of tumour growth [43,107,108].Normalization of PRL and/or tumour shrinkage cannot be achieved with DA treatment in all casesof prolactinomas [25,109]. Prolactinomas are labelled as DA resistant due to either failure to achievenormoprolactinaemia and/or failure to achieve 50% reduction in tumour size with maximum toleratedDA dose (can be up to 30 mg daily for bromocriptine or 12 mg weekly for cabergoline [110,111]) afterat least 6 months of treatment [109]. DA resistance occurs in approximately 20 to 30% of patients onbromocriptine and around 10% of patients on cabergoline [109]. Male sex, younger age at diagnosis,tumour invasiveness (particularly in the cavernous sinus) and size >4 cm have been proposed asclinical factors associated with DA resistance [109,112]. In such cases, switching bromocriptine tocabergoline is an option, leading to normalization of PRL in 80 to 85% of patients [109]. On theJ. Clin. Med. 2019, 8, 2203 12 of 24other hand, changing cabergoline to bromocriptine is rarely effective [111] but systematic data arenot available. For patients already on cabergoline, dose escalation is another option, as a number ofthem (around 15 to 20%) may require higher than the conventional doses of 2 mg per week [25,111].It is uncommon for a prolactinoma initially responsive to DA to become resistant to this treatment;if this occurs, adherence to the DA should be confirmed [43,109,111]. Transsphenoidal surgery andradiotherapy are second and third line management options, respectively, for resistant prolactinomas,as discussed below [25].The above strategies are not always successful in overcoming resistance to DA, and, therefore,alternative medical therapies have been explored [109]. Somatostatin analogues (SSA) alone or incombination with DA have been proposed as a potential approach, due to expression of all somatostatinreceptor (SSTR) subtypes in prolactinomas [109]. However, results from small case series usingfirst generation SSA (octreotide and lanreotide) have been conflicting [109]. Second generation SSA(pasireotide) may confer a theoretical advantage over first generation ones due to greater affinityfor SSTR5, however, successful experience with this agent is limited to two case reports [109]. Dueto the effect of oestrogens on lactotroph proliferation and hyperplasia, case reports and small caseseries have explored use of selective oestrogen receptor modulators and aromatase inhibitors for DAresistant prolactinomas, but the results of these studies are not conclusive [109]. Metformin, tyrosinekinase inhibitors (EGFR and VEGF inhibitors), and mTOR inhibitors have attracted interest, but clinicalevidence is limited to case reports, necessitating further work on this field [109].Temozolomide (TMZ) has been used as first line chemotherapeutic agent in lactotroph carcinomasand aggressive prolactinomas [109]. Lower expression of the DNA repair protein O6-methylguanine-DNAmethyltransferase (MGMT) has been proposed to correlate with TMZ effectiveness and checking forthe MGMT tumour status by immunohistochemistry prior starting treatment is recommended [109].Response to TMZ within three months of treatment is a predictor of efficacy; discontinuation is advisedif there is radiological progression after that interval [109].5.1.3. SurgerySurgery could be considered for prolactinomas where maximum doses of DA are not effectiveor tolerated, for those presenting with pituitary apoplexy with visual deterioration, when thereare cystic tumour components compressing the visual pathway, or if cerebrospinal fluid leakdevelops [25,43,110,111,113]. Surgery may also be an option for young patients with microprolactinoma,as this may be a more cost-effective approach compared with lifelong DA therapy [114]. Rates ofpost-operative remission are widely variable across the literature, and are reported 38 to 100% formicroprolactinomas and 7 to 80 % for macroprolactinomas [115]; lower rates of remission are describedin tumours with cavernous sinus invasion [111,116]. Higher success rates are seen in the hands ofexperienced pituitary surgeons [114]. DA resistant prolactinomas may show improved responsivenessto these agents following debulking surgery [110,111].5.1.4. RadiotherapyRadiotherapy is a third line option for prolactinomas that have failed medical and surgicalmanagement, or for aggressive or malignant ones [25,43,110]. Although it can be effective in controllingtumour growth, normalization of PRL is reported in only one third of patients, and it may requireup to 20 years for maximal effects to be seen [25,43,111]. Pituitary irradiation is associated with lateadverse effects mainly including hypopituitarism, optic nerve damage, cranial nerve dysfunction, aswell as increased risk of stroke and second brain tumours [25,82,117].5.2. “Stalk Effect”Sellar/parasellar tumours leading to hyperprolactinaemia due to the “stalk effect” are usuallymanaged surgically [118]. In a series of 267 patients with NFA, 72 had hyperprolactinaemia secondary to“stalk effect” and eight of them had galactorrhoea [119]. At 12 weeks postoperatively, PRL normalizedJ. Clin. Med. 2019, 8, 2203 13 of 24in 92% and all cases of galactorrhoea resolved [119]. In selected cases, there may be clinically significanthyperprolactinaemia from the “stalk effect” in the absence of other indications for surgery, such ashormone hypersecretion and visual field compromise. In these patients, hypogonadism should betreated, and if galactorrhoea is also bothersome, a pragmatic approach is to trial DA [120]. Notably, DAtreatment has been associated with reduction in the rate of residual adenoma enlargement in patientswith NFA who had surgical removal of the tumour [121].5.3. Other Pathological CausesHyperprolactinaemia secondary to primary hypothyroidism should be managed through treatmentof the underlying hypothyroidism with thyroid hormone replacement [25,43].Hyperprolactinaemia secondary to renal failure has been shown to normalize following successfulrenal transplantation [25]. The use of PRL lowering treatment in patients with hyperprolactinaemiasecondary to chronic kidney or liver disease has not been investigated.5.4. PharmacologicalIn hyperprolactinaemia secondary to medication use, the preferred approach is to discontinue theoffending drug [25,43]. However, this strategy may not be safe for patients with psychiatric disorderson antipsychotics [89]. Although antipsychotic-induced hyperprolactinaemia is common, there is noconsensus on its management due to lack of high quality evidence [89]. Grigg et al. [89] in a systematicreview and critical analysis of published guidelines and literature on this topic proposed that, if possible,baseline PRL level should be drawn prior to initiating or changing antipsychotic therapy [89]. Patientswith asymptomatic hyperprolactinaemia due to antipsychotics should undergo periodic monitoringof PRL, as well as regular clinical assessments for relevant manifestations [56,89]. For those withsymptomatic hyperprolactinaemia, a trial of stopping the antipsychotic medication is not recommendeddue to risk of exacerbation or relapse of psychiatric symptoms [89]. One option is to decrease thedose of the antipsychotic but this may result in reduced control of psychiatric symptoms, and mayalso be ineffective, as hyperprolactinaemia in this setting is not always dose related [55,89]. Due topartial agonism at D2R, addition of aripiprazole as an adjunctive therapy has shown to be an effectivestrategy in reducing hyperprolactinaemia, however, there is concern that this could lead to a reductionin the efficacy of the primary antipsychotic or to increased side effects due to polypharmacy [55,59,89].A further option is initiating hormone replacement therapy with oestrogen (oral contraceptive pillor hormone replacement therapy depending on whether contraception is required) or testosterone,as appropriate [89]. Switching antipsychotics to reduce hyperprolactinaemia is a last resort and shouldbe undertaken with caution only when the psychiatric condition has been stabilized [89]. Use of DA inthis patient population is not currently recommended due risk of worsening psychotic symptoms andlack of established safety [89]. Management of antipsychotics-induced hyperprolactinaemia shouldbe undertaken in close collaboration with psychiatry and be individualized based on the potentialbenefits and risks of each strategy [89].6. Hyperprolactinaemia and Metabolic/Cardiovascular Risk6.1. Metabolic RiskAnimal studies have demonstrated that PRL is implicated in appetite regulation, body weight,and fat deposition [122]. PRL is involved in the development of pancreatic β-cells and has also beenpostulated to have functional importance in the adult pancreas [123]. It may contribute to insulinresistance and hyperglycaemia through decreasing glucose transporter 4 (GLUT4) expression andinducing pyruvate dehydrogenase kinase 4, thereby, reducing glucose uptake and oxidation [123].PRL signalling appears to modulate adipocyte differentiation and impact energy homeostasis andthermogenesis [123].J. Clin. Med. 2019, 8, 2203 14 of 24In large population-based studies from China and USA, normal to high-normal PRL levels(but within the reference range) were related to favourable glucose metabolism profile and low riskof diabetes mellitus type 2 [124,125]. There is limited data on hyperprolactinaemia and metabolicparameters. PRL may impact insulin resistance; patients with hyperprolactinaemia have higher insulin,HOMA-IR, and HOMA-β index levels compared with healthy controls [126]. A correlation betweenhyperprolactinaemia and BMI (body mass index) has also been observed in prolactinoma patientsindependent of hypogonadism [127].Several studies have evaluated the effect of treatment of hyperprolactinaemia with DA onnumerous metabolic parameters. DAs reduce triglycerides, fasting glucose, and LDL cholesterol inindividuals with prolactinomas [127]. In contrast, in another study on prolactinoma patients offered DAdemonstrated no change in fasting glucose, although significant decrease of LDL and total cholesterolwere observed [128]. A report of 20 premenopausal women with prolactinoma described significantdecreases in BMI, total cholesterol, and LDL following treatment with DA [129]. Furthermore, in a seriesof 61 patients with prolactinoma, significant improvements in lipid profile, insulin resistance, visceraladiposity, and prevalence of metabolic syndrome following treatment with cabergoline were found [130].However, it is difficult to discern whether these favourable metabolic effects are directly related toresolution of hyperprolactinaemia or are due to restoration of gonadal function or a combinationof both. Notably, a study of 32 men with prolactinoma demonstrated significant decreases in theprevalence of metabolic syndrome after 12 months of treatment with cabergoline only amongst thosewith hypogonadism at baseline [131]. Nonetheless, significant improvements in weight, BMI, waistcircumference, lipid profile, and insulin resistance were seen in both hypogonadal and eugonadalpatients, suggesting that PRL may play a direct role in mediating these adverse metabolic effects [131].6.2. Cardiovascular RiskIt has been proposed that hyperprolactinaemia has cardiovascular actions, either direct or indirectlythrough hypogonadism [132,133]. PRL increases sympathetic tone and mediates chronotropic andvasoconstrictive effects; for this reason, it has been implicated in cardiovascular (CV) risk [132].In women, PRL >8 µg/L was independently associated with risk of incident hypertension [134].However, the Framingham Heart Study did not find any association between CV risk and variation inPRL levels (when within the reference range) [135]. Furthermore, differences in PRL values have notbeen shown between women with different levels of CV risk [132].Higher concentrations of several cardiac risk markers including total cholesterol, LDL, apo B,platelet count, fibrinogen, AT-III, PAI-1 and PAI-1/t-PA have been reported in patients withprolactinoma [136]. In a retrospective cohort study including 2233 individuals with prolactinomaand 10,355 matched controls, only males were at increased risk of incident cardiovascular disease(incidence rate ratio 1.94; 95% CI: 1.29–2.91, p = 0.001) [137]. However, the contribution of possiblegrowth hormone deficiency and/or hypogonadism in these findings cannot be excluded.7. Hyperprolactinaemia and AutoimmunityPRL modulates humoral and cellular immune responses through different but not completelyunderstood mechanisms. It induces production of IL-1, IL-6, and interferon γ, and expression of IL-2receptors, regulates the maturation of CD4+ and CD8+ T-cell, modulates cytokine production, stimulatespro-B cell generation, and reduces the apoptosis of transitional B cells [138,139]. Hyperprolactinaemia isassociated with enhanced activation of anergic B cells that promote autoreactivity [138,139]. Moreover,pro-inflammatory cytokines stimulate pituitary PRL secretion [140] and lymphocytes express dopaminereceptors (predominantly D4R and D5R) modulating local PRL production and secretion [8]. A recentcase control study by Liu et al. [141] of 202 patients with hyperprolactinaemia found that a significantlyhigher proportion of hyperprolactinaemic patients had at least one detectable autoantibody, as well ashigher levels of IL-4 and IL-6 compared to healthy controls.J. Clin. Med. 2019, 8, 2203 15 of 247.1. LupusA systematic review and meta-analysis of 12 studies by Wang et al. demonstrated significantlyhigher PRL levels in patients with systematic lupus erythematosus (SLE) [142]. It should be notedthough that an association between hyperprolactinaemia and SLE has not been confirmed in allreports [143]; in the systematic review by Wang et al. [142], differences in PRL levels between patientsand controls were statistically significant in populations from Asia and Europe but not from America.Animal studies have found enhanced expression of PRL-R on T-cells, and that metoclopramide-related hyperprolactinaemia induced features of SLE [144,145]. Human studies have also demonstratedan association between hyperprolactinaemia and manifestations of lupus; hyperprolactinaemia inpatients with SLE has been associated with higher risk of serositis and anaemia [139], as well as withneurological manifestations, renal involvement, haematological manifestations, and serological diseasemarkers, namely complement and anti-dsDNA [146].7.2. Rheumatoid ArthritisStudies on PRL levels in RA have provided inconsistent results with lower, higher, or equivocalvalues [139,147]. It has been shown that the risk and severity of RA are decreased in reproductivestates characterized by hyperprolactinaemia (pregnancy and breastfeeding) [148]. However, othershave demonstrated that severe disease is associated with longer period of breast-feeding and largernumber of breastfed children [149]. A randomized placebo controlled study of bromocriptine offeredin 88 patients with active RA on background treatment with methotrexate did not have any significantimpact on disease activity score at three months [150].Various hypotheses have been proposed for the inconsistent findings. It has been postulated thatlower PRL levels are immunostimulatory, whereas higher ones are immunosuppressive [148]. Othershave suggested that extra-pituitary PRL is more important in the pathogenesis of RA than pituitaryPRL; PRL-receptors have been demonstrated in synovial macrophages, and PRL mRNA expression insynovial tissue is positively correlated with clinical disease activity [147,151]. Further reports havealso implicated the significance of extra-pituitary prolactin promoter polymorphisms [152].7.3. Multiple SclerosisPRL has been implicated in the pathogenesis of multiple sclerosis (MS) and other demyelinatingdisorders [149,153]. PRL is thought to have dual effect in the central nervous system; it stimulatesregeneration of neurons, oligodendrocytes, and neural stem cells, and also promotes aberrant immuneresponses through stimulating B cell autoreactivity [149]. The latter mechanism possibly explainsthe correlation between hyperprolactinaemia and MS [140,149]. Patients with MS have higher PRLlevels compared to controls, and this has also been shown in patients with neuromyelitis optica(NMO) [140,153]. Notably, PRL is higher in patients with MS or NMO during attacks compared withphases of remission [153] but it is still unclear whether hyperprolactinaemia is a primary cause or asecondary effect of the disease.7.4. Other Autoimmune DisordersHyperprolactinaemia has been described in numerous other autoimmune disorders includingsystemic sclerosis, Behçet’s disease, and polymyositis [138]. In coeliac disease, a positive correlationbetween serum PRL with disease activity, mucosal atrophy, and concentration of anti-endomysialantibodies has been shown [149]. A small study demonstrated higher levels of the PRL-R in patientswith alopecia areata compared to controls, and levels of the PRL-R were correlated with diseaseseverity [154]. Patients with pemphigus vulgaris have also been shown to have higher PRL comparedwith controls [155]. The pathophysiological significance of these findings remains to be elucidated.J. Clin. Med. 2019, 8, 2203 16 of 248. CancerAn association with PRL levels and breast [156–158], ovarian [159], colon [160,161] andhepatocellular [162] cancer has been suggested. Although basic science studies have implicateda role for PRL and its receptor in the pathogenesis of different malignancies [157,158,163–166], a clearcausal relationship between PRL and cancer remains controversial [158]. Epidemiological studies onthis topic have shown conflicting results [158], and reports suggesting positive association betweenPRL values and cancer risk should be interpreted with caution, as some include individuals withnormal PRL values, or rely on a single measurement of the hormone [156–158]. Notably, a study of1342 women with hyperprolactinaemia treated with DA did not demonstrate increased risk of breastcancer compared with the general population [167]. Well-designed epidemiological and clinical studiesare required to investigate reliably this issue.9. ConclusionsHyperprolactinaemia is a biochemical diagnosis with a broad range of aetiologies. Detailed historyand clinical assessment are important first steps for the differential diagnosis and for verification ofpathological causes. Exclusion of macroprolactin and consideration of the “hook effect” are importantpoints in the diagnostic approach. Medications and sellar/parasellar masses (prolactin secreting oracting through the “stalk effect”) are the most common causes of pathological hyperprolactinaemia.Treatment of hyperprolactinaemia mainly aims at restoration and maintenance of normal gonadalfunction/fertility, and prevention of osteoporosis. Specific management strategies depend on theunderlying cause. A particularly challenging scenario is drug-induced hyperprolactinaemia, especiallywhen this occurs in association with antipsychotics or other psychiatric medications, as the degreeof PRL elevation can be variable and discontinuing or changing the culprit medication may notbe safe. DA are the mainstay of therapy for prolactinomas and specific guidelines are available inclinical practice.Recent data expand the biological effects of prolactin particularly on metabolism, cancer,cardiovascular and immune systems opening new avenues on the clinical implications of prolactinand the consequences of hyperprolactinaemia.Author Contributions: I.S., K.L., and N.K. contributed to the literature review and the preparation of themanuscript. N.K. supervised this work.Funding: No funding to disclose.Conflicts of Interest: The authors declare no conflicts of interest.References1. Tucker, H.A. Hormones, mammary growth, and lactation: A 41-year perspective. J. Dairy Sci. 2000, 83,874–884. [CrossRef]2. Trott, J.F.; Vonderhaar, B.K.; Hovey, R.C. Historical perspectives of prolactin and growth hormone asmammogens, lactogens and galactagogues—Agog for the future! J. Mammary Gland Biol. Neoplasia 2008, 13,3–11. [CrossRef] [PubMed]3. Riddle, O.; Bates, R.W.; Dykshorn, S.W. The preparation, identification and assay of prolactin—A hormoneof the anterior pituitary. Am. J. Physiol. Leg. Content 1933, 105, 191–216. [CrossRef]4. Friesen, H.; Guyda, H.; Hardy, J. Biosynthesis of Human Growth Hormone and Prolactin. J. Clin. Endocrinol.Metab. 1970, 31, 611–624. [CrossRef]5. Lewis, U.J.; Singh, R.N.; Seavey, B.K. Human prolactin: Isolation and some properties. Biochem. Biophys. Res.Commun. 1971, 44, 1169–1176. [CrossRef]6. Prabhakar, V.K.; Davis, J.R. Hyperprolactinaemia. Best Pract. Res. Clin. Obs. Gynaecol. 2008, 22, 341–353.[CrossRef]7. Teilum, K.; Hoch, J.C.; Goffin, V.; Kinet, S.; Martial, J.A.; Kragelund, B.B. Solution structure of humanprolactin. J. Mol. Biol. 2005, 351, 810–823. [CrossRef]J. Clin. Med. 2019, 8, 2203 17 of 248. Freeman, M.E.; Kanyicska, B.; Lerant, A.; Nagy, G. Prolactin: Structure, function, and regulation of secretion.Physiol. Rev. 2000, 80, 1523–1631. [CrossRef]9. Capozzi, A.; Scambia, G.; Pontecorvi, A.; Lello, S. Hyperprolactinemia: Pathophysiology and therapeuticapproach. Gynecol. Endocrinol. 2015, 31, 506–510. [CrossRef]10. Rastrelli, G.; Corona, G.; Maggi, M. The role of prolactin in andrology: What is new? Rev. Endocr. Metab.Disord. 2015, 16, 233–248. [CrossRef]11. Grattan, D.R. 60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-prolactin axis. J. Endocrinol.2015, 226, T101–T122. [CrossRef]12. Cabrera-Reyes, E.A.; Limón-Morales, O.; Rivero-Segura, N.A.; Camacho-Arroyo, I.; Cerbón, M. Prolactinfunction and putative expression in the brain. Endocrine 2017, 57, 199–213. [CrossRef]13. Marano, R.J.; Ben-Jonathan, N. Minireview: Extrapituitary Prolactin: An Update on the Distribution,Regulation, and Functions. Mol. Endocrinol. 2014, 28, 622–633. [CrossRef] [PubMed]14. Ignacak, A.; Kasztelnik, M.; Sliwa, T.; Korbut, R.A.; Rajda, K.; Guzik, T.J. Prolactin–not only lactotrophin.A “new” view of the “old” hormone. J. Physiol. Pharm. 2012, 63, 435–443.15. Levine, S.; Muneyyirci-Delale, O. Stress-Induced Hyperprolactinemia: Pathophysiology and ClinicalApproach. Obs. Gynecol. Int. 2018, 2018, 9253083. [CrossRef]16. Zaidi, M.; Sun, L.; Liu, P.; Davies, T.F.; New, M.; Zallone, A.; Yuen, T. Pituitary-bone connection in skeletalregulation. Horm. Mol. Biol. Clin. Investig. 2016, 28, 85–94. [CrossRef]17. Gregg, C.; Shikar, V.; Larsen, P.; Mak, G.; Chojnacki, A.; Yong, V.W.; Weiss, S. White matter plasticity andenhanced remyelination in the maternal CNS. J. Neurosci. 2007, 27, 1812–1823. [CrossRef]18. Tanner, M.J.; Hadlow, N.C.; Wardrop, R. Variation of female prolactin levels with menopausal status andphase of menstrual cycle. Aust. N. Z. J. Obs. Gynaecol. 2011, 51, 321–324. [CrossRef]19. Hu, Y.; Ding, Y.; Yang, M.; Xiang, Z. Serum prolactin levels across pregnancy and the establishment ofreference intervals. Clin. Chem. Lab. Med. 2018, 56, 803–807. [CrossRef]20. Alvarez-Tutor, E.; Forga-LLenas, L.; Rodriguez-Erdozain, R.; Goñi-Iriarte, M.J.; Mendendez-Torre, E.;Alvarez-Tutor, J. Persistent increase of PRL after oral contraceptive treatment. Alterations in dopaminergicregulation as possible etiology. Arch. Gynecol. Obs. 1999, 263, 45–50. [CrossRef]21. Banaszewska, B.; Pawelczyk, L.; Spaczynski, R.Z.; Dziura, J.; Duleba, A.J. Effects of simvastatin and oralcontraceptive agent on polycystic ovary syndrome: Prospective, randomized, crossover trial. J. Clin.Endocrinol. Metab. 2007, 92, 456–461. [CrossRef] [PubMed]22. Crowley, W.R. Neuroendocrine regulation of lactation and milk production. Compr. Physiol. 2015, 5, 255–291.[CrossRef] [PubMed]23. Muneyyirci-Delale, O.; Goldstein, D.; Reyes, F.I. Diagnosis of stress-related hyperprolactinemia. Evaluationof the hyperprolactinemia rest test. N. Y. State J. Med. 1989, 89, 205–208. [PubMed]24. Hackney, A.C.; Davis, H.C.; Lane, A.R. Growth Hormone-Insulin-Like Growth Factor Axis, Thyroid Axis,Prolactin, and Exercise. Front. Horm. Res. 2016, 47, 1–11. [CrossRef] [PubMed]25. Melmed, S.; Casanueva, F.F.; Hoffman, A.R.; Kleinberg, D.L.; Montori, V.M.; Schlechte, J.A.; Wass, J.A.;Society, E. Diagnosis and treatment of hyperprolactinemia: An Endocrine Society clinical practice guideline.J. Clin. Endocrinol. Metab. 2011, 96, 273–288. [CrossRef]26. Vilar, L.; Fleseriu, M.; Bronstein, M.D. Challenges and pitfalls in the diagnosis of hyperprolactinemia.Arq. Bras. Endocrinol. Metab. 2014, 58, 9–22. [CrossRef]27. Saraç, F.; Tütüncüog˘lu, P.; Ozgen, A.G.; Saygili, F.; Yilmaz, C.; Bilgen, I.; Memis¸, A. Prolactin levels andexamination with breast ultrasound or mammography. Adv. Ther. 2008, 25, 59–66. [CrossRef]28. Jarrell, J.; Franks, S.; McInnes, R.; Gemayel, K.; Guyda, H.; Arronet, G.H.; Naftolin, F. Breast examinationdoes not elevate serum prolactin. Fertil. Steril. 1980, 33, 49–51. [CrossRef]29. Hammond, K.R.; Steinkampf, M.P.; Boots, L.R.; Blackwell, R.E. The effect of routine breast examination onserum prolactin levels. Fertil. Steril. 1996, 65, 869–870. [CrossRef]30. Fernandez, A.; Karavitaki, N.; Wass, J.A. Prevalence of pituitary adenomas: A community-based,cross-sectional study in Banbury (Oxfordshire, UK). Clin. Endocrinol. Oxf. 2010, 72, 377–382. [CrossRef]31. Maiter, D.; Delgrange, E. Therapy of endocrine disease: The challenges in managing giant prolactinomas.Eur. J. Endocrinol. 2014, 170, R213–R227. [CrossRef] [PubMed]J. Clin. Med. 2019, 8, 2203 18 of 2432. Vilar, L.; Freitas, M.C.; Naves, L.A.; Casulari, L.A.; Azevedo, M.; Montenegro, R.; Barros, A.I.; Faria, M.;Nascimento, G.C.; Lima, J.G.; et al. Diagnosis and management of hyperprolactinemia: Results of a Brazilianmulticenter study with 1234 patients. J. Endocrinol. Investig. 2008, 31, 436–444. [CrossRef] [PubMed]33. Vilar, L.; Vilar, C.F.; Lyra, R.; Lyra, R.; Naves, L.A. Acromegaly: Clinical features at diagnosis. Pituitary 2017,20, 22–32. [CrossRef] [PubMed]34. Katznelson, L.; Laws, E.R., Jr.; Melmed, S.; Molitch, M.E.; Murad, M.H.; Utz, A.; Wass, J.A.; Endocrine, S.Acromegaly: An endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 2014, 99, 3933–3951.[CrossRef]35. Mete, O.; Lopes, M.B. Overview of the 2017 WHO Classification of Pituitary Tumors. Endocr. Pathol. 2017, 28,228–243. [CrossRef]36. Schernthaner-Reiter, M.H.; Trivellin, G.; Stratakis, C.A. MEN1, MEN4, and Carney Complex: Pathology andMolecular Genetics. Neuroendocrinology 2016, 103, 18–31. [CrossRef]37. Thakker, R.V. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol. Cell. Endocrinol. 2014,386, 2–15. [CrossRef]38. Agarwal, S.K.; Ozawa, A.; Mateo, C.M.; Marx, S.J. The MEN1 gene and pituitary tumours. Horm. Res. 2009,71 (Suppl. S2), 131–138. [CrossRef]39. Beckers, A.; Aaltonen, L.A.; Daly, A.F.; Karhu, A. Familial isolated pituitary adenomas (FIPA) and thepituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein(AIP) gene. Endocr. Rev. 2013, 34, 239–277. [CrossRef]40. Kurtkaya-Yapicier, O.; Scheithauer, B.W.; Carney, J.A.; Kovacs, K.; Horvath, E.; Stratakis, C.A.; Vidal, S.;Vella, A.; Young, W.F.; Atkinson, J.L.; et al. Pituitary adenoma in Carney complex: An immunohistochemical,ultrastructural, and immunoelectron microscopic study. Ultrastruct. Pathol. 2002, 26, 345–353. [CrossRef]41. Sun, F.; Sun, X.; Du, X.; Xing, H.; Yang, B. Factors related to endocrine changes and hormone substitutiontreatment during pre- and post-operation stages in craniopharyngioma. Oncol. Lett. 2017, 13, 250–252.[CrossRef] [PubMed]42. Karavitaki, N.; Thanabalasingham, G.; Shore, H.C.; Trifanescu, R.; Ansorge, O.; Meston, N.; Turner, H.E.;Wass, J.A. Do the limits of serum prolactin in disconnection hyperprolactinaemia need re-definition? A studyof 226 patients with histologically verified non-functioning pituitary macroadenoma. Clin. Endocrinol. Oxf.2006, 65, 524–529. [CrossRef] [PubMed]43. Vilar, L.; Abucham, J.; Albuquerque, J.L.; Araujo, L.A.; Azevedo, M.F.; Boguszewski, C.L.; Casulari, L.A.;Cunha Neto, M.B.C.; Czepielewski, M.A.; Duarte, F.H.G.; et al. Controversial issues in the managementof hyperprolactinemia and prolactinomas—An overview by the Neuroendocrinology Department of theBrazilian Society of Endocrinology and Metabolism. Arch. Endocrinol. Metab. 2018, 62, 236–263. [CrossRef][PubMed]44. Chiloiro, S.; Giampietro, A.; Bianchi, A.; Tartaglione, T.; Capobianco, A.; Anile, C.; De Marinis, L. Diagnosisof endocrine disease: Primary empty sella: A comprehensive review. Eur. J. Endocrinol. 2017, 177, R275–R285.[CrossRef]45. Lo, J.C.; Beck, G.J.; Kaysen, G.A.; Chan, C.T.; Kliger, A.S.; Rocco, M.V.; Chertow, G.M.; Study, F.Hyperprolactinemia in end-stage renal disease and effects of frequent hemodialysis. Hemodial. Int. 2017,21, 190–196. [CrossRef] [PubMed]46. Balakrishnan, C.H.; Rajeev, H. Correlation of Serum Prolactin Level to Child Pugh Scoring System in Cirrhosisof Liver. J. Clin. Diagn. Res. 2017, 11, OC30–OC33. [CrossRef]47. Sharma, L.K.; Sharma, N.; Gadpayle, A.K.; Dutta, D. Prevalence and predictors of hyperprolactinemia insubclinical hypothyroidism. Eur. J. Intern. Med. 2016, 35, 106–110. [CrossRef]48. Honbo, K.S.; van Herle, A.J.; Kellett, K.A. Serum prolactin levels in untreated primary hypothyroidism.Am. J. Med. 1978, 64, 782–787. [CrossRef]49. Shivaprasad, K.S.; Siddardha, K. Pituitary Hyperplasia from Primary Hypothyroidism. N. Engl. J. Med. 2019,380, e9. [CrossRef]50. Kyritsi, E.M.; Dimitriadis, G.K.; Angelousi, A.; Mehta, H.; Shad, A.; Mytilinaiou, M.; Kaltsas, G.; Randeva, H.S.The value of prolactin in predicting prolactinoma in hyperprolactinaemic polycystic ovarian syndrome.Eur. J. Clin. Investig. 2018, 48, e12961. [CrossRef]51. Kyritsi, E.M.; Dimitriadis, G.K.; Kyrou, I.; Kaltsas, G.; Randeva, H.S. PCOS remains a diagnosis of exclusion:A concise review of key endocrinopathies to exclude. Clin. Endocrinol. Oxf. 2017, 86, 1–6. [CrossRef]J. Clin. Med. 2019, 8, 2203 19 of 2452. Filho, R.B.; Domingues, L.; Naves, L.; Ferraz, E.; Alves, A.; Casulari, L.A. Polycystic ovary syndrome andhyperprolactinemia are distinct entities. Gynecol. Endocrinol. 2007, 23, 267–272. [CrossRef]53. Nass, R.D.; Sassen, R.; Elger, C.E.; Surges, R. The role of postictal laboratory blood analyses in the diagnosisand prognosis of seizures. Seizure 2017, 47, 51–65. [CrossRef]54. Lusic´, I.; Pintaric´, I.; Hozo, I.; Boic´, L.; Capkun, V. Serum prolactin levels after seizure and syncopal attacks.Seizure 1999, 8, 218–222. [CrossRef]55. Peuskens, J.; Pani, L.; Detraux, J.; De Hert, M. The effects of novel and newly approved antipsychotics onserum prolactin levels: A comprehensive review. CNS Drugs 2014, 28, 421–453. [CrossRef]56. Montejo, Á.; Arango, C.; Bernardo, M.; Carrasco, J.L.; Crespo-Facorro, B.; Cruz, J.J.; Del Pino, J.; GarcíaEscudero, M.A.; García Rizo, C.; González-Pinto, A.; et al. Spanish consensus on the risks and detection ofantipsychotic drug-related hyperprolactinaemia. Rev. Psiquiatr. Salud Ment. 2016, 9, 158–173. [CrossRef]57. Cortet-Rudelli, C.; Sapin, R.; Bonneville, J.F.; Brue, T. Etiological diagnosis of hyperprolactinemia.Ann. Endocrinol. Paris 2007, 68, 98–105. [CrossRef]58. Molitch, M.E. Medication-induced hyperprolactinemia. Mayo Clin. Proc. 2005, 80, 1050–1057. [CrossRef]59. Ajmal, A.; Joffe, H.; Nachtigall, L.B. Psychotropic-induced hyperprolactinemia: A clinical review.Psychosomatics 2014, 55, 29–36. [CrossRef]60. Tewksbury, A.; Olander, A. Management of antipsychotic-induced hyperprolactinemia. Ment. Health Clin.2016, 6, 185–190. [CrossRef]61. Reeves, S.; Sugita, E.; Baldeweg, S.E.; Howard, R. Management of antipsychotic related hyperprolactinemiain older people: Can we extrapolate from existing guidance? Int. J. Geriatr. Psychiatry 2018, 33, 1743–1744.[CrossRef]62. McMurdo, M.E.; Howie, P.W.; Lewis, M.; Marnie, M.; McEwen, J.; McNeilly, A.S. Prolactin response to lowdose sulpiride. Br. J. Clin. Pharm. 1987, 24, 133–137. [CrossRef]63. Cookson, J.; Hodgson, R.; Wildgust, H.J. Prolactin, hyperprolactinaemia and antipsychotic treatment:A review and lessons for treatment of early psychosis. J. Psychopharmacol. 2012, 26, 42–51. [CrossRef]64. Ingram, J.; Taylor, H.; Churchill, C.; Pike, A.; Greenwood, R. Metoclopramide or domperidone for increasingmaternal breast milk output: A randomised controlled trial. Arch. Dis. Child. Fetal Neonatal Ed. 2012, 97,F241–F245. [CrossRef]65. Fountas, A.; Chai, S.T.; Kourkouti, C.; Karavitaki, N. Mechanisms of endocrinology: Endocrinology ofopioids. Eur. J. Endocrinol. 2018, 179, R183–R196. [CrossRef]66. Romeo, J.H.; Dombrowski, R.; Kwak, Y.S.; Fuehrer, S.; Aron, D.C. Hyperprolactinaemia and verapamil:Prevalence and potential association with hypogonadism in men. Clin. Endocrinol. Oxf. 1996, 45, 571–575.[CrossRef]67. Kelley, S.R.; Kamal, T.J.; Molitch, M.E. Mechanism of verapamil calcium channel blockade-inducedhyperprolactinemia. Am. J. Physiol. 1996, 270, E96–E100. [CrossRef]68. Veselinovic´, T.; Schorn, H.; Vernaleken, I.B.; Schiﬄ, K.; Klomp, M.; Gründer, G. Impact of differentantidopaminergic mechanisms on the dopaminergic control of prolactin secretion. J. Clin. Psychopharmacol.2011, 31, 214–220. [CrossRef]69. Kleinberg, D.L.; Noel, G.L.; Frantz, A.G. Galactorrhea: A study of 235 cases, including 48 with pituitarytumors. N. Engl. J. Med. 1977, 296, 589–600. [CrossRef]70. Finken, M.J.; Boersma, B.; Rotteveel, J. Hyperprolactinemia and hyperandrogenism in an adolescent girlpresenting with primary amenorrhea. Eur. J. Obs. Gynecol. Reprod. Biol. 2013, 166, 230–231. [CrossRef]71. Majumdar, A.; Mangal, N.S. Hyperprolactinemia. J. Hum. Reprod. Sci. 2013, 6, 168–175. [CrossRef]72. Moria, Y.; Kortbawi, R.; El-Asmar, N.; Arafah, B.M. Increased androgen secretion in patients withprolactinomas: The impact of altered HPA function. Pituitary 2019, 22, 170–178. [CrossRef]73. Carmina, E.; Azziz, R.; Bergfeld, W.; Escobar Morreale, H.F.; Futterweit, W.; Huddleston, H.; Lobo, R.A.;Olsen, E. Female pattern hair loss and androgen excess: A report from the multidisciplinary androgen excessand pcos committee. J. Clin. Endocrinol. Metab. 2019, 104, 2875–2891. [CrossRef]74. Serri, O.; Chik, C.L.; Ur, E.; Ezzat, S. Diagnosis and management of hyperprolactinemia. Can. Med. Assoc. J.2003, 169, 575–581.75. De Rosa, M.; Zarrilli, S.; Di Sarno, A.; Milano, N.; Gaccione, M.; Boggia, B.; Lombardi, G.; Colao, A.Hyperprolactinemia in men: Clinical and biochemical features and response to treatment. Endocrine 2003, 20,75–82. [CrossRef]J. Clin. Med. 2019, 8, 2203 20 of 2476. Tirosh, A.; Benbassat, C.; Lifshitz, A.; Shimon, I. Hypopituitarism patterns and prevalence among men withmacroprolactinomas. Pituitary 2015, 18, 108–115. [CrossRef]77. Mazziotti, G.; Frara, S.; Giustina, A. Pituitary Diseases and Bone. Endocr. Rev. 2018, 39, 440–488. [CrossRef]78. Ozer, F.F.; Dagdelen, S.; Erbas, T. Relation of RANKL and OPG Levels with Bone Resorption in Patients withAcromegaly and Prolactinoma. Horm. Metab. Res. 2018, 50, 562–567. [CrossRef]79. Di Somma, C.; Colao, A.; Di Sarno, A.; Klain, M.; Landi, M.L.; Facciolli, G.; Pivonello, R.; Panza, N.;Salvatore, M.; Lombardi, G. Bone marker and bone density responses to dopamine agonist therapy inhyperprolactinemic males. J. Clin. Endocrinol. Metab. 1998, 83, 807–813. [CrossRef]80. Mazziotti, G.; Mancini, T.; Mormando, M.; De Menis, E.; Bianchi, A.; Doga, M.; Porcelli, T.; Vescovi, P.P.;De Marinis, L.; Giustina, A. High prevalence of radiological vertebral fractures in women withprolactin-secreting pituitary adenomas. Pituitary 2011, 14, 299–306. [CrossRef]81. D’Sylva, C.; Khan, T.; Van Uum, S.; Fraser, L.A. Osteoporotic fractures in patients with untreatedhyperprolactinemia vs. those taking dopamine agonists: A systematic review and meta-analysis.Neuro Endocrinol. Lett. 2015, 36, 745–749.82. Casanueva, F.F.; Molitch, M.E.; Schlechte, J.A.; Abs, R.; Bonert, V.; Bronstein, M.D.; Brue, T.; Cappabianca, P.;Colao, A.; Fahlbusch, R.; et al. Guidelines of the Pituitary Society for the diagnosis and management ofprolactinomas. Clin. Endocrinol. Oxf. 2006, 65, 265–273. [CrossRef]83. Saleem, M.; Martin, H.; Coates, P. Prolactin Biology and Laboratory Measurement: An Update on Physiologyand Current Analytical Issues. Clin. Biochem. Rev. 2018, 39, 3–16.84. Lippi, G.; Plebani, M. Macroprolactin: Searching for a needle in a haystack? Clin. Chem. Lab. Med. 2016, 54,519–522. [CrossRef]85. Samson, S.L.; Hamrahian, A.H.; Ezzat, S.; Aace, N.; Pituitary Scientific Committee. American association ofclinical endocrinologists, American college of endocrinology disease state clinical review: Clinical relevanceof macroprolactin in the absence or presence of true hyperprolactinemia. Endocr. Pract. 2015, 21, 1427–1435.[CrossRef]86. Kasum, M.; Oreškovic´, S.; Cˇehic´, E.; Šunj, M.; Lila, A.; Ejubovic´, E. Laboratory and clinical significanceof macroprolactinemia in women with hyperprolactinemia. Taiwan J. Obs. Gynecol. 2017, 56, 719–724.[CrossRef]87. Kalsi, A.K.; Halder, A.; Jain, M.; Chaturvedi, P.K.; Sharma, J.B. Prevalence and reproductive manifestationsof macroprolactinemia. Endocrine 2019, 63, 332–340. [CrossRef]88. Romijn, J.A. Hyperprolactinemia and prolactinoma. Handb. Clin. Neurol. 2014, 124, 185–195. [CrossRef]89. Grigg, J.; Worsley, R.; Thew, C.; Gurvich, C.; Thomas, N.; Kulkarni, J. Antipsychotic-inducedhyperprolactinemia: Synthesis of world-wide guidelines and integrated recommendations for assessment,management and future research. Psychopharmacology 2017, 234, 3279–3297. [CrossRef]90. Santharam, S.; Fountas, A.; Tampourlou, M.; Arlt, W.; Ayuk, J.; Gittoes, N.; Toogood, A.; Karavitaki, N. Impactof menopause on outcomes in prolactinomas after dopamine agonist treatment withdrawal. Clin. Endocrinol.Oxf. 2018, 89, 346–353. [CrossRef]91. Iacovazzo, D.; De Marinis, L. Treatment of hyperprolactinemia in post-menopausal women: Pros. Endocrine2015, 48, 76–78. [CrossRef]92. Liu, X.; Tang, C.; Wen, G.; Zhong, C.; Yang, J.; Zhu, J.; Ma, C. The Mechanism and Pathways of Dopamineand Dopamine Agonists in Prolactinomas. Front. Endocrinol. Lausanne 2018, 9, 768. [CrossRef] [PubMed]93. Barlier, A.; Jaquet, P. Quinagolide—A valuable treatment option for hyperprolactinaemia. Eur. J. Endocrinol.2006, 154, 187–195. [CrossRef] [PubMed]94. Colao, A.; Di Sarno, A.; Guerra, E.; De Leo, M.; Mentone, A.; Lombardi, G. Drug insight: Cabergoline andbromocriptine in the treatment of hyperprolactinemia in men and women. Nat. Clin. Pract. Endocrinol.Metab. 2006, 2, 200–210. [CrossRef] [PubMed]95. Schade, R.; Andersohn, F.; Suissa, S.; Haverkamp, W.; Garbe, E. Dopamine agonists and the risk ofcardiac-valve regurgitation. N. Engl. J. Med. 2007, 356, 29–38. [CrossRef] [PubMed]96. Stiles, C.E.; Tetteh-Wayoe, E.T.; Bestwick, J.; Steeds, R.P.; Drake, W.M. A meta-analysis of the prevalence ofcardiac valvulopathy in hyperprolactinemic patients treated with Cabergoline. J. Clin. Endocrinol. Metab.2018. [CrossRef]97. Auriemma, R.S.; Pivonello, R.; Ferreri, L.; Priscitelli, P.; Colao, A. Cabergoline use for pituitary tumors andvalvular disorders. Endocrinol. Metab. Clin. N. Am. 2015, 44, 89–97. [CrossRef]J. Clin. Med. 2019, 8, 2203 21 of 2498. Vroonen, L.; Lancellotti, P.; Garcia, M.T.; Dulgheru, R.; Rubio-Almanza, M.; Maiga, I.; Magne, J.; Petrossians, P.;Auriemma, R.; Daly, A.F.; et al. Prospective, long-term study of the effect of cabergoline on valvular status inpatients with prolactinoma and idiopathic hyperprolactinemia. Endocrine 2017, 55, 239–245. [CrossRef]99. Gamble, D.; Fairley, R.; Harvey, R.; Farman, C.; Cantley, N.; Leslie, S.J. Screening for valve disease in patientswith hyperprolactinaemia disorders prescribed cabergoline: A service evaluation and literature review.Adv. Drug Saf. 2017, 8, 215–229. [CrossRef]100. Steeds, R.P.; Stiles, C.E.; Sharma, V.; Chambers, J.B.; Lloyd, G.; Drake, W. Echocardiography and monitoringpatients receiving dopamine agonist therapy for hyperprolactinaemia: A joint position statement of theBritish Society of Echocardiography, the British Heart Valve Society and the Society for Endocrinology.Echo Res. Pract. 2019, 6, G1–G8. [CrossRef]101. Gillam, M.P.; Molitch, M.E.; Lombardi, G.; Colao, A. Advances in the treatment of prolactinomas. Endocr. Rev.2006, 27, 485–534. [CrossRef]102. Noronha, S.; Stokes, V.; Karavitaki, N.; Grossman, A. Treating prolactinomas with dopamine agonists:Always worth the gamble? Endocrine 2016, 51, 205–210. [CrossRef] [PubMed]103. Chng, E.; Dalan, R. Pituitary apoplexy associated with cabergoline therapy. J. Clin. Neurosci. 2013, 20,1637–1643. [CrossRef]104. Ghadirian, H.; Shirani, M.; Ghazi-Mirsaeed, S.; Mohebi, S.; Alimohamadi, M. Pituitary Apoplexy duringTreatment of Prolactinoma with Cabergoline. Asian J. Neurosurg. 2018, 13, 93–95. [CrossRef] [PubMed]105. Glezer, A.; Bronstein, M.D. Pituitary apoplexy: Pathophysiology, diagnosis and management. Arch. Endocrinol.Metab. 2015, 59, 259–264. [CrossRef] [PubMed]106. Huang, W.; Molitch, M.E. Pituitary Tumors in Pregnancy. Endocrinol. Metab. Clin. N. Am. 2019, 48, 569–581.[CrossRef]107. Auriemma, R.S.; Perone, Y.; Di Sarno, A.; Grasso, L.F.; Guerra, E.; Gasperi, M.; Pivonello, R.; Colao, A. Resultsof a single-center observational 10-year survey study on recurrence of hyperprolactinemia after pregnancyand lactation. J. Clin. Endocrinol. Metab. 2013, 98, 372–379. [CrossRef]108. Domingue, M.E.; Devuyst, F.; Alexopoulou, O.; Corvilain, B.; Maiter, D. Outcome of prolactinoma afterpregnancy and lactation: A study on 73 patients. Clin. Endocrinol. Oxf. 2014, 80, 642–648. [CrossRef]109. Souteiro, P.; Karavitaki, N. Dopamine agonist resistant prolactinomas: Any alternative medical treatment?Pituitary 2019, 1–11. [CrossRef]110. Maiter, D. Management of Dopamine Agonist-Resistant Prolactinoma. Neuroendocrinology 2019, 109, 42–50.[CrossRef]111. Molitch, M.E. Management of medically refractory prolactinoma. J. Neurooncol. 2014, 117, 421–428. [CrossRef]112. Raverot, G.; Burman, P.; McCormack, A.I.; Heaney, A.P.; Petersenn, S.; Popovic, V.; Trouillas, J.; Dekkers, O.European Society of Endocrinology clinical practice guidelines for the management of aggressive pituitarytumours and carcinomas. Eur. J. Endocrinol. 2017, 178, G1–G24. [CrossRef] [PubMed]113. Nakhleh, A.; Shehadeh, N.; Hochberg, I.; Zloczower, M.; Zolotov, S.; Taher, R.; Daoud Naccache, D.Management of cystic prolactinomas: A review. Pituitary 2018, 21, 425–430. [CrossRef] [PubMed]114. Tampourlou, M.; Trifanescu, R.; Paluzzi, A.; Ahmed, S.K.; Karavitaki, N. Therapy of endocrine disease:Surgery in microprolactinomas: Effectiveness and risks based on contemporary literature. Eur. J. Endocrinol.2016, 175, R89–R96. [CrossRef] [PubMed]115. Colao, A. Pituitary tumours: The prolactinoma. Best Pract. Res. Clin. Endocrinol. Metab. 2009, 23, 575–596.[CrossRef] [PubMed]116. Han, Y.L.; Chen, D.M.; Zhang, C.; Pan, M.; Yang, X.P.; Wu, Y.G. Retrospective analysis of 52 patients withprolactinomas following endoscopic endonasal transsphenoidal surgery. Med. Baltim. 2018, 97, e13198.[CrossRef]117. Ntali, G.; Karavitaki, N. Efficacy and complications of pituitary irradiation. Endocrinol. Metab. Clin. N. Am.2015, 44, 117–126. [CrossRef]118. Pereira, A.M.; Romijn, J.A.; Dekkers, O.M. Treatment and Follow-Up of Clinically Nonfunctioning PituitaryMacroadenomas. J. Clin. Endocrinol. Metab. 2008, 93, 3717–3726. [CrossRef]119. Zaidi, H.A.; Cote, D.J.; Castlen, J.P.; Burke, W.T.; Liu, Y.H.; Smith, T.R.; Laws, E.R. Time Course of Resolutionof Hyperprolactinemia After Transsphenoidal Surgery Among Patients Presenting with Pituitary StalkCompression. World Neurosurg. 2017, 97, 2–7. [CrossRef]J. Clin. Med. 2019, 8, 2203 22 of 24120. Huang, W.; Molitch, M.E. Evaluation and management of galactorrhea. Am. Fam. Physician 2012, 85,1073–1080.121. Greenman, Y.; Cooper, O.; Yaish, I.; Robenshtok, E.; Sagiv, N.; Jonas-Kimchi, T.; Yuan, X.; Gertych, A.;Shimon, I.; Ram, Z.; et al. Treatment of clinically nonfunctioning pituitary adenomas with dopamine agonists.Eur. J. Endocrinol. 2016, 175, 63–72. [CrossRef]122. Ben-Jonathan, N.; Hugo, E. Prolactin (PRL) in adipose tissue: Regulation and functions. Adv. Exp. Med. Biol.2015, 846, 1–35. [CrossRef] [PubMed]123. Carré, N.; Binart, N. Prolactin and adipose tissue. Biochimie 2014, 97, 16–21. [CrossRef] [PubMed]124. Wang, T.; Lu, J.; Xu, Y.; Li, M.; Sun, J.; Zhang, J.; Xu, B.; Xu, M.; Chen, Y.; Bi, Y.; et al. Circulating prolactinassociates with diabetes and impaired glucose regulation: A population-based study. Diabetes Care 2013, 36,1974–1980. [CrossRef] [PubMed]125. Li, J.; Rice, M.S.; Huang, T.; Hankinson, S.E.; Clevenger, C.V.; Hu, F.B.; Tworoger, S.S. Circulating prolactinconcentrations and risk of type 2 diabetes in US women. Diabetologia 2018, 61, 2549–2560. [CrossRef]126. Atmaca, A.; Bilgici, B.; Ecemis, G.C.; Tuncel, O.K. Evaluation of body weight, insulin resistance, leptinand adiponectin levels in premenopausal women with hyperprolactinemia. Endocrine 2013, 44, 756–761.[CrossRef]127. Dos Santos Silva, C.M.; Barbosa, F.R.; Lima, G.A.; Warszawski, L.; Fontes, R.; Domingues, R.C.; Gadelha, M.R.BMI and metabolic profile in patients with prolactinoma before and after treatment with dopamine agonists.Obes. Silver Spring 2011, 19, 800–805. [CrossRef]128. Schwetz, V.; Librizzi, R.; Trummer, C.; Theiler, G.; Stiegler, C.; Pieber, T.R.; Obermayer-Pietsch, B.; Pilz, S.Treatment of hyperprolactinaemia reduces total cholesterol and LDL in patients with prolactinomas.Metab. Brain Dis. 2017, 32, 155–161. [CrossRef]129. Medic-Stojanoska, M.; Icin, T.; Pletikosic, I.; Bajkin, I.; Novakovic-Paro, J.; Stokic, E.; Spasic, D.T.;Kovacev-Zavisic, B.; Abenavoli, L. Risk factors for accelerated atherosclerosis in young women withhyperprolactinemia. Med. Hypotheses 2015, 84, 321–326. [CrossRef]130. Auriemma, R.S.; Granieri, L.; Galdiero, M.; Simeoli, C.; Perone, Y.; Vitale, P.; Pivonello, C.; Negri, M.;Mannarino, T.; Giordano, C.; et al. Effect of cabergoline on metabolism in prolactinomas. Neuroendocrinology2013, 98, 299–310. [CrossRef]131. Auriemma, R.S.; Galdiero, M.; Vitale, P.; Granieri, L.; Lo Calzo, F.; Salzano, C.; Ferreri, L.; Pivonello, C.;Cariati, F.; Coppola, G.; et al. Effect of chronic cabergoline treatment and testosterone replacement onmetabolism in male patients with prolactinomas. Neuroendocrinology 2015, 101, 66–81. [CrossRef]132. Ozdemir, E.D.; Caglar, G.S.; Akgul, E.; Cengiz, S.D.; Tombak, G. The association between prolactin,high-sensitivity C-reactive protein and Framingham risk score in menopause. Gynecol. Obs. Investig. 2014,78, 119–123. [CrossRef] [PubMed]133. Fleseriu, M.; Hashim, I.A.; Karavitaki, N.; Melmed, S.; Murad, M.H.; Salvatori, R.; Samuels, M.H. HormonalReplacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline. J. Clin.Endocrinol. Metab. 2016, 101, 3888–3921. [CrossRef] [PubMed]134. Zhang, L.; Curhan, G.C.; Forman, J.P. Plasma prolactin level and risk of incident hypertension inpostmenopausal women. J. Hypertens. 2010, 28, 1400–1405. [CrossRef] [PubMed]135. Therkelsen, K.E.; Abraham, T.M.; Pedley, A.; Massaro, J.M.; Sutherland, P.; Hoffmann, U.; Fox, C.S. AssociationBetween Prolactin and Incidence of Cardiovascular Risk Factors in the Framingham Heart Study. J. Am.Heart Assoc. 2016, 5. [CrossRef] [PubMed]136. Erem, C.; Kocak, M.; Nuhoglu, I.; Yılmaz, M.; Ucuncu, O. Blood coagulation, fibrinolysis and lipid profile inpatients with prolactinoma. Clin. Endocrinol. Oxf. 2010, 73, 502–507. [CrossRef]137. Toulis, K.A.; Robbins, T.; Reddy, N.; Balachandran, K.; Gokhale, K.; Wijesinghe, H.; Cheng, K.K.; Karavitaki, N.;Wass, J.; Nirantharakumar, K. Males with prolactinoma are at increased risk of incident cardiovasculardisease. Clin. Endocrinol. Oxf. 2018, 88, 71–76. [CrossRef]138. Shelly, S.; Boaz, M.; Orbach, H. Prolactin and autoimmunity. Autoimmun. Rev. 2012, 11, A465–A470.[CrossRef]139. Orbach, H.; Zandman-Goddard, G.; Boaz, M.; Agmon-Levin, N.; Amital, H.; Szekanecz, Z.; Szucs, G.;Rovensky, J.; Kiss, E.; Doria, A.; et al. Prolactin and autoimmunity: Hyperprolactinemia correlates withserositis and anemia in SLE patients. Clin. Rev. Allergy Immunol. 2012, 42, 189–198. [CrossRef]J. Clin. Med. 2019, 8, 2203 23 of 24140. Correale, J.; Farez, M.F.; Ysrraelit, M.C. Role of prolactin in B cell regulation in multiple sclerosis.J. Neuroimmunol. 2014, 269, 76–86. [CrossRef]141. Liu, Y.; Zhang, Z.; Jin, Q.; Kang, Z.; Huo, Y.; He, Z.; Feng, X.; Yin, J.; Wu, X.; Wang, H.; et al. Hyperprolactinemiais associated with a high prevalence of serum autoantibodies, high levels of inflammatory cytokines and anabnormal distribution of peripheral B-cell subsets. Endocrine 2019, 64, 648–656. [CrossRef]142. Wang, P.; Lv, T.T.; Guan, S.Y.; Li, H.M.; Leng, R.X.; Zou, Y.F.; Pan, H.F. Increased plasma/serum levels ofprolactin in systemic lupus erythematosus: A systematic review and meta-analysis. Postgrad. Med. 2017, 129,126–132. [CrossRef] [PubMed]143. Aulestia, C.; De Zubiría, A.; Granados, C.; Suárez, J.; Cervera, R. Prolactin and Estradiol Profile in a Cohortof Colombian Women with Systemic Lupus Erythematosus. Isr. Med. Assoc. J. 2016, 18, 537–541. [PubMed]144. Ledesma-Soto, Y.; Blanco-Favela, F.; Fuentes-Pananá, E.M.; Tesoro-Cruz, E.; Hernández-González, R.;Arriaga-Pizano, L.; Legorreta-Haquet, M.V.; Montoya-Diaz, E.; Chávez-Sánchez, L.; Castro-Mussot, M.E.;et al. Increased levels of prolactin receptor expression correlate with the early onset of lupus symptoms andincreased numbers of transitional-1 B cells after prolactin treatment. BMC Immunol. 2012, 13, 11. [CrossRef][PubMed]145. Savino, W. Prolactin: An Immunomodulator in Health and Disease. Front. Horm. Res. 2017, 48, 69–75.[CrossRef] [PubMed]146. Leaños-Miranda, A.; Cárdenas-Mondragón, G. Serum free prolactin concentrations in patients with systemiclupus erythematosus are associated with lupus activity. Rheumatol. Oxf. 2006, 45, 97–101. [CrossRef]147. Tang, M.W.; Garcia, S.; Gerlag, D.M.; Tak, P.P.; Reedquist, K.A. Insight into the Endocrine System and theImmune System: A Review of the Inflammatory Role of Prolactin in Rheumatoid Arthritis and PsoriaticArthritis. Front. Immunol. 2017, 8, 720. [CrossRef]148. Clapp, C.; Adán, N.; Ledesma-Colunga, M.G.; Solís-Gutiérrez, M.; Triebel, J.; Martínez de la Escalera, G.The role of the prolactin/vasoinhibin axis in rheumatoid arthritis: An integrative overview. Cell. Mol. Life Sci.2016, 73, 2929–2948. [CrossRef]149. Borba, V.V.; Zandman-Goddard, G.; Shoenfeld, Y. Prolactin and Autoimmunity. Front. Immunol. 2018, 9, 73.[CrossRef]150. Salesi, M.; Sadeghihaddadzavareh, S.; Nasri, P.; Namdarigharaghani, N.; Farajzadegan, Z.; Hajalikhani, M.The role of bromocriptine in the treatment of patients with active rheumatoid arthritis. Int. J. Rheum. Dis.2013, 16, 662–666. [CrossRef]151. Tang, M.W.; Garcia, S.; Malvar Fernandez, B.; Gerlag, D.M.; Tak, P.P.; Reedquist, K.A. Rheumatoid arthritisand psoriatic arthritis synovial fluids stimulate prolactin production by macrophages. J. Leukoc. Biol. 2017,102, 897–904. [CrossRef]152. Reyes-Castillo, Z.; Pereira-Suárez, A.L.; Palafox-Sanchez, C.A.; Rangel-Villalobos, H.; Estrada-Chávez, C.;Oregón-Romero, E.; Angel-Chávez, L.I.; Muñoz-Barrios, S.; Bueno-Topete, M.R.; Muñoz-Valle, J.F.The extrapituitary prolactin promoter polymorphism is associated with rheumatoid arthritis and anti-CCPantibodies in Mexican population. Gene 2013, 525, 130–135. [CrossRef] [PubMed]153. Türkog˘lu, R.; Giris¸, M.; Gencer, M.; Akcan, U.; Örçen, A. Serum Prolactin Levels in Multiple Sclerosis,Neuromyelitis Optica, and Clinically Isolated Syndrome Patients. Noro Psikiyatr. Arsivi 2016, 53, 353–356.[CrossRef] [PubMed]154. El Tahlawi, S.M.; El Eishi, N.H.; Kahhal, R.K.; Hegazy, R.A.; El Hanafy, G.M.; Abdel Hay, R.M.; Shaker, O.G.Do Prolactin and its Receptor Play a Role in Alopecia Areata? Indian J. Derm. 2018, 63, 241–245. [CrossRef][PubMed]155. Lajevardi, V.; Hallaji, Z.; Daneshpazhooh, M.; Ghandi, N.; Shekari, P.; Khani, S. Evaluation of prolactin levelsin patients with newly diagnosed pemphigus vulgaris and its correlation with pemphigus disease area index.Int. J. Womens Derm. 2016, 2, 53–55. [CrossRef]156. Tworoger, S.S.; Hankinson, S.E. Prolactin and breast cancer etiology: An epidemiologic perspective.J. Mammary Gland Biol. Neoplasia 2008, 13, 41–53. [CrossRef]157. Tworoger, S.S.; Eliassen, A.H.; Zhang, X.; Qian, J.; Sluss, P.M.; Rosner, B.A.; Hankinson, S.E. A 20-yearprospective study of plasma prolactin as a risk marker of breast cancer development. Cancer Res. 2013, 73,4810–4819. [CrossRef]158. Bernard, V.; Young, J.; Chanson, P.; Binart, N. New insights in prolactin: Pathological implications. Nat. Rev.Endocrinol. 2015, 11, 265–275. [CrossRef]J. Clin. Med. 2019, 8, 2203 24 of 24159. Clendenen, T.V.; Arslan, A.A.; Lokshin, A.E.; Liu, M.; Lundin, E.; Koenig, K.L.; Berrino, F.; Hallmans, G.;Idahl, A.; Krogh, V.; et al. Circulating prolactin levels and risk of epithelial ovarian cancer. Cancer CausesControl 2013, 24, 741–748. [CrossRef]160. Ilan, Y.; Sibirsky, O.; Livni, N.; Gofrit, O.; Barack, V.; Goldin, E. Plasma and tumor prolactin in colorectalcancer patients. Dig. Dis. Sci. 1995, 40, 2010–2015. [CrossRef]161. Bhatavdekar, J.M.; Patel, D.D.; Giri, D.D.; Karelia, N.H.; Vora, H.H.; Ghosh, N.; Shah, N.G.; Trivedi, S.N.;Balar, D.B. Comparison of plasma prolactin and CEA in monitoring patients with adenocarcinoma of colonand rectum. Br. J. Cancer 1992, 66, 977–980. [CrossRef]162. Yeh, Y.T.; Lee, K.T.; Tsai, C.J.; Chen, Y.J.; Wang, S.N. Prolactin promotes hepatocellular carcinoma throughJanus kinase 2. World J. Surg. 2012, 36, 1128–1135. [CrossRef] [PubMed]163. Yonezawa, T.; Chen, K.H.; Ghosh, M.K.; Rivera, L.; Dill, R.; Ma, L.; Villa, P.A.; Kawaminami, M.; Walker, A.M.Anti-metastatic outcome of isoform-specific prolactin receptor targeting in breast cancer. Cancer Lett. 2015,366, 84–92. [CrossRef] [PubMed]164. Goffin, V. Prolactin receptor targeting in breast and prostate cancers: New insights into an old challenge.Pharm. Ther. 2017, 179, 111–126. [CrossRef] [PubMed]165. Ding, K.; Yuan, Y.; Chong, Q.Y.; Yang, Y.; Li, R.; Li, X.; Kong, X.; Qian, P.; Xiong, Z.; Pandey, V.; et al.Autocrine Prolactin Stimulates Endometrial Carcinoma Growth and Metastasis and Reduces Sensitivity toChemotherapy. Endocrinology 2017, 158, 1595–1611. [CrossRef] [PubMed]166. Neradugomma, N.K.; Subramaniam, D.; Tawfik, O.W.; Goffin, V.; Kumar, T.R.; Jensen, R.A.; Anant, S.Prolactin signaling enhances colon cancer stemness by modulating Notch signaling in a Jak2-STAT3/ERKmanner. Carcinogenesis 2014, 35, 795–806. [CrossRef] [PubMed]167. Dekkers, O.M.; Romijn, J.A.; de Boer, A.; Vandenbroucke, J.P. The risk for breast cancer is not evidentlyincreased in women with hyperprolactinemia. Pituitary 2010, 13, 195–198. [CrossRef] [PubMed]© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open accessarticle distributed under the terms and conditions of the Creative Commons Attribution(CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Hyperprolactinemia

Abstract

Extracted data

Hyperprolactinemia

Abstract

Extracted data

Topics

Related items

Topics

Related items